线粒体功能障碍在急性肾损伤向慢性肾脏疾病转变中的作用

急性肾损伤(AKI)是一种发病率较高的临床综合征,会使远期慢性肾脏病(CKD)的发病率明显上升,其机制目前尚不完全明确,可能包括细胞周期停滞、小管上皮周围毛细血管变少、炎性细胞浸润等。线粒体功能障碍在其中的作用主要包括导致了过度氧化应激、促进炎性反应的发生及进展、直接诱导肾小管细胞凋亡等。     

中医药防治慢性肾脏病的临床证据及效应机制

慢性肾脏病 (Chronic Kidney Disease, CKD) 是严重危害人类健康的重大疾病。中医药防治 CKD 有特色疗效, 在降低尿蛋白、保护肾功能、延缓CKD进展及缓解相关并发症等方面具有一定的优势。本文梳理了近年来CKD的中医理论新认识,总结了中医药治疗CKD疗效的循证医学证据及其效应机制相关的研究成果,综合当前CKD临床和基础研究及成果转化现状,提出未来研究展望,以期对中医药防治CKD的进一步创新发展有所助益。     

线粒体在急性肾损伤与慢性肾脏病中的研究新进展

急性肾损伤 (Acute Kidney Injury,AKI) 是常见的临床急危重症,其病因不清,机制不明。单核巨噬细胞 (Mono-nuclear Macrophage,MPC) 是肾脏损伤后的主要炎症效应细胞,在AKI的发生发展及慢性转归中发挥重要作用,可能成为AKI的治疗靶点。肾脏MPC在分子表型、起源、细胞功能等方面具有高度异质性。本文将对MPC的异质性,及其介导AKI发病机制的研究进展进行综述。     

单核巨噬细胞介导急性肾损伤发病的研究进展

急性肾损伤 (Acute Kidney Injury,AKI) 和慢性肾脏病 (Chronic Kidney Disease,CKD) 是最常见的肾损伤形式,已成为新的“公共健康问题”。高效识别肾脏高危易损者是目前临床精准监测、精准防治的迫切需要。肾损伤后的信号分子,特别是肾小管上皮细胞损伤后表达的小分子蛋白,能释放至尿液中,尿中水平与肾损伤程度密切相关,是新的肾损伤指标。本文围绕主要的尿液肾损伤生物标志物,介绍它们从基础发现到临床验证,再到临床应用的全过程,最后初步探讨尿液肾损伤标志物研究的未来方向。     

T 细胞在急性肾损伤中的作用

急性肾损伤(AKI)是指各种原因引起的短时间内肾功能快速丢失的临床综合征,发生AKI 的患者进展为慢性肾脏病(CKD)的风险高,死亡率增加,给患者家庭和社会造成极大的经济负担。许多因素介导AKI 的发生发展,目前认为,固有免疫和适应性免疫介导的炎症反应参与了AKI 的起始、进展以及修复的各个阶段,而T 淋巴细胞在其中扮演了关键角色。本文将对T 细胞在AKI 中的作用的研究进展进行综述。     

肾小管上皮细胞坏死新机制研究进展——Necroptosis与急性肾损伤

Necroptosis（程序性坏死）是近年新发现的一种不依赖于caspase的新型细胞死亡途径,在肾脏疾病领域的研究刚起步,可能在缺血再灌注导致的急性肾损伤（AKI）,顺铂诱导的AKI,尿石症和输尿管梗阻后继发的急性肾损伤等常见的急性肾损伤发病中起关键的致病作用。Necroptosis可通过受体相互作用蛋白1/3（RIPK）,线粒体和多核苷酸二磷酸-核糖聚合酶-1（PARP-1）介导的途径等诱发肾小管上皮细胞的坏死,因此,靶向抑制necroptosis发生过程中的一些关键分子,如RIPK1、RIPK3、亲环蛋白D（CypD）和PARP-1等,有望为预防AKI的发生及AKI向CKD进展提供新的策略。因此,探讨necroptosis相关通路在AKI中的作用,有利于进一步明确AKI的发病机制,且对AKI治疗靶点的确证以及治疗药物的研究也具有重要意义。     

Hippo信号通路与肾病

Hippo信号通路是近年来备受关注的一条调节器官生长和组织大小的重要信号通路,其已被证实在肿瘤的发生、发展中发挥重要作用.目前Hippo信号通路与肾病的相关性研究仍处于起步阶段.在急性肾损伤(acute renal injury,AKI)方面,Hippo信号通路可能参与小管上皮细胞的凋亡、上皮-间质转化(epithelial-mesenchymal transition,EMT)以及AKI进展至慢性肾脏病(chronic kidney disease,CKD)等多个环节.此外,Hippo信号通路还参与多种慢性肾脏病,包括局灶节段性肾小球硬化症、糖尿病肾病、多囊肾等的发生和疾病进展.     

钠-葡萄糖协同转运蛋白2抑制剂在非糖尿病慢性肾脏病患者中应用的研究进展

钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂是一种新型降糖药物。近年来临床研究发现SGLT2抑制剂对非糖尿病导致的慢性肾脏病(CKD)具有肾脏保护作用:在肾素-血管紧张素-醛固酮系统抑制剂基础上联合应用SGLT2抑制剂,可进一步降低IgA肾病、轻中度蛋白尿的局灶节段性肾小球硬化患者的尿蛋白水平,延缓CKD进展。根据临床试验结果,推测SGLT2抑制剂在非糖尿病CKD中应用的理论依据:促进葡萄糖排泄,促进钠和水的排泄,通过减少热量来减轻患者体重;改善肾小管-肾小球管球反馈,收缩肾小球入球小动脉,降低肾小球滤过压。现有的临床证据将有助于进一步探讨CKD的进展机制,特别是SGLT2在CKD进展中发挥的作用,将来可能成为非糖尿病CKD的一线治疗。     

肾纤维化发生的细胞及分子生物学机制研究进展

肾纤维化是在慢性肾脏病(CKD)进展过程中多种细胞外基质广泛沉积的结果,是CKD发展的终末阶段,患者常常需要透析或者进行肾脏移植来维持生命.肾纤维化发生的细胞及分子生物学机制目前尚不十分明确,可能与细胞内一系列细胞增殖相关的信号通路的活化、microRNA的作用、细胞的凋亡和继发性坏死、肾脏中的肌成纤维细胞的异常分化与重构有关.因而研究肾纤维化发病机制的研究进展,特别是调控细胞增殖及纤维化发生分子生物学机制及肾肌成纤维细胞的重构和异常分化对肾纤维化的影响很有意义.     

尿蛋白及晚期糖基化终产物对肾小管上皮细胞溶酶体的影响

目的:探讨慢性肾脏病(CKD)病程中所产生的病理产物尿蛋白及晚期糖基化终产物(AGE)对肾小管上皮细胞(tubular epithelial cells,TECs)溶酶体结构与功能的影响,为阻止或延缓CKD病情进展探索新思路。方法:临床上选取未经特殊治疗的微小病变肾病综合征(MCNS)患者(n=11)、糖尿病肾病(DN)患者(n=11)及活检基本正常(n=6)的肾组织标本,以溶酶体相关膜蛋白1(lysosomal-associated membrane protein 1,LAMP1)和组织蛋白酶B(cathepsin B,CB)行间接免疫荧光染色;体外以8 g/LJ尿蛋白或100 mg/L晚期糖基化终产物刺激人肾小管上皮细胞系(HK-2细胞),以LAMP1和CB行间接免疫荧光染色,检测CB及组织蛋白酶L(cathepsin L,CL)活性,并观察DQ-卵清蛋白降解情况。结果:MCNS及DN患者TECs存在溶酶体膜透化(lysosomal membrane permeabilization,LMP)现象。与正常对照组相比,尿蛋白及AGE-BSA均可致HK-2细胞LMP发生率上升,CB及CL活性降低,溶酶体对DQ-卵清蛋白的降解能力降低(P0.05)。结论:CKD病理产物尿蛋白和晚期糖基化终产物均可致TECs出现LMP现象,并使溶酶体消化功能下降,这可能是CKD肾小管间质纤维化进展的重要机制之一。     

Renal hypoxia in kidney disease: Cause or consequence?

Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a “common pathway” to both AKI and CKD still remains to be adequately tested.     

Impact of hospital-acquired acute kidney injury on Covid-19 outcomes in patients with and without chronic kidney disease: a multicenter retrospective cohort study

Background/aim Hospital-acquired acute kidney injury (HA-AKI) may commonly develop in Covid-19 patients and is expected to have higher mortality. There is little comparative data investigating the effect of HA-AKI on mortality of chronic kidney disease (CKD) patients and a control group of general population suffering from Covid-19.Materials and methodsHA-AKI development was assessed in a group of stage 3–5 CKD patients and control group without CKD among adult patients hospitalized for Covid-19. The role of AKI development on the outcome (in-hospital mortality and admission to the intensive care unit [ICU]) of patients with and without CKD was compared.Results Among 621 hospitalized patients (age 60 [IQR: 47–73]), women: 44.1%), AKI developed in 32.5% of the patients, as stage 1 in 84.2%, stage 2 in 8.4%, and stage 3 in 7.4%. AKI developed in 48.0 % of CKD patients, whereas it developed in 17.6% of patients without CKD. CKD patients with HA-AKI had the highest mortality rate of 41.1% compared to 14.3% of patients with HA-AKI but no CKD (p < 0.001). However, patients with AKI+non-CKD had similar rates of ICU admission, mechanical ventilation, and death rate to patients with CKD without AKI. Adjusted mortality risks of the AKI+non-CKD group (HR: 9.0, 95% CI: 1.9–44.2) and AKI+CKD group (HR: 7.9, 95% CI: 1.9–33.3) were significantly higher than that of the non-AKI+non-CKD group.ConclusionAKI frequently develops in hospitalized patients due to Covid-19 and is associated with high mortality. HA-AKI has worse outcomes whether it develops in patients with or without CKD, but the worst outcome was seen in AKI+CKD patients.     

Endothelial colony‐forming cells and pro‐angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury

Acute kidney injury (AKI) represents a significant clinical concern that is associated with high mortality rates and also represents a significant risk factor for the development of chronic kidney disease (CKD). This article will consider alterations in renal endothelial function in the setting of AKI that may underlie impairment in renal perfusion and how inefficient vascular repair may manifest post‐AKI and contribute to the potential transition to CKD. We provide updated terminology for cells previously classified as ‘endothelial progenitor’ that may mediate vascular repair such as pro‐angiogenic cells and endothelial colony‐forming cells. We consider how endothelial repair may be mediated by these different cell types following vascular injury, particularly in models of AKI. We further summarize the potential ability of these different cells to mitigate the severity of AKI, improve perfusion and maintain vascular structure in pre‐clinical studies.     

Epithelial–mesenchymal transition of renal tubules: Divergent processes of repairing in acute or chronic injury?

Epithelial–mesenchymal transition (EMT) of tubular epithelial cells (TECs) is commonly considered as the major mechanism leading to renal fibrosis in chronic kidney diseases (CKD) injury. We raise the hypothesis that EMT in adult kidney may be an event of “atavistic” phenotypic transition, which mimics but reverses the genetic and cellular processes of development of renal tubules. Transformed TECs may be regarded as induced mesenchymal stem-like cells, representing a cellular self-adaptation when in acute or chronic injury. The reasons are as follows: (1) Embryonic gene WT1 and Pax2, which govern tubule development, have been found to re-express during tubular EMT when facing injury. (2) The common factors that induce EMT in vitro, like IL-1, angiotension II and hypoxia could also promote WT1 and/or Pax2 re-expression. (3) Expression of WT1 and Pax2 are found to be associated with progenitor cells. (4) Beside embryonic gene WT1 and Pax2, we also found that some stem cell markers like CD133 were expressed during EMT process. (5) The process of EMT is not only take place in chronic kidney injury (CKD), but also in acute kidney injury (AKI) as well. (6) The phenotype transition of TECs and genetic event during AKI are entirely consistent with what happened in CKD, but the outcome is completely different. Thus, we thought tubular injury of CKD and AKI may share a common initiative repair mechanism: tubular EMT, that is TECs are transformed into induced mesenchymal stem-like cells, and then interpret the injurious signal differently in acute versus chronic conditions, so as to possess a divergent fates, tubular regeneration or fibrosis formation, depending on a different microenvironment or the duration of the injury. In this sense, tubular EMT could be purposefully orientated into a constructively pathway that repair kidney injury via tubular regeneration, matrix remodeling and tissue structure and function restoration.     

Exploring the origin and limitations of kidney regeneration

Epidemiological findings indicate that acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD), although the molecular mechanism remains unclear. Genetic fate mapping demonstrated that nephrons, functional units in the kidney, are repaired by surviving nephrons after AKI. However, the cell population that repairs damaged nephrons and their repair capacity limitations remain controversial. To answer these questions, we generated a new transgenic mouse strain in which mature proximal tubules, the segment predominantly damaged during AKI, could be genetically labelled at desired time points. Using this strain, massive proliferation of mature proximal tubules is observed during repair, with no dilution of the genetic label after the repair process, demonstrating that proximal tubules are repaired mainly by their own proliferation. Furthermore, acute tubular injury caused significant shortening of proximal tubules associated with interstitial fibrosis, suggesting that proximal tubules have a limited capacity to repair. Understanding the mechanism of this limitation might clarify the mechanism of the AKI‐to‐CKD continuum. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Prevalence of renal dysfunction in patients with cirrhosis according to ADQI-IAC working party proposal

Background/Aims

A revised classification system for renal dysfunction in patients with cirrhosis was proposed by the Acute Dialysis Quality Initiative and the International Ascites Club Working Group in 2011. The aim of this study was to determine the prevalence of renal dysfunction according to the criteria in this proposal.

Methods

The medical records of cirrhotic patients who were admitted to Konkuk University Hospital between 2006 and 2010 were reviewed retrospectively. The data obtained at first admission were collected. Acute kidney injury (AKI) and chronic kidney disease (CKD) were defined using the proposed diagnostic criteria of kidney dysfunction in cirrhosis.

Results

Six hundred and forty-three patients were admitted, of whom 190 (29.5%), 273 (42.5%), and 180 (28.0%) were Child-Pugh class A, B, and C, respectively. Eighty-three patients (12.9%) were diagnosed with AKI, the most common cause for which was dehydration (30 patients). Three patients had hepatorenal syndrome type 1 and 26 patients had prerenal-type AKI caused by volume deficiency after variceal bleeding. In addition, 22 patients (3.4%) were diagnosed with CKD, 1 patient with hepatorenal syndrome type 2, and 3 patients (0.5%) with AKI on CKD.

Conclusions

Both AKI and CKD are common among hospitalized cirrhotic patients, and often occur simultaneously (16.8%). The most common type of renal dysfunction was AKI (12.9%). Diagnosis of type 2 hepatorenal syndrome remains difficult. A prospective cohort study is warranted to evaluate the clinical course in cirrhotic patients with renal dysfunction.