斑马鱼在急性肾损伤研究中的应用进展

急性肾损伤(AKI)是临床常见的危急重症,以肾功能的突发持续下降为特征。斑马鱼作为一种脊椎动物模式生物,在肾形态、生理和功能方面与人高度相似,是理想的研究肾脏疾病的动物模型,弥补了哺乳动物模型的不足。本文将简述斑马鱼肾脏的结构和功能、在AKI研究中的建模方法以及斑马鱼模型应用于AKI研究的优势。     

早期移植肾功能恢复中尿肾损伤分子1的监测价值

背景:肾损伤分子1已被证实是一种诊断急性肾缺血损伤的特异性分子并参与肾损伤修复过程,研究表明肾损伤分子1可作为诊断移植肾肾小管上皮细胞损伤的标志物,但其在早期移植肾功能恢复过程中动态表达的意义尚未见报道。目的:观察肾移植后尿肾损伤分子1含量和早期肾功能恢复的关系,为临床更好地评估及预测移植肾功能恢复能力提供依据。方法:纳入46例肾移植受者,根据早期肾功能恢复情况分为3组,肾功能迅速恢复组22例,肾功能缓慢恢复组14例,肾功能延迟恢复组10例。肾移植后2周内每天收集24h尿液标本,用ELISA方法检测尿液肾损伤分子1含量,同时检测尿液肌酐浓度和当天血清肌酐浓度。观察肾功能恢复过程中尿肾损伤分子1含量变化,并分析尿肾损伤分子1含量和血清肌酐浓度变化的关系。结果与结论:各组肾移植后2d内尿肾损伤分子1含量处于高水平状态,组间差异无显著性意义(P0.05)。肾移植2d后肾功能迅速恢复组尿肾损伤分子1含量随肌酐的下降而迅速下降;肾功能缓慢恢复组尿肾损伤分子1含量持续处于高水平状态,肌酐正常后开始下降;肾功能延迟恢复组尿肾损伤分子1含量迅速下降,但在肌酐开始下降的前一两天迅速上升并持续到肌酐恢复正常。提示尿肾损伤分子1动态检测对预测肾移植后肾功能恢复有重要意义,肾损伤分子1水平高可能预示肾功能的恢复。     

氢气饱和生理盐水抑制ROS/NF-κB通路激活、减轻重症急性胰腺炎大鼠肾损伤

<正>1研究背景和目的:氢气能够选择性地清除羟自由基(·OH)及过氧亚硝基阴离子(ONOO-),不影响机体内正常新陈代谢发生的氧化还原反应及活性氧(ROS)参与的细胞信号通路。重症急性胰腺炎时机体内大量ROS的产生及其激发的炎症级联反应,可损伤肾功能,甚至引起肾衰竭。本研究通过静脉注射氢气饱和生理盐水(HRS),观察其对重症急性胰腺炎大鼠肾损伤的保护作用,并探讨其保护机制。     

干细胞移植在急性肾损伤中的应用及研究进展

背景：干细胞移植治疗急性肾损伤是近年来研究的热点,不同来源的干细胞在治疗急性肾损伤方面都取得了很大的进展。 目的：对干细胞生物学特性、干细胞的临床研究、不同来源的干细胞治疗急性肾损伤的实验性研究、存在问题及前景进行综述。 方法：应用计算机检索中国学术期刊全文数据库(CNKI)和Pubmed 数据库2001-01/2012-02 关于干细胞移植治疗急性肾损伤的文章,检索主题词“干细胞,移植,肾脏疾病,急性肾损伤”或“stem cell,transplantation,kidney disease,acute kidney injury”。初检索到205 篇文献,据纳入标准保留41篇进行分析、综述。 结果与结论：干细胞移植是一种尝试用于急性肾损伤治疗的新方法,可以改善肾功能的损伤,加快肾脏修复。虽然仍存在不少有待解决的问题,但干细胞移植仍以其传统方法无法比拟的优势在急性肾损伤领域展现了诱人的应用前景。     

丹参酮ⅡA减轻脓毒症大鼠急性肝肾损伤

目的:研究丹参酮ⅡA对脓毒症大鼠急性肝肾损伤的治疗作用。方法:采用中线剖腹手术和盲肠结扎穿孔法将大鼠随机分为4组:假手术组(CTRL)、盲肠结扎穿孔模型组(CLP)、利奈唑胺模型组(LNZ)、丹参酮ⅡA模型组(TAN)进行后续实验。HE染色检测肝肾组织病理损伤程度,TUNEL染色检测肝肾细胞凋亡情况,全自动生化分析仪检测大鼠肾功能指标,酶标仪检测肝功能指标,ELISA试剂盒检测大鼠炎症因子水平,记录大鼠存活率。结果:丹参酮ⅡA能降低肝肾组织病理损伤程度,抑制肝肾细胞凋亡,下调肝功能指标ALT、AST水平,下调肾功能指标血清肌酐、尿素氮、蛋白尿水平,下调炎症因子IL-6、TNF-α、IL-1β水平,降低脓毒症大鼠死亡率。结论:丹参酮ⅡA具有减轻脓毒症大鼠急性肝肾损伤的作用。     

连续性血液净化在重症急性胰腺炎并急性肾损伤患者救治中的应用

目的:研究连续性血液净化(Continuous blood purification,CBP)治疗重症急性胰腺炎(Severe acutepancreatitis,SAP)并急性肾损伤(Acute kidney injury,AKI)患者的临床效果.方法:选取2018年5月至2019年12月于我院接受治疗的115例SAP合并AKI患者为本次研究对象,依照随机数表法分为对照组(n=57)和观察组(n=58).在常规治疗的基础上,对照组患者给予间歇性血液透析治疗,观察组给予CBP治疗;比较治疗一周内两组患者死亡率,比较治疗前和治疗1周后两组患者血清炎症因子[白细胞介素-6(Interleukin-6,IL-6)、降钙素原(Procalcitonin,PCT)、C反应蛋白(C-reactive protein,CRP)]、肾功能指标[尿素氮(blood urea nitrogen,BUN)、尿酸(Uric acid,UA)、尿量、血肌酐(Serum creatinine,Scr)]、生理和健康状况[急性生理与慢性健康评分(Acute Physiology and Chronic Health EvaluationⅡ,APACHEⅡ)].结果:治疗1周内观察组患者死亡率明显低于对照组(P<0.05);治疗1周后,两组患者IL-6、PCT、CRP、BUN、UA、Scr水平和APACHEⅡ评分较治疗前均明显降低,且观察组低于对照组(P<0.05);两组患者尿量较治疗前均有明显升高,且观察组高于对照组(P<0.05).结论:CBP治疗SAP合并AKI患者疗效明确,可降低患者死亡率,并改善患者肾功能,消除血清炎症因子,对改善其预后有重要意义.     

小鼠急性缺血-再灌注肾损伤模型的建立及体会

目的观察应用小鼠制备急性缺血-再灌注性肾损伤模型的效果。方法应用微型动脉夹夹闭小鼠双侧肾动脉制备急性缺血-再灌注肾损伤模型,其中两组分别于术后24h和48h后处死观察肾功能及肾脏病理变化,另一组观察其病情及存活情况14天。结果各次造模成功率均达85%以上;术后24h及48h实验组血清肌酐(Scr)和血尿素氮(BUN)水平明显升高,与对照组比较差异有统计学意义(P<0.01);实验组肾脏外观出现典型"大白肾"表现,镜下出现典型急性肾小管坏死表现,并有较多炎症细胞浸润,肾小管组织学评分与对照组比较差异有统计学意义(P均<0.01);实验组在观察期间逐渐出现典型急肾衰竭表现,至14天末,死亡率达91.7%,而对照组全部正常存活。结论应用微型动脉夹夹闭小鼠双侧肾动脉可制备稳定急性缺血-再灌注肾损伤模型,而且成功率较高。     

血液透析冶疗蜂蜇伤致急性肾功衰治疗体会

目的 观察血液透析(HD)治疗蜂蛰伤所致急性肾功能衰竭的疗效.方法 行血液透析(HD)治疗,观察血液透析治疗后肾功能(血尿素氮、肌酐)的变化情况.结果 部分患者经过短期治疗后,肾功能在早期可完全恢复正常,大部分患者均有不同程度恢复.结论 血液透析治疗可促使蜂蜇伤引起的急性肾功能衰竭患者尽早恢复肾功能,缩短病程,降低死亡率.     

急诊患者连续性肾脏替代治疗的病因及疗效分析

目的了解急诊患者连续肾脏替代治疗(CRRT)的病因并分析其疗效。方法回顾分析北京大学第一医院急诊监护室2005年5月~2011年7月接受CRRT的217例患者,其中男性120例,女性97例(男女比例1.24∶1);年龄50~77岁,中位年龄68岁。分析病因,并比较患者治疗前后的急性生理学及慢性健康状况评价Ⅱ(APACHEⅡ)评分和感染相关器官功能衰竭评分(SOFA)及生命体征、生物化学指标的变化。结果 217例急诊患者病因中内科疾病占首位,187例;其次是外科和神经系统疾病,均是15例。在住院治疗期间,63例死亡,病死率29.0%。其中急性肾损伤(AKI)患者100例,肾功能恢复38例(38.0%);死亡36例(36.0%)。治疗后的生命体征较前平稳,生物化学指标较前好转,APACHEⅡ评分下降(P0.001),SOFA变化差异无统计学意义(P0.05)。结论 CRRT患者APACHEⅡ评分下降,病死率较低,但CRRT是否降低死亡率仍有待进一步研究证实。     

急性重症胰腺炎并腹腔间室综合征患者腹腔穿刺引流前后腹内压及肾脏血流动力学的变化

目的 探讨腹腔穿刺引流前后急性重症胰腺炎并腹腔间室综合征患者腹内压及肾脏血流动力学的变化.方法 采用腹腔穿刺引流治疗急性重症胰腺炎并腹腔间隔室综合征患者15例,并监测治疗前后腹内压及肾动脉、弓形动脉、段动脉的血液流速及阻力指数的变化.结果 急性重症胰腺炎并患者腹腔间室综合腹腔穿刺引流后,腹内压下降,肾动脉、弓形动脉、段动脉,血液流速增加,阻力指数下降,肾功能好转.差异有显著性.结论 急性重症胰腺炎并腹腔间室综合征患者早期采用腹腔穿刺引流治疗可有效地降低腹腔内压,提高肾动脉、弓形动脉、段动脉,血液流速,降低阻力指数,改善肾功能.     

Tumour necrosis factor‐α plus interleukin‐10 low producer phenotype predicts acute kidney injury and death in intensive care unit patients

Genetic polymorphism studies of cytokines may provide an insight into the understanding of acute kidney injury (AKI) and death in intensive care unit (ICU) patients. The aim of this study was to investigate whether the genetic polymorphisms of −308 G < A tumour necrosis factor (TNF)-α, −174 G > C interleukin (IL)-6 and −1082 G > A IL-10 may predispose ICU patients to the development of AKI and/or death. In a prospective nested case–control study, 303 ICU patients and 244 healthy individuals were evaluated. The study group included ICU patients who developed AKI (n = 139) and 164 ICU patients without AKI. The GG genotype of TNF-α (low producer phenotype) was significantly lower in the with AKI than without AKI groups and healthy individuals (55 versus 62 versus 73%, respectively; P = 0·01). When genotypes were stratified into four categories of TNF-α/IL-10 combinations, it was observed that low TNF-α plus low IL-10 producer phenotypes were more prevalent in patients with AKI, renal replacement therapy and death (P < 0·05). In logistic regression analysis, low TNF-α producer plus low IL-10 producer phenotypes remained as independent risk factors for AKI and/or death [odds ratio (OR) = 2·37, 95% confidence interval (CI): 1·16–4·84; P = 0·02] and for renal replacement therapy (RRT) and/or death (OR = 3·82, 95% CI: 1·19–12·23; P = 0·02). In this study, the combination of low TNF-α plus low IL-10 producer phenotypes was an independent risk factor to AKI and/or death and RRT and/or death in critically ill patients. Our results should be validated in a larger prospective study with long-term follow-up to emphasize the combination of these genotypes as potential risk factors to AKI in critically ill patients.     

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.     

Advances in understanding ischemic acute kidney injury

Acute kidney injury (AKI) is independently associated with increased morbidity and mortality. Ischemia is the leading cause of AKI, and short of supportive measures, no currently available therapy can effectively treat or prevent ischemic AKI. This paper discusses recent developments in the understanding of ischemic AKI pathophysiology, the emerging relationship between ischemic AKI and development of progressive chronic kidney disease, and promising novel therapies currently under investigation. On the basis of recent breakthroughs in understanding the pathophysiology of ischemic AKI, therapies that can treat or even prevent ischemic AKI may become a reality in the near future.     

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。     

UCP2-dependent improvement of mitochondrial dynamics protects against acute kidney injury

Acute kidney injury (AKI) is a public health concern, with high morbidity and mortality rates in hospitalized patients and because survivors have an increased risk of progression to chronic kidney disease. Mitochondrial damage is the critical driver of AKI-associated dysfunction and loss of tubular epithelial cells; however, the pathways that mediate these events are poorly defined. Here, in murine ischemia/reperfusion (I/R)-induced AKI, we determined that mitochondrial damage is associated with the level of renal uncoupling protein 2 (UCP2). In hypoxia-damaged proximal tubular cells, a disruption of mitochondrial dynamics demonstrated by mitochondrial fragmentation and disturbance between fusion and fission was clearly indicated. Ucp2-deficient mice (knockout mice) with I/R injury experienced more severe AKI and mitochondrial fragmentation than wild-type mice. Moreover, genetic or pharmacological treatment increased UCP2 expression, improved renal function, reduced tubular injury and limited mitochondrial fission. In cultured proximal tubular epithelial cells, hypoxia-induced mitochondrial fission was exacerbated in cells with UCP2 deletion, whereas an increase in UCP2 ameliorated the hypoxia-induced disturbance of the balance between mitochondrial fusion and fission. Furthermore, results following modulation of UCP2 suggested it has a role in preserving mitochondrial integrity by preventing loss of membrane potential and reducing subsequent mitophagy. Taken together, our results indicate that UCP2 is protective against AKI and suggest that enhancing UCP2 to improve mitochondrial dynamics has potential as a strategy for improving outcomes of renal injury. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Improving outcomes from acute kidney injury (AKI): Report on an initiative

Acute Kidney Injury (AKI) is a complex disorder for which currently there is no accepted definition. We describe an initiative to develop uniform standards for defining and classifying AKI and establish a forum for multidisciplinary interaction to improve care for patients with, or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a 2-day conference in Amsterdam in September 2005 to draft consensus recommendations for diagnosing and staging AKI. This report describes the proposed diagnostic and staging criteria for AKI and the formation of a multidisciplinary collaborative network.     

Iron,ferroptosis, and new insights for prevention in acute kidney injury

Acute kidney injury (AKI) is a very common condition with high morbidity and mortality, which can be seen in 5–7% of all hospitalized patients and in up to 57% of all intensive care unit admissions. Despite recent advances in clinical care, the prevalence of AKI has been shown to increase with virtually no change in mortality. AKI is a complex syndrome occurring in a variety of clinical settings. Early detection is crucial to prevent irreversible loss of renal function. The pathogenesis of AKI is highly multifactorial and complex, including vasoconstriction, reactive oxygen species formation, cell death, abnormal immune modulators and growth factors. Emerging evidence from both human and animal studies suggests that dysregulation of iron metabolism may play a potentially important role in AKI. Therefore, targeting the iron homeostasis may provide a new therapeutic intervention for AKI. New therapeutic strategies including iron chelation therapy, targeting iron metabolism related proteins and direct inhibitors of ferroptosis are imperative to improve the outcomes of patients. Taking into consideration the complexity of AKI, one intervention may not be enough for therapeutic success. Future preclinical studies in animal disease models followed by well-designed clinical trials should be conducted to extend findings from animal AKI models to humans.     

Acute Kidney Injury in Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation: Incidence,Risk Factors,and Outcomes

Acute kidney injury (AKI) is a common adverse event after hematopoietic cell transplantation (HCT). AKI is associated with early death or chronic kidney disease among transplant survivors. However, large-scale pediatric studies based on standardized criteria are lacking. We performed a retrospective analysis of 1057 pediatric patients who received allogeneic HCT to evaluate the incidence and risk factors of AKI according to AKI Network criteria within the first 100 days of HCT. We also determined the effect of AKI on patient survival. The 100-day cumulative incidences of all stages of AKI, stage 3 AKI, and AKI requiring renal replacement therapy (RRT) were 68.2%?±?1.4%, 25.0%?±?1.3%, and 7.6%?±?.8%, respectively. Overall survival at 1 year was not different between patients without AKI and those with stage 1 or 2 AKI (66.1% versus 73.4% versus 63.9%, respectively) but was significantly different between patients without AKI and patients with stage 3 AKI with or without RRT requirement (66.1% versus 47.3% versus 7.5%, respectively; P?<?.001). Age, year of transplantation, donor type, sinusoidal obstruction syndrome (SOS), and acute graft-versus-host disease (GVHD) were independent risk factors for stages 1 through 3 AKI. Age, donor, conditioning regimen, number of HCTs, SOS, and acute GVHD were independent risk factors for AKI requiring RRT. Our study revealed that AKI was a prevalent adverse event, and severe stage 3 AKI, which was associated with reduced survival, was common after pediatric allogeneic HCT. All patients receiving allogeneic HCT, especially those with multiple risk factors, require careful renal monitoring according to standardized criteria to minimize nephrotoxic insults.     

Impact of Acute Kidney Injury on Long-Term Mortality after Nonmyeloablative Hematopoietic Cell Transplantation

Acute kidney injury (AKI) occurs frequently after nonmyeloablative hematopoietic cell transplantation (HCT). The severity of AKI after nonmyeloablative HCT has association with short-term mortality. However, the long-term effect of AKI on survival after nonmyeloablative HCT is not known. We performed a retrospective analysis of patients who underwent an HLA matched nonmyeloablative HCT between 1997 and 2006. Patients were followed for a median of 36 (range: 3-99) months. AKI occurring up to day 100 was defined as a >2-fold increase in serum creatinine or requirement of dialysis. Of the 358 patients who were included in the analysis, 200 (56%) had AKI, 158 (44%) had no AKI. Overall, 158 patients (43%) died during follow-up. After controlling for potential confounders, the adjusted hazard ratio for overall mortality associated with AKI was 1.57 (95 % confidence interval [CI] 1.2-2.3; P = .0006). The adjusted hazards ratio of nonrelapse mortality (NRM) associated with AKI was 1.72 (95% CI 0.9-3.1; P = .07). AKI is an independent predictor of overall mortality after nonmyeloablative HCT. This finding reiterates the importance of identifying preventative strategies in nonmyeloablative HCT for attenuating incidence and severity of AKI.     

Relationship between Serum Uric Acid Concentration and Acute Kidney Injury after Coronary Artery Bypass Surgery

An elevated serum concentration of uric acid may be associated with an increased risk of acute kidney injury (AKI). The aim of this study was to investigate the impact of preoperative uric acid concentration on the risk of AKI after coronary artery bypass surgery (CABG). Perioperative data were evaluated from patients who underwent CABG. AKI was defined by the AKI Network criteria based on serum creatinine changes within the first 48 hr after CABG. Multivariate logistic regression was utilized to evaluate the association between preoperative uric acid and postoperative AKI. We evaluated changes in C statistic, the net reclassification improvement, and the integrated discrimination improvement to determine whether the addition of preoperative uric acid improved prediction of AKI. Of the 2,185 patients, 787 (36.0%) developed AKI. Preoperative uric acid was significantly associated with postoperative AKI (odds ratio, 1.18; 95% confidence interval, 1.10-1.26; P<0.001). Adding uric acid levels improved the C statistic and had significant impact on risk reclassification and integrated discrimination for AKI. Preoperative uric acid is related to postoperative AKI and improves the predictive ability of AKI. This finding suggests that preoperative measurement of uric acid may help stratify risks for AKI in in patients undergoing CABG.

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