Background: Cardiovascular and infective complications are commonly observed in patients receiving hemodialysis (HD) with cardiovascular events and infection-related complications being the first and second leading causes of death. Infective endocarditis (IE) is characterized by inflammation of the endocardium caused by infection, typically affecting the cardiac valves and can be in acute, subacute or chronic forms. It is a serious complication within the HD population due to their predisposition for both infection and valvular damage. Considering the frailty and burden of co-morbidities in those receiving HD, management of IE in the HD population is very challenging. There has been continuous discussion and debate on optimizing the diagnostic and treatment approach of IE in this patient group to improve their clinical outcomes. Currently reported outcomes are relatively poor and there are updates from numerous guidelines relating to advances in IE management. Summary: In this review, we will evaluate the evidence in relation to the epidemiology of HD-associated IE and discuss the important risk factors of IE in patients requiring dialysis. We will also evaluate the current recommendations regarding diagnosis and treatment for suspected or confirmed IE cases amongst HD patients and present the updated data regarding clinical outcomes relating to HD-associated IE. Key Messages: The incidence of IE in HD patients is expected to increase going forward as HD becomes more easily accessible alongside an emerging uptake of home HD. A more thorough insight into this topic is required to improve clinical practice relating to IE prevention and management in the HD population, given relatively poor clinical outcomes.
{"title":"Infective endocarditis in patients receiving hemodialysis: A current review","authors":"Uzhe Ding, Lijin Ooi, H. H. Wu, R. Chinnadurai","doi":"10.1159/000540513","DOIUrl":"https://doi.org/10.1159/000540513","url":null,"abstract":"\u0000Background: Cardiovascular and infective complications are commonly observed in patients receiving hemodialysis (HD) with cardiovascular events and infection-related complications being the first and second leading causes of death. Infective endocarditis (IE) is characterized by inflammation of the endocardium caused by infection, typically affecting the cardiac valves and can be in acute, subacute or chronic forms. It is a serious complication within the HD population due to their predisposition for both infection and valvular damage. Considering the frailty and burden of co-morbidities in those receiving HD, management of IE in the HD population is very challenging. There has been continuous discussion and debate on optimizing the diagnostic and treatment approach of IE in this patient group to improve their clinical outcomes. Currently reported outcomes are relatively poor and there are updates from numerous guidelines relating to advances in IE management. \u0000\u0000Summary: In this review, we will evaluate the evidence in relation to the epidemiology of HD-associated IE and discuss the important risk factors of IE in patients requiring dialysis. We will also evaluate the current recommendations regarding diagnosis and treatment for suspected or confirmed IE cases amongst HD patients and present the updated data regarding clinical outcomes relating to HD-associated IE. \u0000\u0000Key Messages: The incidence of IE in HD patients is expected to increase going forward as HD becomes more easily accessible alongside an emerging uptake of home HD. A more thorough insight into this topic is required to improve clinical practice relating to IE prevention and management in the HD population, given relatively poor clinical outcomes. \u0000","PeriodicalId":506859,"journal":{"name":"Kidney Diseases","volume":"50 40","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141799617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lulin Min, Yixin Chen, Fang Zhong, Leyi Gu, Kyung Lee, J. He
Background: Podocyte loss occurs in both primary and secondary glomerular diseases, leading to the progression of kidney disease. A large body of evidence suggests that apoptosis and detachment are the mechanisms mediating the reduction in podocyte numbers in glomerular diseases. Recent studies demonstrate a renal protective effect of Protein S (PS) through the activation of Tyro3, one of the TAM receptors. Tyro3 is predominantly expressed in podocytes within the kidney, and its expression increases in early diabetic kidney disease (DKD) but decreases in patients with progressive DKD and FSGS. Glomerular expression of Tyro3 also correlates with the progression of DKD and predicts the progression of primary glomerular diseases. High glucose increases Tyro3 expression, while TNF-α suppresses the expression of PS and Tyro3. PS has anti-inflammatory and anti-apoptotic effects in podocytes, likely via the activation of the Akt pathway and the inhibition of NF-kB activation. In vivo, the knockout of PS or Tyro3 exacerbates podocyte loss and glomerular disease, while the overexpression of PS and Tyro3 attenuates the injury in mice with DKD and FSGS. Tyro3 agonists have also been shown to protect podocytes from injury in these animal models. Summary: Tyro3 plays a critical role in podocyte biology and glomerular disease. Tyro3 agonists could potentially be developed as a new therapy for glomerular disease. Key Message: The aim of this review article is to summarize the role and mechanisms mediating the protective effects of Tyro3 in podocyte biology and glomerular disease. Additionally, we discuss the possibility of developing Tyro3 agonists as potential treatment for glomerular diseases.
{"title":"Role and Mechanisms of Tyro3 in podocyte biology and glomerular disease","authors":"Lulin Min, Yixin Chen, Fang Zhong, Leyi Gu, Kyung Lee, J. He","doi":"10.1159/000540452","DOIUrl":"https://doi.org/10.1159/000540452","url":null,"abstract":"Background: Podocyte loss occurs in both primary and secondary glomerular diseases, leading to the progression of kidney disease. A large body of evidence suggests that apoptosis and detachment are the mechanisms mediating the reduction in podocyte numbers in glomerular diseases. Recent studies demonstrate a renal protective effect of Protein S (PS) through the activation of Tyro3, one of the TAM receptors. Tyro3 is predominantly expressed in podocytes within the kidney, and its expression increases in early diabetic kidney disease (DKD) but decreases in patients with progressive DKD and FSGS. Glomerular expression of Tyro3 also correlates with the progression of DKD and predicts the progression of primary glomerular diseases. High glucose increases Tyro3 expression, while TNF-α suppresses the expression of PS and Tyro3. PS has anti-inflammatory and anti-apoptotic effects in podocytes, likely via the activation of the Akt pathway and the inhibition of NF-kB activation. In vivo, the knockout of PS or Tyro3 exacerbates podocyte loss and glomerular disease, while the overexpression of PS and Tyro3 attenuates the injury in mice with DKD and FSGS. Tyro3 agonists have also been shown to protect podocytes from injury in these animal models. Summary: Tyro3 plays a critical role in podocyte biology and glomerular disease. Tyro3 agonists could potentially be developed as a new therapy for glomerular disease. Key Message: The aim of this review article is to summarize the role and mechanisms mediating the protective effects of Tyro3 in podocyte biology and glomerular disease. Additionally, we discuss the possibility of developing Tyro3 agonists as potential treatment for glomerular diseases.","PeriodicalId":506859,"journal":{"name":"Kidney Diseases","volume":"22 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141810313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Li, J. Ng, Guangyan Cai, Wei Chen, Kai Ming Chow, S. Fan, John Cijiang He, L. Hooi, York Pei, Boon Wee Teo, Muh Geot Wong, I-Wen Wu, Jianhui Zhou, Na Tian, Zhiming Ye, Xueqing Yu
Background: Chronic kidney disease (CKD) continues to be a significant global public health issue. The escalating burden of CKD is probably driven by the aging population and the rising prevalence of diabetes. CKD not only adversely impacts an individual's health and well-being, but also poses significant challenge on the economy of the society. Summary: Experts from ten countries and regions around the world (Australia, Canada, China, Hong Kong, Malaysia, New Zealand, Singapore, Taiwan, United Kingdom, and United States) convened in the 4th International Congress of Chinese Nephrologists on 1st December 2023 to discuss the global dialysis burden. Although the cost of kidney replacement therapy (KRT) accounts for 2-3% of total healthcare expenditure in developed countries, patients with end stage kidney disease (ESKD) only represent a small percentage (<0.5%) of the population. Importantly, the economic impact of ESKD is not limited to direct medical costs, but extends to indirect societal costs, such as productivity loss by patients and caregivers. Primary prevention of CKD, early screening and treatment to delay progression to ESKD (where treatment costs rise dramatically), and utilization of home-based dialysis therapy (including peritoneal dialysis and home hemodialysis) shall be implemented as part of cost-containment strategy. Kidney transplant provides better outcomes than dialysis and is cost-effective in long run, whereas conservative kidney management should be considered for elderly frail patients. Key messages: Implementation of preventive measures and cost-effective treatment strategies are the cornerstone to combat the global CKD epidemic.
{"title":"Navigating the Global Economic Landscape of Dialysis: A Summary of Expert Opinions from The 4th International Congress of Chinese Nephrologists","authors":"P. Li, J. Ng, Guangyan Cai, Wei Chen, Kai Ming Chow, S. Fan, John Cijiang He, L. Hooi, York Pei, Boon Wee Teo, Muh Geot Wong, I-Wen Wu, Jianhui Zhou, Na Tian, Zhiming Ye, Xueqing Yu","doi":"10.1159/000540152","DOIUrl":"https://doi.org/10.1159/000540152","url":null,"abstract":"Background: Chronic kidney disease (CKD) continues to be a significant global public health issue. The escalating burden of CKD is probably driven by the aging population and the rising prevalence of diabetes. CKD not only adversely impacts an individual's health and well-being, but also poses significant challenge on the economy of the society. Summary: Experts from ten countries and regions around the world (Australia, Canada, China, Hong Kong, Malaysia, New Zealand, Singapore, Taiwan, United Kingdom, and United States) convened in the 4th International Congress of Chinese Nephrologists on 1st December 2023 to discuss the global dialysis burden. Although the cost of kidney replacement therapy (KRT) accounts for 2-3% of total healthcare expenditure in developed countries, patients with end stage kidney disease (ESKD) only represent a small percentage (<0.5%) of the population. Importantly, the economic impact of ESKD is not limited to direct medical costs, but extends to indirect societal costs, such as productivity loss by patients and caregivers. Primary prevention of CKD, early screening and treatment to delay progression to ESKD (where treatment costs rise dramatically), and utilization of home-based dialysis therapy (including peritoneal dialysis and home hemodialysis) shall be implemented as part of cost-containment strategy. Kidney transplant provides better outcomes than dialysis and is cost-effective in long run, whereas conservative kidney management should be considered for elderly frail patients. Key messages: Implementation of preventive measures and cost-effective treatment strategies are the cornerstone to combat the global CKD epidemic.","PeriodicalId":506859,"journal":{"name":"Kidney Diseases","volume":"50 16","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141807051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuan Ma, Jing Ji, Xintong Liu, Xizi Zheng, Lingyi Xu, Qingqing Zhou, Zehua Li, Li Yang
Introduction: The growing incidence of diabetic kidney disease (DKD) and the difficulties in its management underscore the need for a more comprehensive understanding of its pathogenesis. Recent studies have emphasized the significant impact of circulating immunity on the development of diabetic microvascular complications including retinopathy and neuropathy, research on circulating immunity in DKD remains limited. Methods: This study utilized mendelian randomization (MR) analysis to explore the potential independent causal relationships between circulating immune cells and DKD pathogenesis. Additionally, a combination of single-cell disease relevance score (scDRS) and immune cell infiltration analysis was employed to map the circulating immunity landscape in DKD patients. Results: Ten immune traits, including 5 of B cells, 2 of T cells, 2 of granulocytes and one of monocytes, were defined to be associated with the pathogenesis of DKD. Notably, IgD-CD27- B cell Absolute Count [IVW: OR, 1.102 (1.023 to 1.189), p=0.011] and IgD-CD24- B cell Absolute Count [IVW: OR, 1.106 (1.030 to 1.188), p=0.005] were associated with promoting DKD pathogenesis, while CD24+CD27+ B cell %B cell [IVW: OR, 0.943 (0.898 to 0.989), p=0.016] demonstrated a protective effect against DKD onset. The presence of B cell activating factor receptor (BAFF-R) on CD20-CD38- B cell [IVW: OR, 0.946 (0.904 to 0.989), p=0.015] and BAFF-R on IgD-CD38+ B cell [IVW: OR, 0.902 (0.834 to 0.975), p=0.009] also indicated a potential role in preventing DKD. Single-cell disease relevance score (scDRS) analysis revealed that two main subsets of B cells, naïve B and memory B cells, had a higher proportion of DKD-related cells or a higher scDRS score of DKD phenotype, indicating their strong association with DKD. Furthermore, immune infiltrate deconvolution analysis showed a notable decrease in the circulating memory B cells and class-switched memory B cells in DKD patients compared to those of DM patients without DKD. Conclusion: Our study revealed the causal relations between circulating immunity and DKD susceptibility, particularly highlighted the potential roles of B cell subtypes in DKD development. Further studies addressing the related mechanisms would broaden the current understanding of DKD pathogenesis.
导言：糖尿病肾病（DKD）的发病率越来越高，治疗难度也越来越大，因此需要对其发病机制有更全面的了解。最近的研究强调了循环免疫对包括视网膜病变和神经病变在内的糖尿病微血管并发症发展的重要影响，但对 DKD 中循环免疫的研究仍然有限。研究方法本研究利用亡羊补牢随机化（MR）分析法探讨了循环免疫细胞与 DKD 发病机制之间潜在的独立因果关系。此外，还采用了单细胞疾病相关性评分（scDRS）和免疫细胞浸润分析相结合的方法来绘制 DKD 患者的循环免疫图谱。结果显示确定了与 DKD 发病机制相关的 10 种免疫特征，包括 5 种 B 细胞特征、2 种 T 细胞特征、2 种粒细胞特征和 1 种单核细胞特征。值得注意的是，IgD-CD27- B 细胞绝对计数[IVW：OR，1.102（1.023 至 1.189），p=0.011]和 IgD-CD24- B 细胞绝对计数[IVW：OR，1.106（1.030 至 1.188），p=0.而 CD24+CD27+ B 细胞 %B 细胞 [IVW: OR, 0.943 (0.898 to 0.989), p=0.016] 对 DKD 的发病有保护作用。CD20-CD38-B细胞上的B细胞活化因子受体（BAFF-R）[IVW：OR，0.946（0.904-0.989），p=0.015]和IgD-CD38+B细胞上的BAFF-R[IVW：OR，0.902（0.834-0.975），p=0.009]也显示了在预防DKD中的潜在作用。单细胞疾病相关性评分（scDRS）分析显示，B细胞的两个主要亚群，即幼稚B细胞和记忆B细胞，具有较高的DKD相关细胞比例或较高的DKD表型scDRS评分，表明它们与DKD密切相关。此外，免疫浸润解卷积分析表明，与无 DKD 的 DM 患者相比，DKD 患者的循环记忆 B 细胞和类调换记忆 B 细胞明显减少。结论我们的研究揭示了循环免疫与 DKD 易感性之间的因果关系，特别强调了 B 细胞亚型在 DKD 发病中的潜在作用。针对相关机制的进一步研究将拓宽目前对 DKD 发病机制的认识。
{"title":"Integrative analysis by mendelian randomization and large-scale single-cell transcriptomics reveals causal links between B cell subtypes and diabetic kidney disease","authors":"Yuan Ma, Jing Ji, Xintong Liu, Xizi Zheng, Lingyi Xu, Qingqing Zhou, Zehua Li, Li Yang","doi":"10.1159/000539689","DOIUrl":"https://doi.org/10.1159/000539689","url":null,"abstract":"Introduction: The growing incidence of diabetic kidney disease (DKD) and the difficulties in its management underscore the need for a more comprehensive understanding of its pathogenesis. Recent studies have emphasized the significant impact of circulating immunity on the development of diabetic microvascular complications including retinopathy and neuropathy, research on circulating immunity in DKD remains limited. Methods: This study utilized mendelian randomization (MR) analysis to explore the potential independent causal relationships between circulating immune cells and DKD pathogenesis. Additionally, a combination of single-cell disease relevance score (scDRS) and immune cell infiltration analysis was employed to map the circulating immunity landscape in DKD patients. Results: Ten immune traits, including 5 of B cells, 2 of T cells, 2 of granulocytes and one of monocytes, were defined to be associated with the pathogenesis of DKD. Notably, IgD-CD27- B cell Absolute Count [IVW: OR, 1.102 (1.023 to 1.189), p=0.011] and IgD-CD24- B cell Absolute Count [IVW: OR, 1.106 (1.030 to 1.188), p=0.005] were associated with promoting DKD pathogenesis, while CD24+CD27+ B cell %B cell [IVW: OR, 0.943 (0.898 to 0.989), p=0.016] demonstrated a protective effect against DKD onset. The presence of B cell activating factor receptor (BAFF-R) on CD20-CD38- B cell [IVW: OR, 0.946 (0.904 to 0.989), p=0.015] and BAFF-R on IgD-CD38+ B cell [IVW: OR, 0.902 (0.834 to 0.975), p=0.009] also indicated a potential role in preventing DKD. Single-cell disease relevance score (scDRS) analysis revealed that two main subsets of B cells, naïve B and memory B cells, had a higher proportion of DKD-related cells or a higher scDRS score of DKD phenotype, indicating their strong association with DKD. Furthermore, immune infiltrate deconvolution analysis showed a notable decrease in the circulating memory B cells and class-switched memory B cells in DKD patients compared to those of DM patients without DKD. Conclusion: Our study revealed the causal relations between circulating immunity and DKD susceptibility, particularly highlighted the potential roles of B cell subtypes in DKD development. Further studies addressing the related mechanisms would broaden the current understanding of DKD pathogenesis.","PeriodicalId":506859,"journal":{"name":"Kidney Diseases","volume":"70 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141338051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lingxi Guo, Xiaojing Wu, Xiaoyan Cui, Meiyuan Li, Lu Yang, Yiming Feng, Qingyuan Zhan, Linna Huang
Introduction: The incidence and impact of acute kidney injury (AKI) in patients with invasive pulmonary aspergillosis (IPA) admitted to the intensive care unit (ICU) are unknown. Methods: This retrospective study included 140 patients who were diagnosed IPA and admitted to the medical ICU of China–Japan Friendship Hospital in Beijing, China. AKI was defined according to the kidney disease improving global outcomes guidelines. Data on demographic characteristics, comorbidities, laboratory tests, treatments, and prognosis at ICU admission were collected. Results: The rate of AKI was 71.4% (n = 100), and approximately 30% of the patients had preadmission acute kidney dysfunction. Of the 100 patients with AKI, 19, 8, and 73 patients had stage I, II, and III AKI, respectively, and 64 (87.6%) patients required continuous renal replacement therapy. Overall ICU mortality rate was 52.1%. Irreversible AKI was a strong independent risk factor for ICU mortality (odds ratio 13.36, 95% confidence interval 4.52–39.48, p < 0.001), followed by chronic lung disease, use of intermittent positive-pressure ventilation, and long-term corticosteroid treatment within 1 year prior to ICU admission. Higher cardiac troponin I levels at admission and worse volume control during the first 7 days of ICU stay were potential predictive factors of irreversible kidney dysfunction. Patients with irreversible AKI and those who died during the ICU stay had greater volume overload during the first 14 days of ICU stay. Patients who survived received earlier renal replacement therapy support after ICU admission compared to those who died (median, 2 vs. 5 days; p = 0.026). Conclusion: Compared to the patients with IPA in the absence of AKI, those with AKI presented with more volume overload, worse disease burden, and required stronger respiratory support, while experiencing worse prognosis. Irreversible AKI was a strong predictor of mortality in patients with critical IPA. Better volume control and earlier CRRT initiation should be considered key points in AKI management and prognostic improvement.
简介：入住重症监护室（ICU）的侵袭性肺曲霉菌病（IPA）患者急性肾损伤（AKI）的发生率和影响尚不清楚。研究方法这项回顾性研究纳入了 140 名确诊为 IPA 并入住中国北京中日友好医院内科 ICU 的患者。AKI根据肾脏疾病改善全球结局指南进行定义。收集了入院时的人口统计学特征、合并症、实验室检查、治疗和预后等数据：AKI发生率为71.4%（n = 100），约30%的患者入院前存在急性肾功能不全。在 100 名出现 AKI 的患者中，分别有 19、8 和 73 名患者出现 I 期、II 期和 III 期 AKI，64 名患者（87.6%）需要持续接受肾脏替代治疗。重症监护室的总死亡率为 52.1%。不可逆性 AKI 是 ICU 死亡率的一个强有力的独立风险因素（几率比 13.36，95% 置信区间 4.52-39.48，P <0.001），其次是慢性肺部疾病、使用间歇性正压通气和入院前一年内长期接受皮质类固醇治疗。入院时较高的心肌肌钙蛋白 I 水平和入住 ICU 头 7 天内较差的血容量控制是不可逆肾功能障碍的潜在预测因素。不可逆性肾功能损伤患者和在重症监护室住院期间死亡的患者在重症监护室住院的前14天内血容量超负荷程度更高。与死亡患者相比，存活患者在入院后接受肾脏替代治疗的时间更早（中位数为2天对5天；P = 0.026）：结论：与没有发生肾脏缺血的IPA患者相比，发生肾脏缺血的患者血容量超负荷更严重，疾病负担更重，需要更强的呼吸支持，预后更差。不可逆的 AKI 是预测危重 IPA 患者死亡率的重要因素。更好的容量控制和更早启动 CRRT 应被视为 AKI 管理和改善预后的关键点。
{"title":"Clinical characteristics and the prognostic impact of acute kidney injury in critically ill patients with invasive pulmonary Aspergillosis in the intensive care unit: A retrospective, single-center study","authors":"Lingxi Guo, Xiaojing Wu, Xiaoyan Cui, Meiyuan Li, Lu Yang, Yiming Feng, Qingyuan Zhan, Linna Huang","doi":"10.1159/000539139","DOIUrl":"https://doi.org/10.1159/000539139","url":null,"abstract":"Introduction: The incidence and impact of acute kidney injury (AKI) in patients with invasive pulmonary aspergillosis (IPA) admitted to the intensive care unit (ICU) are unknown. \u0000Methods: This retrospective study included 140 patients who were diagnosed IPA and admitted to the medical ICU of China–Japan Friendship Hospital in Beijing, China. AKI was defined according to the kidney disease improving global outcomes guidelines. Data on demographic characteristics, comorbidities, laboratory tests, treatments, and prognosis at ICU admission were collected.\u0000Results: The rate of AKI was 71.4% (n = 100), and approximately 30% of the patients had preadmission acute kidney dysfunction. Of the 100 patients with AKI, 19, 8, and 73 patients had stage I, II, and III AKI, respectively, and 64 (87.6%) patients required continuous renal replacement therapy. Overall ICU mortality rate was 52.1%. Irreversible AKI was a strong independent risk factor for ICU mortality (odds ratio 13.36, 95% confidence interval 4.52–39.48, p < 0.001), followed by chronic lung disease, use of intermittent positive-pressure ventilation, and long-term corticosteroid treatment within 1 year prior to ICU admission. Higher cardiac troponin I levels at admission and worse volume control during the first 7 days of ICU stay were potential predictive factors of irreversible kidney dysfunction. Patients with irreversible AKI and those who died during the ICU stay had greater volume overload during the first 14 days of ICU stay. Patients who survived received earlier renal replacement therapy support after ICU admission compared to those who died (median, 2 vs. 5 days; p = 0.026).\u0000Conclusion: Compared to the patients with IPA in the absence of AKI, those with AKI presented with more volume overload, worse disease burden, and required stronger respiratory support, while experiencing worse prognosis. Irreversible AKI was a strong predictor of mortality in patients with critical IPA. Better volume control and earlier CRRT initiation should be considered key points in AKI management and prognostic improvement.\u0000","PeriodicalId":506859,"journal":{"name":"Kidney Diseases","volume":"143 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141002117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yanlin Guo, Rong-fang Qiao, Guixiang Xie, Yao Yao, Chunxiu Du, Yunxia Shao, Youfei Guan, Xiaoyan Zhang
Introduction: G protein-coupled bile acid receptor (TGR5), the first G protein-coupled receptor for bile acids identified, is capable of activating a variety of intracellular signaling pathways after interacting with bile acids. TGR5 plays an important role in multiple physiological processes and is considered to be a potential target for the treatment of various metabolic diseases including type 2 diabetes. Evidence has been emerged that genetically deletion of TGR5 results in an increase in basal urine output, suggesting that it may play a critical role in renal water and salt reabsorption. The present study aims to elucidate the effect and mechanism of TGR5 activation on urine concentration. Methods：Mice were treated with TGR5 agonists (LCA and INT-777) for 3 days. The 24-hour urine of mice was collected and analyzed for urine biochemical parameters. The mRNA expressions were detected by real-time PCR, and the protein expressions were detected by western blot. Immunohistochemistry (IHC) and immunofluorescence (IF) were performed to examine the cellular location of proteins. The primary cultured medullary collecting duct cells were pretreated with H89 (a PKA inhibitor) for 1h, followed by 12-hour treatment of LCA and INT-777. Luciferase reporter assays was used to detect the effect of CREB on gene transcription of AQPs. Gel electrophoretic mobility shift assays were used to analyze DNA–protein interactions. Results: Treatment of mice with the TGR5 agonist LCA and INT-777 markedly reduced urine output and increased urine osmolality, accompanied by a marked increase in AQP2 and AQP3 protein expression and membrane translocation. In cultured primary medullary collecting duct cells, LCA and INT-777 dose-dependently upregulated AQP2 and AQP3 expression in an cAMP/PKA-dependent manner. Mechanistically, both AQP2 and AQP3 gene promoter contains a putative CREB binding site, which can be bound and activated by CREB as assessed by both gene promoter-driven luciferase and gel shift assays. Conclusion: Collectively, our findings demonstrate that activation of TGR5 can promote urine concentration by upregulation of AQP2 and AQP3 expression in renal collecting ducts. TGR5 may represent an attractive target for the treatment of patients with urine concentration defect.
{"title":"Activation of TGR5 increases urine concentration by inducing AQP2 and AQP3 expression in renal medullary collecting ducts","authors":"Yanlin Guo, Rong-fang Qiao, Guixiang Xie, Yao Yao, Chunxiu Du, Yunxia Shao, Youfei Guan, Xiaoyan Zhang","doi":"10.1159/000538107","DOIUrl":"https://doi.org/10.1159/000538107","url":null,"abstract":"Introduction: G protein-coupled bile acid receptor (TGR5), the first G protein-coupled receptor for bile acids identified, is capable of activating a variety of intracellular signaling pathways after interacting with bile acids. TGR5 plays an important role in multiple physiological processes and is considered to be a potential target for the treatment of various metabolic diseases including type 2 diabetes. Evidence has been emerged that genetically deletion of TGR5 results in an increase in basal urine output, suggesting that it may play a critical role in renal water and salt reabsorption. The present study aims to elucidate the effect and mechanism of TGR5 activation on urine concentration. \u0000Methods：Mice were treated with TGR5 agonists (LCA and INT-777) for 3 days. The 24-hour urine of mice was collected and analyzed for urine biochemical parameters. The mRNA expressions were detected by real-time PCR, and the protein expressions were detected by western blot. Immunohistochemistry (IHC) and immunofluorescence (IF) were performed to examine the cellular location of proteins. The primary cultured medullary collecting duct cells were pretreated with H89 (a PKA inhibitor) for 1h, followed by 12-hour treatment of LCA and INT-777. Luciferase reporter assays was used to detect the effect of CREB on gene transcription of AQPs. Gel electrophoretic mobility shift assays were used to analyze DNA–protein interactions.\u0000Results: Treatment of mice with the TGR5 agonist LCA and INT-777 markedly reduced urine output and increased urine osmolality, accompanied by a marked increase in AQP2 and AQP3 protein expression and membrane translocation. In cultured primary medullary collecting duct cells, LCA and INT-777 dose-dependently upregulated AQP2 and AQP3 expression in an cAMP/PKA-dependent manner. Mechanistically, both AQP2 and AQP3 gene promoter contains a putative CREB binding site, which can be bound and activated by CREB as assessed by both gene promoter-driven luciferase and gel shift assays. \u0000Conclusion: Collectively, our findings demonstrate that activation of TGR5 can promote urine concentration by upregulation of AQP2 and AQP3 expression in renal collecting ducts. TGR5 may represent an attractive target for the treatment of patients with urine concentration defect. \u0000","PeriodicalId":506859,"journal":{"name":"Kidney Diseases","volume":"17 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140264281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Linfan Xu, Ting Gan, Yang Li, Pei Chen, S. Shi, Lijun Liu, Ji-cheng Lv, Hong Zhang, Xu-jie Zhou
Introduction: IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno) proteasome probably plays an important role in IgAN. Methods: We firstly analyzed the association of variants in the UBE2L3 region with susceptibility to IgA nephropathy in 3495 patients and 9101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including UBE2L3 were analyzed in peripheral blood mononuclear cells (PBMCs) from 53 patients and 28 healthy controls. The associations between UBE2L3 and the expression levels of genes involved in Gd-IgA1 production were also explored. Results: The rs131654 showed the most significant association signal in UBE2L3 region (OR 1.10, 95% CI 1.04-1.16, P = 2.29×10-3), whose genotypes were also associated with the levels of Gd-IgA1 (P = 0.04). The rs131654 was observed to exert cis-eQTL effects on UBE2L3 in various tissues and cell types, particularly in immune-cell types in multiple databases. The UBE2L3, LUBAC, and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of UBE2L3 were not only associated with higher proteinuria (r = 0.34, P = 0.01) and lower eGFR (r = -0.28, P = 0.04), also positively correlated with the gene expression of LUBAC and other proteasome subunits. Additionally, mRNA expression levels of UBE2L3 were also positively correlated with IL-6 and RELA, but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including C1GALT1 and C1GALT1C1. Conclusion: In conclusion, by combined genetic association and differed expression analysis of UBE2L3, our data support a role of genetically conferred dysregulation of the (immuno) proteasome in regulating galactose-deficient IgA1 in the development of IgAN.
{"title":"Combined genetic association and differed expression analysis of UBE2L3 uncovers a genetic regulatory role of (immuno) proteasome in IgA Nephropathy","authors":"Linfan Xu, Ting Gan, Yang Li, Pei Chen, S. Shi, Lijun Liu, Ji-cheng Lv, Hong Zhang, Xu-jie Zhou","doi":"10.1159/000537987","DOIUrl":"https://doi.org/10.1159/000537987","url":null,"abstract":"Introduction: IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno) proteasome probably plays an important role in IgAN.\u0000Methods: We firstly analyzed the association of variants in the UBE2L3 region with susceptibility to IgA nephropathy in 3495 patients and 9101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including UBE2L3 were analyzed in peripheral blood mononuclear cells (PBMCs) from 53 patients and 28 healthy controls. The associations between UBE2L3 and the expression levels of genes involved in Gd-IgA1 production were also explored.\u0000Results: The rs131654 showed the most significant association signal in UBE2L3 region (OR 1.10, 95% CI 1.04-1.16, P = 2.29×10-3), whose genotypes were also associated with the levels of Gd-IgA1 (P = 0.04). The rs131654 was observed to exert cis-eQTL effects on UBE2L3 in various tissues and cell types, particularly in immune-cell types in multiple databases. The UBE2L3, LUBAC, and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of UBE2L3 were not only associated with higher proteinuria (r = 0.34, P = 0.01) and lower eGFR (r = -0.28, P = 0.04), also positively correlated with the gene expression of LUBAC and other proteasome subunits. Additionally, mRNA expression levels of UBE2L3 were also positively correlated with IL-6 and RELA, but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including C1GALT1 and C1GALT1C1.\u0000Conclusion: In conclusion, by combined genetic association and differed expression analysis of UBE2L3, our data support a role of genetically conferred dysregulation of the (immuno) proteasome in regulating galactose-deficient IgA1 in the development of IgAN.\u0000","PeriodicalId":506859,"journal":{"name":"Kidney Diseases","volume":"41 21","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140082732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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