早期诊断急性肾损伤的生物学标志物研究现状

急性肾损伤(AKI)是一种常见的严重疾病.由于缺乏诊断AKI的早期生物学标志物,往往导致早期有效治疗的延误.目前对于诊断AKI新的生物学标志物的研究已发展到了临床研究阶段,最有希望成为早期诊断AKI的生物学标志物包括中性粒细胞明胶酶相关脂质运载蛋白、IL-18、肾损伤分子-1和L-脂肪酸结合蛋白.本文就近年来关于上述几种生物学标志物的研究作一综述,为应用早期诊断AKI的生物学标志物提供理论依据.     

急性肾损伤与早期诊断生物标志物

急性肾损伤（acute kidney injury,AKI）是一种临床常见的综合征。目前国内外临床上对肾损伤的评估仍然依赖于血肌酐和尿量的变化,缺乏有效的生物标志物来早期识别,导致治疗延迟,AKI病死率居高不下。寻找理想的生物标志物,实现AKI早期诊治是亟待解决的临床实际问题。儿童AKI与成人相比具有一定特殊性,已发现的AKI生物学标志物是否适用于儿童及新生儿尚需进一步验证。文章通过对颇具儿科临床应用前景的几种AKI生物标志物及其作为早期识别AKI标志物的优点和局限性进行综述,为儿童AKI的早期诊断提供方向。     

急性肾损伤的定义、诊断及治疗

近年来凼际肾脏病和急救医学界趋向于用急性肾损伤(AKI)来取代急性肾衰竭(ARF)的概念,这对于早期诊断、早期治疗和降低病死率具有更积极的意义.新的AKI诊断标准为48 h内血肌酐上升26.5 μmol/L(0.3 mg/dl)或较原先水平增高50%;和(或)尿量减少<0.5 ml/(kg·h),持续6 h以上.AKI诊断的新生物学标志物正处于研究中.AKI的治疗仍以肾脏替代治疗为主,但目前关于肾脏替代治疗的时机、模式、剂量尚存在争议.     

儿童急性肾损伤的诊断及早期标志物

近年来国际肾脏病和急救医学界应用急性肾损伤取代传统急性肾功能衰竭的概念,旨在早期诊断,以期达到早期干预、早期治疗、降低病死率的目的.单纯根据尿量及血肌酐值的变化不能早期及时诊断急性肾损伤,目前一些新的生物学标志物的出现为急性肾损伤的早期诊断和早期干预提供了可能.     

新生儿急性肾损伤研究进展

新生儿急性肾损伤(AKI)的发生率并不低,在缺氧缺血性损伤、感染、肾毒性药物的使用及泌尿道梗阻等情况下均可发生,其中我国以围生期窒息排在病因的首位.近年来由于食品安全问题形势严峻,泌尿道梗阻的发生率也在上升.对于AKI高危儿,儿童卫生保健系统应更加注重此类疾病的预防及筛查.在新生儿AKI人群中,由于血清肌酐及尿液受较多因素影响,波动较大或难以定量计算,使得明确诊断有一定困难,因此关于新生儿AKI早期标志物的研究有极大的临床意义,目前研究热点包括中性粒细胞明胶酶相关脂质运载蛋白及胱抑素C.新生儿AKI的治疗应该注重解决原发疾病如缺氧缺血等,严重病例可考虑肾脏替代治疗,但病死率仍较高,主要与原发疾病严重度及并发症的出现有关.     

认识儿童急性肾损伤

急性肾损伤（acute kidney injury,AKI）以可逆性的血肌酐和尿素氮升高以及肾脏对水、电解质调节失衡为临床特征。AKI在儿童的发病率逐年升高,住院儿童及成人AKI发病率的增加与其病死率密切相关。继续依赖血肌酐和尿量去诊断AKI导致不能早期提供有效的治疗和支持性的干预措施去阻止和缓解AKI的发生。最近10年实验研究重点在发现和验证在肾功能改变之前识别AKI及有助于鉴别诊断的新的生物标志物。     

尿L-FABP与尿NGAL联合应用在儿童心脏术后急性肾损伤早期诊断中的价值

目的探讨尿肝型脂肪酸结合蛋白(L-FABP)与尿中性粒细胞明胶酶相关脂质运载蛋白(NGAL)联合应用在儿童心脏术后急性肾损伤(AKI)早期诊断中的价值。方法以需建立体外循环(CPB)的97例先天性心脏病儿童为研究对象,收集其心脏手术前及术后不同时间点的血尿标本,分别测定血清肌酐(Scr)、尿L-FABP和尿NGAL水平,并比较AKI组(n=18)和非AKI组(n=79)患儿术后各标志物的动态变化。应用受试者工作特征(ROC)曲线及曲线下面积(AUC)评估标志物单独及其联合应用在预测术后AKI发生中的作用。结果 AKI组患儿尿L-FABP和尿NGAL水平在术后2 h、6 h均显著高于非AKI组,其浓度变化明显早于Scr的升高。尿L-FABP在术后2 h、6 h单独预测AKI发生的AUC分别为0.921和0.896;尿NGAL在术后2 h、6 h单独预测AKI发生的AUC分别为0.908和0.928。术后2 h及6 h尿L-FABP及NGAL联合应用预测术后AKI发生的AUC分别为0.942和0.929。结论尿L-FABP和尿NGAL在儿童心脏术后AKI早期即显著升高,明显早于Scr的改变,可早期预测AKI的发生,而两者联合应用可使诊断的精确性进一步提高。     

早产儿肾损伤及监测

急性肾损伤（AKI）是新生儿重症监护病房常见的并发症,不仅造成早产儿高病死率,还引起成年后多种慢性肾疾病。早产儿出生时肾脏发育不成熟,在生后特定时间窗内肾脏持续加速发育,但受孕期和产后多种因素影响,容易发生急性肾损伤。目前传统的评价肾损伤的指标为血清肌酐和尿量,但其早期敏感性和特异性问题日渐受到关注。最近多种新的生物学标志物被发现可用来早期识别急性肾损伤,本文就早产儿急性肾损伤、影响因素及肾功能评价和防治进行概述,为提高早产儿急性肾损伤早期诊治水平和远期生存质量提供参考。     

中性粒细胞明胶酶相关脂质运载蛋白与急性肾损伤

中性粒细胞明胶酶相关脂质运载蛋白（neutrophil gelatinase-associated lipocalin,NGAL）是脂质蛋白家族成员之一,首先于中性粒细胞中分离得到的一种稳定多肽。作为新型临床早期诊断急性肾损伤的标志物,NGAL不易受机体、药物及。肾外因素影响,血液和尿液中浓度升高都可以预测急性肾损伤。动态监测NGAL可以评估临床治疗手段是否有效,对急性肾损伤的救治有参考意义。     

急性肾损伤生物标记物的临床研究进展

急性肾损伤是一组以急性肾功能减退为特征的临床综合征,是危重症患者的常见并发症之一,治疗棘手,病死率高.临床上大多数使用血肌酐和尿量作为急性肾损伤的诊断标准,不能及时和准确反映肾功能变化.目前一些新的生物学标记物的出现为急性肾损伤的早期诊断和治疗提供了可能,本文就目前研究较热的几种生物学标记物作一简单综述.     

Biomarkers of acute kidney injury in neonatal encephalopathy

Acute kidney injury (AKI) is a common complication of neonatal encephalopathy (NE). The accurate diagnosis of neonatal AKI, irrespective of the cause, relies on suboptimal methods such as identification of rising serum creatinine, decreased urinary output and glomerular filtration rate. Studies of AKI biomarkers in adults and children have shown that biomarkers can improve the early diagnosis of AKI. Hypoxia–ischaemia is the proposed aetiological basis of AKI in both NE and cardiopulmonary bypass (CPB). However, there is a paucity of studies examining the role of AKI biomarkers specifically in NE. Urinary cystatin C (CysC), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18, kidney injury molecule-1, liver-type fatty acid-binding protein, serum CysC and serum NGAL all show good ability to predict early AKI in a heterogeneous critically ill neonatal population including infants post-CPB. Moreover, serum and urinary NGAL and urinary CysC are early predictors of AKI secondary to NE. These findings are promising and open up the possibility of biomarkers playing a significant role in the early diagnosis and treatment of NE-related AKI. There is an urgent need to explore the role of AKI biomarkers in infants with NE as establishing the diagnosis of AKI earlier may allow more timely intervention with potential for improving long-term outcome.     

Baseline values of candidate urine acute kidney injury biomarkers vary by gestational age in premature infants

Acute kidney injury (AKI) is common in premature infants and is associated with poor outcomes. Novel biomarkers can detect AKI promptly. Because premature infants are born with underdeveloped kidneys, baseline biomarker values may differ. We describe baseline values of urinary neutrophil gelatinase-associated lipocalin (NGAL), IL-18, kidney injury molecule-1 (KIM-1), osteopontin (OPN), beta-2 microglobulin (B2mG), and Cystatin-C (Cys-C). Next, we test the hypothesis that these biomarkers are inversely related to GA. Candidate markers were compared according to GA categories in 123 infants. Mixed linear regression models were performed to determine the independent association between demographics/interventions and baseline biomarker values. We found that urine NGAL, KIM-1, Cys-C, and B2mG decreased with increasing GA. With correction for urine creatinine (cr), these markers and OPN/cr decreased with increasing GA. IL-18 (with or without correction for urine creatinine) did not differ across GA categories. Controlling for other potential clinical and demographic confounders with regression analysis shows that NGAL/cr, OPN/cr, and B2mG/cr are independently associated with GA. We conclude that urine values of candidate AKI biomarkers are higher in the most premature infants. These findings should be considered when designing and analyzing biomarker studies in newborn with AKI.     

Comparison of Urinary Biomarkers for Early Detection of Acute Kidney Injury After Cardiopulmonary Bypass Surgery in Infants and Young Children

Acute kidney injury (AKI) is a potential complication for children with congenital heart disease (CHD) after cardiopulmonary bypass (CPB) surgery. This study was designed to investigate and compare the predictive values of urinary biomarkers for AKI after CPB surgery in infants and young children and to determine the optimal timing of testing and the cutoff value for each biomarker. The study prospectively enrolled 58 CHD children 3 years of age or younger who were undergoing CPB surgery. Urinary neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), microalbumin (MA), N-acetyl-ß-D-glucosaminidase (NAG), α1-microglobulin (α1-MG), and creatinine (UCr) were measured at baseline and at various time points after surgery. Children who experienced AKI had more complex cardiac surgical procedures as evaluated by Risk Adjustment for Congenital Heart Surgery 1 (RACHS-1), longer CPB and aortic clamping times, and worse clinical outcomes than those who did not. In the AKI group, all five urinary biomarkers increased substantially and peaked at 4 h after surgery. In contrast, in the non-AKI group, they increased slightly or had no significant changes during the first 24 h. All the biomarkers had the best predictive performances at 4 h after surgery. At this time point, NAG had the minimum area under the curve (AUC) (0.747), which was significantly lower than that of the others (AUC, 0.82–0.85; P < 0.05). The optimal cutoff value of each biomarker was 290 ng/mg UCr for NAGL, 1,477 pg/mg UCr for IL-18, 400 mg/g UCr for MA, 225 U/g UCr for NAG, and 290 mg/g UCr for α1-MG. In conclusion, urinary NGAL, IL-18, MA, and α1-MG had similar predictive performances for the early detection of AKI after CPB surgery in infants and young children.     

Urinary NGAL in premature infants

Premature infants are at unique risk for developing acute kidney injury (AKI) due to incomplete nephrogenesis, early exposure to nephrotoxic medications, and coexisting conditions such as patent ductus arteriosus (PDA) and respiratory distress syndrome (RDS). Unfortunately, laboratory testing for the diagnosis of AKI in this population is problematic because of the physiology of both the placenta and the extra-uterine premature kidney. Recent research has led to the development of promising biomarkers for the early detection of AKI in children but there are no published reports in neonates. Our goal was to determine whether urine neutrophil gelatinase-associated lipocalin (NGAL) was detectable in premature infants and to correlate levels with gestational age, birth weight (BW), or indomethacin exposure. We enrolled 20 infants in four BW groups: 500-750, 751-1000, 1001-1250, and 1251-1500 g. Urine was collected every day for the first 14 d of life. Neonates born at earlier gestational ages and lower BWs had higher urine NGAL levels (p < 0.01). We conclude that urine NGAL is easily obtained in premature infants and that it correlates significantly with both BW and gestational age. The use of urinary NGAL as a biomarker of AKI in premature infants warrants further investigation.     

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??Acute kidney injury??AKI?? is a common syndrome. Serum creatinine and urine output are the most commonly used in clinical evaluation of kidney injury??but they are poor markers for early diagnosis of AKI??which results in delayed treatment and high mortality. Research in AKI has focused on identifying biomarkers for early detection. Since AKI in children and adults is not the same??investigation is needed to explore the role of potential biomarkers for prediction of AKI in pediatriccohorts. This review serves to update the topic of promising AKI biomarkers and focuses on pediatric biomarker’s advantages and limitations to improve early detection in children.     

KIM-1及NGAL在婴幼儿复杂先心病术后早期肾功能损伤中的预测作用

目的探讨尿中肾脏损伤分子-1(Kidney injury molecule-1,KIM-1)及中性粒细胞明胶酶相关脂质运载蛋白(reutrophil gelatinase-associated lipocalin,NGAL)在复杂先心病根治术后急性肾功能损伤评估中(acute kidney injury,AKI)的敏感性及临床价值。方法回顾性分析本院2011年12月年至2014年12月收治的复杂先心病术后急性肾功能衰竭患儿临床资料,共23例,其中男性15例,女性8例,年龄4~18个月,平均年龄(8.38±1.75)个月,体重3~14kg,平均体重(5.15±3.82)kg,观察术前、术后2 h、4 h、6h内尿中NGAL、KIM-1及血肌酐、尿素氮、K~+、平均动脉压及尿量的变化。结果术后2 h尿液中NGAL开始上升,为(1.28±0.63)ng/L,术后4 h尿液中KIM-1上升,为(1.14±0.16)ng/L,与手术前比较,差异有统计学意义。经积极干预治疗后,23例患儿中,19例存活,4例因多器官功能衰竭而死亡。结论尿中KIM-1及NGAL有助于复杂先心病术后急性肾功能损伤的早期检测,可为临床治疗提供重要线索。