Pub Date : 2024-08-12DOI: 10.1016/j.kint.2024.07.020
Danyang Zhao, Chao Han, Elmina Mammadova-Bach, Kanako Watanabe-Kusunoki, Tamisa Seeko Bandeira Honda, Yihong Li, Chenyu Li, Qiubo Li, Hao Long, Lyuben Lyubenov, Chongxu Shi, Donato Santovito, Christian Weber, Peter Boor, Patrick Droste, Samir Parikh, John Shapiro, Letizia De Chiara, Giulia Carangelo, Paola Romagnani, Sven Klussmann, Axel Vater, Hans-Joachim Anders
Cholesterol crystal embolism (CCE) implies immunothrombosis, tissue necrosis, and organ failure but no specific treatments are available. As CCE involves complement activation, we speculated that inhibitors of the C5a/C5aR axis would be sufficient to attenuate the consequences of CCE like that with systemic vasculitis. Cholesterol microcrystal injection into the kidney artery of wild-type mice initiated intra-kidney immunothrombosis within a few hours followed by a sudden drop of glomerular filtration rate and ischemic kidney necrosis after 24 hours. Genetic deficiency of either C3 or C5aR prevented immunothrombosis, glomerular filtration rate drop, and ischemic necrosis at 24 hours as did preemptive treatment with inhibitors of either C5a or C5aR. Delayed C5a blockade after crystal injection still resolved crystal clots and prevented all consequences. Thus, selective blockade of C5a or C5aR is sufficient to attenuate the consequences of established CCE and prospective inhibition in high-risk patients may be clinically feasible and safe.
{"title":"Inhibition of complement factor C5a or C5aR for cholesterol crystal embolism-related vascular thrombosis with microvascular injury and its consequences.","authors":"Danyang Zhao, Chao Han, Elmina Mammadova-Bach, Kanako Watanabe-Kusunoki, Tamisa Seeko Bandeira Honda, Yihong Li, Chenyu Li, Qiubo Li, Hao Long, Lyuben Lyubenov, Chongxu Shi, Donato Santovito, Christian Weber, Peter Boor, Patrick Droste, Samir Parikh, John Shapiro, Letizia De Chiara, Giulia Carangelo, Paola Romagnani, Sven Klussmann, Axel Vater, Hans-Joachim Anders","doi":"10.1016/j.kint.2024.07.020","DOIUrl":"10.1016/j.kint.2024.07.020","url":null,"abstract":"<p><p>Cholesterol crystal embolism (CCE) implies immunothrombosis, tissue necrosis, and organ failure but no specific treatments are available. As CCE involves complement activation, we speculated that inhibitors of the C5a/C5aR axis would be sufficient to attenuate the consequences of CCE like that with systemic vasculitis. Cholesterol microcrystal injection into the kidney artery of wild-type mice initiated intra-kidney immunothrombosis within a few hours followed by a sudden drop of glomerular filtration rate and ischemic kidney necrosis after 24 hours. Genetic deficiency of either C3 or C5aR prevented immunothrombosis, glomerular filtration rate drop, and ischemic necrosis at 24 hours as did preemptive treatment with inhibitors of either C5a or C5aR. Delayed C5a blockade after crystal injection still resolved crystal clots and prevented all consequences. Thus, selective blockade of C5a or C5aR is sufficient to attenuate the consequences of established CCE and prospective inhibition in high-risk patients may be clinically feasible and safe.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1016/j.kint.2024.07.022
Ibrahim Batal, Andrew J B Watts, Jean-Baptiste Gibier, Aghiles Hamroun, Isabelle Top, François Provot, Keith Keller, Xiaoyi Ye, Hilda E Fernandez, Rita Leal, Nicole K Andeen, Russell J Crew, Geoffrey K Dube, Elena-Rodica Vasilescu, Lloyd E Ratner, Nicole Bowman, Andrew S Bomback, Simone Sanna-Cherchi, Krzysztof Kiryluk, Astrid Weins
{"title":"Pre-transplant anti-nephrin antibodies are specific predictors of recurrent diffuse podocytopathy in the kidney allograft.","authors":"Ibrahim Batal, Andrew J B Watts, Jean-Baptiste Gibier, Aghiles Hamroun, Isabelle Top, François Provot, Keith Keller, Xiaoyi Ye, Hilda E Fernandez, Rita Leal, Nicole K Andeen, Russell J Crew, Geoffrey K Dube, Elena-Rodica Vasilescu, Lloyd E Ratner, Nicole Bowman, Andrew S Bomback, Simone Sanna-Cherchi, Krzysztof Kiryluk, Astrid Weins","doi":"10.1016/j.kint.2024.07.022","DOIUrl":"10.1016/j.kint.2024.07.022","url":null,"abstract":"","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-07DOI: 10.1016/j.kint.2024.06.029
Natalie Ebert, Elke Schaeffner, Jesse C Seegmiller, Marco van Londen, Arend Bökenkamp, Etienne Cavalier, Pierre Delanaye, Laurence Derain-Dubourg, Bjørn O Eriksen, Olafur S Indridason, Runolfur Palsson, Tariq Shafi, Anders Christensson, Sebastjan Bevc, Fabiola Carrara, Marie Courbebaisse, R Neil Dalton, Markus van der Giet, Toralf Melsom, Shona Methven, Gunnar Nordin, Hans Pottel, Andrew D Rule, Matias Trillini, Christine A White
International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation.
{"title":"Iohexol plasma clearance measurement protocol standardization for adults: a consensus paper of the European Kidney Function Consortium.","authors":"Natalie Ebert, Elke Schaeffner, Jesse C Seegmiller, Marco van Londen, Arend Bökenkamp, Etienne Cavalier, Pierre Delanaye, Laurence Derain-Dubourg, Bjørn O Eriksen, Olafur S Indridason, Runolfur Palsson, Tariq Shafi, Anders Christensson, Sebastjan Bevc, Fabiola Carrara, Marie Courbebaisse, R Neil Dalton, Markus van der Giet, Toralf Melsom, Shona Methven, Gunnar Nordin, Hans Pottel, Andrew D Rule, Matias Trillini, Christine A White","doi":"10.1016/j.kint.2024.06.029","DOIUrl":"10.1016/j.kint.2024.06.029","url":null,"abstract":"<p><p>International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-03DOI: 10.1016/j.kint.2024.07.015
Jiawen Huang, Shuang Cui, Xiaohua Chi, Ansheng Cong, Xiaoqiang Yang, Huanjuan Su, Zhanmei Zhou, Cailing Su, Zuoyu Hu, Zhijie Huang, Jiao Luo, Guobao Wang, Ying Jiang, Ganghua Tang, Wei Cao
A major challenge in prevention and early treatment of organ fibrosis is the lack of valuable tools to assess the evolving profibrotic maladaptive repair after injury in vivo in a non-invasive way. Here, using acute kidney injury (AKI) as an example, we tested the utility of fibroblast activation protein (FAP) imaging for dynamic assessment of maladaptive repair after injury. The temporospatial pattern of kidney FAP expression after injury was first characterized. Single-cell RNA sequencing and immunostaining analysis of patient biopsies were combined to show that FAP was specifically upregulated in kidney fibroblasts after AKI and was associated with fibroblast activation and chronic kidney disease (CKD) progression. This was corroborated in AKI mouse models, where a sustained and exaggerated kidney FAP upregulation was coupled to persistent fibroblast activation and a fibrotic outcome, linking kidney FAP level to post-insult maladaptive repair. Furthermore, using positron emission tomography (PET)/CT scanning with FAP-inhibitor tracers ([18F]FAPI-42, [18F]FAPT) targeting FAP, we demonstrated the feasibility of non-invasively tracking of maladaptive repair evolution toward kidney fibrosis. Importantly, a sustained increase in kidney [18F]FAPT (less hepatobiliary metabolized than [18F]FAPI-42) uptake reflected persistent kidney upregulation of FAP and characterized maladaptive repair after AKI. Kidney [18F]FAPT uptake at hour 2-day 7 correlated with kidney fibrosis 14 days after AKI. Similar changes in [18F]FAPI-42 PET/CT imaging were observed in patients with AKI and CKD progression. Thus, persistent kidney FAP upregulation after AKI was associated with maladaptive repair and a fibrotic outcome. Hence, FAP-specific PET/CT imaging enables dynamic visualization of maladaptive repair after AKI and prediction of kidney fibrosis within a clinically actionable window.
预防和早期治疗器官纤维化的一个主要挑战是缺乏有价值的工具,以非侵入性的方式评估体内损伤后不断演变的坏死性适应性修复。在这里,我们以急性肾损伤(AKI)为例,测试了成纤维细胞活化蛋白(FAP)成像在动态评估损伤后适应性不良修复方面的实用性。首先确定了损伤后肾脏 FAP 表达的时空模式。对患者活检组织进行的单细胞 RNA 测序和免疫染色分析表明,肾脏成纤维细胞在 AKI 后特异性上调 FAP,这与成纤维细胞活化和慢性肾脏病(CKD)进展有关。这一点在 AKI 小鼠模型中得到了证实,在该模型中,肾脏 FAP 的持续和夸张上调与成纤维细胞的持续活化和纤维化结果相关联,从而将肾脏 FAP 水平与损伤后的适应性不良修复联系起来。此外,利用正电子发射断层扫描(PET)/CT 扫描和针对 FAP 的 FAP 抑制剂示踪剂([18F]FAPI-42、[18F]FAPT),证明了无创追踪肾脏纤维化的适应性不良修复演变的可行性。重要的是,肾脏[18F]FAPT(比[18F]FAPI-42更少被肝胆代谢)摄取量的持续增加反映了肾脏对FAP的持续上调,是AKI后适应不良修复的特征。第 2 天第 7 小时的肾脏[18F]FAPT 摄取与 AKI 14 天后的肾脏纤维化相关。在 AKI 和 CKD 进展患者中也观察到了 [18F]FAPI-42 PET/CT 成像的类似变化。因此,AKI 后肾脏 FAP 持续上调与适应性修复不良和纤维化结果有关。因此,FAP特异性PET/CT成像可动态观察到AKI后的适应性不良修复,并在临床可操作窗口期内预测肾脏纤维化。
{"title":"Dynamically visualizing profibrotic maladaptive repair after acute kidney injury by fibroblast activation protein imaging.","authors":"Jiawen Huang, Shuang Cui, Xiaohua Chi, Ansheng Cong, Xiaoqiang Yang, Huanjuan Su, Zhanmei Zhou, Cailing Su, Zuoyu Hu, Zhijie Huang, Jiao Luo, Guobao Wang, Ying Jiang, Ganghua Tang, Wei Cao","doi":"10.1016/j.kint.2024.07.015","DOIUrl":"10.1016/j.kint.2024.07.015","url":null,"abstract":"<p><p>A major challenge in prevention and early treatment of organ fibrosis is the lack of valuable tools to assess the evolving profibrotic maladaptive repair after injury in vivo in a non-invasive way. Here, using acute kidney injury (AKI) as an example, we tested the utility of fibroblast activation protein (FAP) imaging for dynamic assessment of maladaptive repair after injury. The temporospatial pattern of kidney FAP expression after injury was first characterized. Single-cell RNA sequencing and immunostaining analysis of patient biopsies were combined to show that FAP was specifically upregulated in kidney fibroblasts after AKI and was associated with fibroblast activation and chronic kidney disease (CKD) progression. This was corroborated in AKI mouse models, where a sustained and exaggerated kidney FAP upregulation was coupled to persistent fibroblast activation and a fibrotic outcome, linking kidney FAP level to post-insult maladaptive repair. Furthermore, using positron emission tomography (PET)/CT scanning with FAP-inhibitor tracers ([<sup>18</sup>F]FAPI-42, [<sup>18</sup>F]FAPT) targeting FAP, we demonstrated the feasibility of non-invasively tracking of maladaptive repair evolution toward kidney fibrosis. Importantly, a sustained increase in kidney [<sup>18</sup>F]FAPT (less hepatobiliary metabolized than [<sup>18</sup>F]FAPI-42) uptake reflected persistent kidney upregulation of FAP and characterized maladaptive repair after AKI. Kidney [<sup>18</sup>F]FAPT uptake at hour 2-day 7 correlated with kidney fibrosis 14 days after AKI. Similar changes in [<sup>18</sup>F]FAPI-42 PET/CT imaging were observed in patients with AKI and CKD progression. Thus, persistent kidney FAP upregulation after AKI was associated with maladaptive repair and a fibrotic outcome. Hence, FAP-specific PET/CT imaging enables dynamic visualization of maladaptive repair after AKI and prediction of kidney fibrosis within a clinically actionable window.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1016/j.kint.2024.07.012
Sean J Barbour, Rosanna Coppo, Lee Er, Maria Luisa Russo, Zhi-Hong Liu, Jie Ding, Xuhui Zhong, Ritsuko Katafuchi, Norishige Yoshikawa, Hong Xu, Shoji Kagami, Yukio Yuzawa, Francesco Emma, Alexandra Cambier, Licia Peruzzi, Robert J Wyatt, Daniel C Cattran
The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two years after biopsy. Trajectories of eGFR after a baseline one year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old and then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to re-evaluate risk one or two years after biopsy.
儿科国际 IgA 肾病(IgAN)预测工具包括两个模型,分别包含种族因素和不包含种族因素,是首个利用临床风险因素和牛津 MEST 组织学评分预测儿童活检时估计肾小球滤过率(eGFR)下降 30% 或肾衰竭风险的方法。然而,预测工具能否在活检后的观察期后应用尚不得而知。我们利用一个由947名IgAN患儿组成的多种族国际队列,对预测工具进行了更新,以便在活检一年后使用。与最初的儿科预测工具相比,活检后更新的预测工具具有更好的模型拟合度,R2D更高(51%/50% vs 20%),4年C统计量显著增加(0.83 vs 0.73/0.69, ΔC 0.09 [95%置信区间0.07-0.10]和ΔC 0.14 [0.12-0.15]),4年校准效果更好,综合校准指数更低(0.74/0.54 vs 2.45/1.01)。内部验证和活检两年后应用模型的结果相似。活组织检查后一年的 eGFR 基线轨迹是非线性的,预测风险较高的人开始时 eGFR 较低,随着时间的推移下降得更快。在儿童中,eGFR 在 15-18 岁之前的增长速度不一,之后呈线性下降,高风险组的下降速度更快,这与风险相当的年轻成人相似。因此,原始的儿科预测工具应在活检时用于儿童,而更新的儿科预测工具则应在活检后一两年用于重新评估风险。
{"title":"Application of the updated International IgA Nephropathy Prediction Tool in children one or two years post-biopsy.","authors":"Sean J Barbour, Rosanna Coppo, Lee Er, Maria Luisa Russo, Zhi-Hong Liu, Jie Ding, Xuhui Zhong, Ritsuko Katafuchi, Norishige Yoshikawa, Hong Xu, Shoji Kagami, Yukio Yuzawa, Francesco Emma, Alexandra Cambier, Licia Peruzzi, Robert J Wyatt, Daniel C Cattran","doi":"10.1016/j.kint.2024.07.012","DOIUrl":"10.1016/j.kint.2024.07.012","url":null,"abstract":"<p><p>The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R<sup>2</sup><sub>D</sub> (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two years after biopsy. Trajectories of eGFR after a baseline one year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old and then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to re-evaluate risk one or two years after biopsy.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1016/j.kint.2024.07.011
Ioana Alesutan, Mehdi Razazian, Trang T D Luong, Misael Estepa, Lakmi Pitigala, Laura A Henze, Jakob Obereigner, Gregor Mitter, Daniel Zickler, Mirjam Schuchardt, Christine Deisl, Manousos Makridakis, Can Gollmann-Tepeköylü, Andreas Pasch, Daniel Cejka, Susanne Suessner, Marlies Antlanger, Bernhard Bielesz, Mathias Müller, Antonia Vlahou, Johannes Holfeld, Kai-Uwe Eckardt, Jakob Voelkl
Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD.
{"title":"Augmentative effects of leukemia inhibitory factor reveal a critical role for TYK2 signaling in vascular calcification.","authors":"Ioana Alesutan, Mehdi Razazian, Trang T D Luong, Misael Estepa, Lakmi Pitigala, Laura A Henze, Jakob Obereigner, Gregor Mitter, Daniel Zickler, Mirjam Schuchardt, Christine Deisl, Manousos Makridakis, Can Gollmann-Tepeköylü, Andreas Pasch, Daniel Cejka, Susanne Suessner, Marlies Antlanger, Bernhard Bielesz, Mathias Müller, Antonia Vlahou, Johannes Holfeld, Kai-Uwe Eckardt, Jakob Voelkl","doi":"10.1016/j.kint.2024.07.011","DOIUrl":"10.1016/j.kint.2024.07.011","url":null,"abstract":"<p><p>Medial vascular calcification in chronic kidney disease (CKD) involves pro-inflammatory pathways induced by hyperphosphatemia. Several interleukin 6 family members have been associated with pro-calcific effects in vascular smooth muscle cells (VSMCs) and are considered as therapeutic targets. Therefore, we investigated the role of leukemia inhibitory factor (LIF) during VSMC calcification. LIF expression was found to be increased following phosphate exposure of VSMCs. LIF supplementation aggravated, while silencing of endogenous LIF or LIF receptor (LIFR) ameliorated the pro-calcific effects of phosphate in VSMCs. The soluble LIFR mediated antagonistic effects towards LIF and reduced VSMC calcification. Mechanistically, LIF induced phosphorylation of the non-receptor tyrosine-protein kinase 2 (TYK2) and signal transducer and activator of transcription-3 (STAT3) in VSMCs. TYK2 inhibition by deucravacitinib, a selective, allosteric oral immunosuppressant used in psoriasis treatment, not only blunted the effects of LIF, but also interfered with the pro-calcific effects induced by phosphate. Conversely, TYK2 overexpression aggravated VSMC calcification. Ex vivo calcification of mouse aortic rings was ameliorated by Tyk2 pharmacological inhibition and genetic deficiency. Cholecalciferol-induced vascular calcification in mice was improved by Tyk2 inhibition and in the Tyk2-deficient mice. Similarly, calcification was ameliorated in Abcc6/Tyk2-deficient mice after adenine/high phosphorus-induced CKD. Thus, our observations indicate a role for LIF in CKD-associated vascular calcification. Hence, the effects of LIF identify a central pro-calcific role of TYK2 signaling, which may be a future target to reduce the burden of vascular calcification in CKD.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1016/j.kint.2024.07.014
Matthias Rose, Felix H Fischer, Gregor Liegl, Giovanni F M Strippoli, Carina Hockham, Robin W M Vernooij, Claudia Barth, Bernard Canaud, Adrian Covic, Krister Cromm, Andrea M Cucui, Andrew Davenport, Kathrin I Fischer, Jörgen Hegbrant, Hanna Jaha, Anna Schappert, Marietta Török, Mark Woodward, Michiel L Bots, Peter J Blankestijn
In the CONVINCE trial, the primary analysis demonstrated a survival benefit for patients receiving high-dose hemodiafiltration (HDF) as compared with high-flux hemodialysis (HD). A secondary objective was to evaluate effects on health-related quality of life (HRQoL); assessed in eight domains (physical function, cognitive function, fatigue, sleep disturbance, anxiety, depression, pain interference, social participation) applying instruments from the Patient-Reported Outcome Measurement Information System (PROMIS) before randomization and every three months thereafter. In total 1360 adults with dialysis-dependent chronic kidney disease, eligible to receive high-flux HDF (23 liters or more), were randomized (1:1); 84% response rate to all questionnaires. Both groups reported a continuous deterioration in all HRQoL domains. Overall, raw score changes from baseline were more favorable in the HDF group, resulting in a significant omnibus test after a median observation period of 30 months. Most relevant single raw score differences were reported for cognitive function. Patients receiving HDF reported a decline of -0.95 units (95% confidence interval - 2.23 to +0.34) whereas HD treated patients declined by -3.90 units (-5.28 to - 2.52). A joint model, adjusted for mortality differences, utilizing all quarterly assessments, identified a significantly slower HRQoL decline in physical function, cognitive function, pain interference, and social participation for the HDF group. Their physical health summary score declined -0.46 units/year slower compared to the HD group. Thus, the CONVINCE trial showed a beneficial effect of high-dose hemodiafiltration for survival as well as a moderate positive effect on patients' quality of life, most pronounced with respect to their cognitive function. REGISTRATION: NTR7138 on the International Clinical Trials Registry Platform.
{"title":"The CONVINCE randomized trial found positive effects on quality of life for patients with chronic kidney disease treated with hemodiafiltration.","authors":"Matthias Rose, Felix H Fischer, Gregor Liegl, Giovanni F M Strippoli, Carina Hockham, Robin W M Vernooij, Claudia Barth, Bernard Canaud, Adrian Covic, Krister Cromm, Andrea M Cucui, Andrew Davenport, Kathrin I Fischer, Jörgen Hegbrant, Hanna Jaha, Anna Schappert, Marietta Török, Mark Woodward, Michiel L Bots, Peter J Blankestijn","doi":"10.1016/j.kint.2024.07.014","DOIUrl":"10.1016/j.kint.2024.07.014","url":null,"abstract":"<p><p>In the CONVINCE trial, the primary analysis demonstrated a survival benefit for patients receiving high-dose hemodiafiltration (HDF) as compared with high-flux hemodialysis (HD). A secondary objective was to evaluate effects on health-related quality of life (HRQoL); assessed in eight domains (physical function, cognitive function, fatigue, sleep disturbance, anxiety, depression, pain interference, social participation) applying instruments from the Patient-Reported Outcome Measurement Information System (PROMIS) before randomization and every three months thereafter. In total 1360 adults with dialysis-dependent chronic kidney disease, eligible to receive high-flux HDF (23 liters or more), were randomized (1:1); 84% response rate to all questionnaires. Both groups reported a continuous deterioration in all HRQoL domains. Overall, raw score changes from baseline were more favorable in the HDF group, resulting in a significant omnibus test after a median observation period of 30 months. Most relevant single raw score differences were reported for cognitive function. Patients receiving HDF reported a decline of -0.95 units (95% confidence interval - 2.23 to +0.34) whereas HD treated patients declined by -3.90 units (-5.28 to - 2.52). A joint model, adjusted for mortality differences, utilizing all quarterly assessments, identified a significantly slower HRQoL decline in physical function, cognitive function, pain interference, and social participation for the HDF group. Their physical health summary score declined -0.46 units/year slower compared to the HD group. Thus, the CONVINCE trial showed a beneficial effect of high-dose hemodiafiltration for survival as well as a moderate positive effect on patients' quality of life, most pronounced with respect to their cognitive function. REGISTRATION: NTR7138 on the International Clinical Trials Registry Platform.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 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 (NHE3loxloxPax8 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.
{"title":"Genetic deletion of the kidney sodium/proton exchanger-3 (NHE3) does not alter calcium and phosphate balance due to compensatory responses.","authors":"Søren B Poulsen, Sathish K Murali, Linto Thomas, Adrienne Assmus, Lena L Rosenbæk, Rikke Nielsen, Henrik Dimke, Timo Rieg, Robert A Fenton","doi":"10.1016/j.kint.2024.07.013","DOIUrl":"10.1016/j.kint.2024.07.013","url":null,"abstract":"<p><p>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<sup>loxloxPax8</sup> 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 <sup>32</sup>Phosphate 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.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1016/j.kint.2024.06.028
Silke Zimmermann, Akash Mathew, Olga Bondareva, Ahmed Elwakiel, Klarina Waldmann, Shihai Jiang, Rajiv Rana, Kunal Singh, Shrey Kohli, Khurrum Shahzad, Ronald Biemann, Thomas Roskoden, Silke Diana Storsberg, Christian Mawrin, Ute Krügel, Ingo Bechmann, Jürgen Goldschmidt, Bilal N Sheikh, Berend Isermann
Cognitive impairment is common in extracerebral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that cognitive impairment driven by CKD is therapeutically amendable. However, we lack mechanistic insights allowing development of targeted therapies. Using a combination of mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single-nuclei RNA-sequencing and single-cell thallium autometallography), human samples and in vitro experiments we demonstrate that microglia activation impairs neuronal potassium homeostasis and cognition in CKD. CKD disrupts the barrier of brain endothelial cells in vitro and the blood-brain barrier in vivo, establishing that the uremic state modifies vascular permeability in the brain. Exposure to uremic conditions impairs calcium homeostasis in microglia, enhances microglial potassium efflux via the calcium-dependent channel KCa3.1, and induces p38-MAPK associated IL-1β maturation in microglia. Restoring potassium homeostasis in microglia using a KCa3.1-specific inhibitor (TRAM34) improves CKD-triggered cognitive impairment. Likewise, inhibition of the IL-1β receptor 1 (IL-1R1) using anakinra or genetically abolishing neuronal IL-1R1 expression in neurons prevent CKD-mediated reduced neuronal potassium turnover and CKD-induced impaired cognition. Accordingly, in CKD mice, impaired cognition can be ameliorated by either preventing microglia activation or inhibiting IL-1R-signaling in neurons. Thus, our data suggest that potassium efflux from microglia triggers their activation, which promotes microglia IL-1β release and IL-1R1-mediated neuronal dysfunction in CKD. Hence, our study provides new mechanistic insight into cognitive impairment in association with CKD and identifies possible new therapeutic approaches.
{"title":"Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain.","authors":"Silke Zimmermann, Akash Mathew, Olga Bondareva, Ahmed Elwakiel, Klarina Waldmann, Shihai Jiang, Rajiv Rana, Kunal Singh, Shrey Kohli, Khurrum Shahzad, Ronald Biemann, Thomas Roskoden, Silke Diana Storsberg, Christian Mawrin, Ute Krügel, Ingo Bechmann, Jürgen Goldschmidt, Bilal N Sheikh, Berend Isermann","doi":"10.1016/j.kint.2024.06.028","DOIUrl":"10.1016/j.kint.2024.06.028","url":null,"abstract":"<p><p>Cognitive impairment is common in extracerebral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that cognitive impairment driven by CKD is therapeutically amendable. However, we lack mechanistic insights allowing development of targeted therapies. Using a combination of mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single-nuclei RNA-sequencing and single-cell thallium autometallography), human samples and in vitro experiments we demonstrate that microglia activation impairs neuronal potassium homeostasis and cognition in CKD. CKD disrupts the barrier of brain endothelial cells in vitro and the blood-brain barrier in vivo, establishing that the uremic state modifies vascular permeability in the brain. Exposure to uremic conditions impairs calcium homeostasis in microglia, enhances microglial potassium efflux via the calcium-dependent channel K<sub>Ca</sub>3.1, and induces p38-MAPK associated IL-1β maturation in microglia. Restoring potassium homeostasis in microglia using a K<sub>Ca</sub>3.1-specific inhibitor (TRAM34) improves CKD-triggered cognitive impairment. Likewise, inhibition of the IL-1β receptor 1 (IL-1R1) using anakinra or genetically abolishing neuronal IL-1R1 expression in neurons prevent CKD-mediated reduced neuronal potassium turnover and CKD-induced impaired cognition. Accordingly, in CKD mice, impaired cognition can be ameliorated by either preventing microglia activation or inhibiting IL-1R-signaling in neurons. Thus, our data suggest that potassium efflux from microglia triggers their activation, which promotes microglia IL-1β release and IL-1R1-mediated neuronal dysfunction in CKD. Hence, our study provides new mechanistic insight into cognitive impairment in association with CKD and identifies possible new therapeutic approaches.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 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.
{"title":"The membrane transporter SLC25A48 enables transport of choline into human mitochondria.","authors":"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","doi":"10.1016/j.kint.2024.06.022","DOIUrl":"10.1016/j.kint.2024.06.022","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":17801,"journal":{"name":"Kidney international","volume":null,"pages":null},"PeriodicalIF":14.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}