急性肾损伤的生物标志物课件.ppt
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1、急性肾损伤的生物标志物急性肾损伤的生物标志物Abstract Acute kidney injury(AKI)is common after major surgery and reportedly occurs in approximately 36%of ICU patients.It is associated with increased mortality,greater cost,and prolonged Intensive Care Unit(ICU)and hospital stay,despite attempts to develop therapies to preve
2、nt or attenuate AKI,which have had limited success.急性肾损伤(AKI)常见于大手术和约36%的ICU患者,它增加死亡率、治疗费用和延长ICU住院时间,目前虽然正努力发展预防或减轻AKI的治疗措施,但收效甚微。Abstract One major reason for this lack of success may be the result of delayed implementation due to the inability to detect AKI early.Traditional biomarkers of AKI(crea
3、tinine and urea)do not detect injury early enough.Thus,It is a priority to find reliable,early biomarkers that predict subsequent AKI.其中主要原因是缺乏早期诊断AKI的措施。传统的AKI生物标志物(肌酐和尿素氮)不能早期诊断损伤。所以,急需寻找可靠、可早期预示AKI的生物标志物。Abstract Innovative technologies such as functional genomics and proteomics have facilitated
4、detection of several promising early biomarkers of AKI,such as neutyophil gelatinase-associated lipocalin(NGAL),cystatin C(CyC),liver-type fatty acid binding protein(L-FABP),interleukin-18(IL-18),and kidney injury molecule-1(KIM-1).新技术如功能基因组学和蛋白组学已帮着发现了几种有前景的,可早期提示AKI的生物标志物,如人中性粒细胞明胶酶相关脂质运载蛋白(NGAL)、
5、半胱氨酸蛋白酶抑制剂C(CyC)、肝脏型脂肪酸结合蛋白(L-FABP)、白介素18(IL-18)和肾损伤分子1(KIM-1)。Abstract These biomarkers have many potential applications function,as safety markers to monitor toxicity and as measures of treatment effect.For example,NGAL and cystatin C have been used in a safety monitoring trial of hydroxyethylstar
6、ch therapy and to detect AKI early,during or immediately after cardiac surgery.Clinical use beyond research settings is rapidly expanding.这些生物标志物在麻醉科和ICU中有很多潜在的应用。它们可用于评估新技术和治疗在肾功能上的影响,监测肾中毒程度和治疗效果。比如,NGAL和CyC已经用于一心脏手术期间羟乙基淀粉治疗安全监测试验以及早期预测AKI。Key words Kidney failure Creatinine Urea Biological marke
7、rs Lipocalins Cystatin C Fatty acid binding protein Interleukin-18肾衰竭 肌酐 尿素氮 生物学标志物 脂质运载蛋白 半胱氨酸蛋白酶抑制剂C 脂肪酸结合蛋白 白介素18 AKI is common with major surgery and critical illness AKI is the consensus term now used to describe the continuum of the condition previously called acute renal failure.AKI as classi
8、fied by the RIFLE criteria(acronym for Risk,Injury,Failure,Loss and Endstage)has been reported to occur in approximately 36%of critically ill patients and is common after major surgery such as open heart surgery.急性肾损伤(AKI)是一个共识性名称,目前用于描述以前叫急性肾衰竭的连续性过程。AKI被报道发生于约36%重症患者和常见于如开放性心脏手术等大手术后患者,它按FIFLE标准分级
9、(首字母缩写于风险、损伤、衰竭、肾功能丧失和终末期肾病)。AKI is common with major surgery and critical illness AKI is independently associated with an increased risk of death and with prolonged length of stay.Severe cases require costly treatment,can result in prolonged kidney dysfunction,and escalate the human and financial c
10、osts of care.Therefore,it seems desirable to detect AKI as early as possible in order to develop or implement potentially protective therapy.急性肾损伤与死亡风险的增加和住院时间的延长有关。需昂贵治疗的严重病例将导致长时间肾功能紊乱,增加监护人力和成本。所以,尽早诊断AKI有助于发展或实现保护性治疗。Why therapies have been unsuccessful The capacity of N-acetyl cysteine to preve
11、nt AKI after radiocontrast has been tested with unconvincing result,and the benefits of perioperative IV sodium bicarbonate infusion in cardiac surgical patients are yet to be confirmed.the most widely accepted treatment to prevent or treat AKI(although untested in controlled trials)remains prompt f
12、luid resuscitation of circulatory volume and appropriate cardiac output and perfusion pressure.预防造影剂引发的AKI的乙酰半胱胺酸的作用被证明不确定,在心脏手术患者中围手术期的静注碳酸氢钠的益处也未被确定。目前广泛预防或治疗AKI的措施(虽然未被对照试验证明)依然是及时补充液体恢复血循环的复苏以及适度应用强心剂/血管加压素以维持充足的心输出量和灌注压。Why therapies have been unsuccessful Beyond these measures,cases unresponsi
13、ve to fluid resuscitation in the presence of hyperkalemia,metabolic acidosis or fluid overload commonly receive renal replacement therapy/dialysis to support the kidneys.除了这些措施外,高钾血症,代谢性酸中毒或液体负荷过重的病例对液体复苏无反应,此时多需接受肾脏替代治疗/透析。Why therapies have been unsuccessfulWhy therapies have been unsuccessful 至于为
14、什么没有可再生的持续性的有效的对AKI的治疗有这么几个原因。第一,急性肾损伤可由多因素诱发并可发生在疾病过程中。即使某些治疗可能对部分亚组有益,由于疾病的多样性致使特定的治疗方案不可能适用于所有类型的AKI。第二,目前对AKI的发病机制的认识仍是有限的。这将导致预防或治疗上的困难重重。Why therapies have been unsuccessfulWhy therapies have been unsuccessful 第三,介入治疗实施不及时。由于我们依赖传统生物标志物(肌酐,尿素氮,尿量)来诊断AKI才出现治疗上耽搁。这些生物标志物既不能及时提示损伤,而且多在损伤后好几小时才出现异
15、常(肌酐,尿素氮)也缺乏特异性(尿量)。Why therapies have been unsuccessful 由此,如果我们能尽早诊断AKI,那么我们能及早治疗也能更好得预防或减轻损伤。The limitations of traditional biomarkersThe limitations of traditional biomarkers 传统临床急性肾损伤生物标志物是肌酐、尿素氮和尿量。对早期诊断急性肾损伤都有严重的局限性。肌酐是骨骼肌中产生的肌酸在肝脏中转化形成。它的产生并释放入血浆有相对稳定的速率,并能从肾小球滤过。少部分肌酐分泌入尿。肌酐不能在肾小管重吸收或在肾脏代谢。如
16、果肌酐滤过功能不佳,那么血肌酐将升高,伴GFR下降。The limitations of traditional biomarkersThe limitations of traditional biomarkers 然而,血清肌酐作为急性肾损伤的标志物有这么几个局限性。第一,肌酐产生因年龄、性别、饮食、肌肉情况、药物及激烈运动差异明显。第二,肌酐分泌约占肌酐清除的10-40%,这将导致GFR的假性降低。第三,血清肌酐试验精确性可以因假象而降低。第四,肌酐出现异常时,GFR减少大都已超过50%并且需超过24小时才能测得血肌酐浓度足够升高。The limitations of tradition
17、al biomarkers 尿素氮是水溶性的、低分子量的蛋白质代谢产物。它的血浓度与GFR相反,部分因素可影响它的产生和清除,这就限制了它评估GFR的可靠性。The limitations of traditional biomarkers尿素氮的产生是多变的,它的值可因循环血量、蛋白质摄入、胃肠道出血等的改变而改变。肾脏尿素氮清除率也是变化的;40-50%滤过的尿素氮在肾小管重吸收。所以,尿素氮是不太适合评估GFR的,因为浓度升高需时间累积,不能及时反映GFR变化。The limitations of traditional biomarkers手术室和ICU病人中留置导尿的一般会常规统计尿
18、量。尿量估计可粗测肾功能或比溶质清除率能更敏感评估肾脏血流动力学变化。但是,很多AKI病人并没有出现少尿,很多手术及ICU病人出现少尿也并不一定是急性肾损伤。The limitations of traditional biomarkers最后,很多药物在手术室及ICU病人的应用(如利尿剂和血管加压素)也可作为额外的干扰因素。为了应对这些问题,目前已经发现了数个可更早期诊断急性肾损伤的生物标志物。这些标志物中包括人中性粒细胞明胶酶相关脂质运载蛋白(NGAL),半胱氨酸蛋白酶抑制剂C(CyC),肝脏型脂肪酸结合蛋白(L-FABP),并已适用于部分人群。NGAL The expression of
19、 NAGL in early,actute tubular injury was identified using functional genomics.NAGL is a measure of tubular stress(Table1);its concentration increases dramatically in response to tubular injury and precedes rises in SCr by 24 hours.NAGL normally exerts protective bacteriostatic and antioxidant effect
20、s involving iron transport and is thought to act as an iron scavenger and growth factor(table1).the proposed role of NGAL and its twin molecule,hepcidin(a“master regulator”of iron)are summarized in Figure1.NGAL 功能基因组学证明NGAL 在早期急性肾小管损伤时就已经表达。NGAL可以反映肾小管功能紊乱(如表1);它浓度的升高可靠地提示肾小管损伤,而血肌酐升高需大于24小时。NGAL通过涉
21、及铁转运而实施保护性抑菌和杀菌作用,并被认为是铁的清除剂、生长因子(如表1)。NGAL和它兄弟分子,肝杀菌肽(铁的高级调节剂)的可能功能总结在图1。NGALNGALNGAL NGAL has been intensely investigated in recent years,predominantly in adult cardiac surgery.ELISA techniques have been used to measure NGAL;however,accurate and sensitive point of care tests that reduce costs and
22、the potential for measurement error are now available(TableII-IV).NGAL近些年已被重点研究,特别在成人心脏手术患者中。ELISA技术已经用于测定NGAL。以下是一些人的研究情况。NGALNGALNGALNGAL cardiac surgery-children在一项里程碑式研究中,用血肌酐诊断AKI多在术后1-3天,而用血和尿NGAL则多在术后2小时以内。随后的多项研究进一步证明了这发现。并且血NGAL可提示AKI的持续性时间,住院时间以及死亡率。NGAL cardiac surgery-adults The findings
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