Urinary neutrophil gelatinase-associated lipocalin and L-type fatty acid binding protein as diagnostic markers of early acute kidney injury after liver transplantation

Objective: We examined the value of two potential novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) and L-type fatty acid binding protein (L-FABP), in diagnosing acute kidney injury (AKI) in liver transplant recipients.

Methods: NGAL and L-FABP in urinary sample from Twenty-five patients before surgery and at 2, 4, 6, 12, 24, 48, 72 and 120 h after the anhepatic phase were tested. Standard statistics were used along with receiver-operating characteristic (ROC) analysis to evaluate the diagnostic value of selected markers.

Results: Urinary NGAL was only slightly elevated at 2 h in the non-AKI group while rose and stayed high from 2–6 h in the AKI group. However, urinary L-FABP rose transiently in both groups 2–120 h following surgery. The level of urinary NGAL presented differences at 2–6 h (p < 0.05) and urinary L-FABP at 4 h (p < 0.05) between AKI and non-AKI groups. ROC analysis showed that area under the curves (AUCs) of NGAL were 0.766, 0.773, and 0.773 at 2, 4 and 6 h respectively while 0.760 of L-FABP at 4 h.

Conclusion: Urinary NGAL rather than L-FABP appeared to be a sensitive and specific marker of AKI in liver transplant recipients.     

Mortality prediction by acute kidney injury biomarkers in comparison with serum creatinine

Abstract

Objectives: To investigate the performance of acute kidney injury (AKI) biomarkers for mortality prediction.

Materials and methods: Cutoff values of urinary L-type fatty acid-binding protein (L-FABP) and N-acetyl-β-d-glucosaminidase (NAG) for AKI diagnosis in ICU were determined in the derivation cohort. The performance of these AKI biomarkers for mortality prediction was evaluated in the validation cohort with stratification of serum-creatinine based AKI diagnosis.

Results: Mortality in the AKI patients diagnosed by serum creatinine was increased remarkably when urinary L-FABP and NAG were positive.

Conclusions: These AKI biomarkers can specifically detect high-risk patients among creatinine-base diagnosed AKI.     

Comparison of Plasma and Urine Biomarker Performance in Acute Kidney Injury

Background

New renal biomarkers measured in urine promise to increase specificity for risk stratification and early diagnosis of acute kidney injury (AKI) but concomitantly may be altered by urine concentration effects and chronic renal insufficiency. This study therefore directly compared the performance of AKI biomarkers in urine and plasma.

Methods

This single-center, prospective cohort study included 110 unselected adults undergoing cardiac surgery with cardiopulmonary bypass between 2009 and 2010. Plasma and/or urine concentrations of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid-binding protein (L-FABP), kidney injury molecule 1 (KIM1), and albumin as well as 15 additional biomarkers in plasma and urine were measured during the perioperative period. The primary outcome was AKI defined by AKIN serum creatinine criteria within 72 hours after surgery.

Results

Biomarkers in plasma showed markedly better discriminative performance for preoperative risk stratification and early postoperative (within 24h after surgery) detection of AKI than urine biomarkers. Discriminative power of urine biomarkers improved when concentrations were normalized to urinary creatinine, but urine biomarkers had still lower AUC values than plasma biomarkers. Best diagnostic performance 4h after surgery had plasma NGAL (AUC 0.83), cystatin C (0.76), MIG (0.74), and L-FAPB (0.73). Combinations of multiple biomarkers did not improve their diagnostic power. Preoperative clinical scoring systems (EuroSCORE and Cleveland Clinic Foundation Score) predicted the risk for AKI (AUC 0.76 and 0.71) and were not inferior to biomarkers. Preexisting chronic kidney disease limited the diagnostic performance of both plasma and urine biomarkers.

Conclusions

In our cohort plasma biomarkers had higher discriminative power for risk stratification and early diagnosis of AKI than urine biomarkers. For preoperative risk stratification of AKI clinical models showed similar discriminative performance to biomarkers. The discriminative performance of both plasma and urine biomarkers was reduced by preexisting chronic kidney disease.     

Netrin-1 and Semaphorin 3A Predict the Development of Acute Kidney Injury in Liver Transplant Patients

Acute kidney injury (AKI) is a serious complication after liver transplantation. Currently there are no validated biomarkers available for early diagnosis of AKI. The current study was carried out to determine the usefulness of the recently identified biomarkers netrin-1 and semaphorin 3A in predicting AKI in liver transplant patients. A total of 63 patients’ samples were collected and analyzed. AKI was detected at 48 hours after liver transplantation using serum creatinine as a marker. In contrast, urine netrin-1 (897.8±112.4 pg/mg creatinine), semaphorin 3A (847.9±93.3 pg/mg creatinine) and NGAL (2172.2±378.1 ng/mg creatinine) levels were increased significantly and peaked at 2 hours after liver transplantation but were no longer significantly elevated at 6 hours after transplantation. The predictive power of netrin-1, as demonstrated by the area under the receiver-operating characteristic curve for diagnosis of AKI at 2, 6, and 24 hours after liver transplantation was 0.66, 0.57 and 0.59, respectively. The area under the curve for diagnosis of AKI was 0.63 and 0.65 for semaphorin 3A and NGAL at 2 hr respectively. Combined analysis of two or more biomarkers for simultaneous occurrence in urine did not improve the AUC for the prediction of AKI whereas the AUC was improved significantly (0.732) only when at least 1 of the 3 biomarkers in urine was positive for predicting AKI. Adjusting for BMI, all three biomarkers at 2 hours remained independent predictors of AKI with an odds ratio of 1.003 (95% confidence interval: 1.000 to 1.006; P = 0.0364). These studies demonstrate that semaphorin 3A and netrin-1 can be useful early diagnostic biomarkers of AKI after liver transplantation.     

NGAL、KIM-1和PCT在脓毒症AKI中的标志物作用

探讨NGAL与KIM-1联合检测和PCT在重症监护病房重症患者中急性肾损伤(AKI)发生中的作用。选取2018年1月至2019年6月我院101例重症患者,其中脓毒症AKI组61例,非AKI组40例,通过分析NGAL、KIM-1和PCT在2组患者中表达水平变化情况,结合与ACR指标对比分析,评价NGAL、KIM-1和PCT在脓毒症急性肾损伤早期诊断中的价值。结果显示,所有脓毒症AKI患者均检测出明显更高的尿NGAL生物标志物水平(67.32μg/g Cr)。尿KIM-1和尿NGAL水平升高与患者ACR升高均呈正相关(p<0.001),而在脓毒症AKI患者中PCT和ACR之间观察到显著的负相关(r_s=-0.102 5, p=0.307)。通过Kruskal-Wallis检验发现,NGAL和KIM-1值显示出与脓毒症严重程度具有显著统计学意义,且直接成比例的关系(p≤0.01)。进一步检查NGAL、KIM-1和PCT标志物与病情发展的相关性表明,PCT值似乎与临床结果没有很强的相关性。尿KIM-1联合NGAL在早期检测脓毒症AKI中具有较大的预测价值;PCT是有希望的脓毒症标志物之一,但不足以提供可靠诊断依据,在肾功能下降的患者中通过PCT进行脓毒症的临床诊断需要更加谨慎。     

Combined Biomarker Analysis for Risk of Acute Kidney Injury in Patients with ST-Segment Elevation Myocardial Infarction

Background

Acute kidney injury (AKI) complicating ST-segment elevation myocardial infarction (STEMI) increases subsequent morbidity and mortality. We combined the biomarkers of heart failure (HF; B-type natriuretic peptide [BNP] and soluble ST2 [sST2]) and renal injury (NGAL [neutrophil gelatinase-associated lipocalin] and cystatin C) in predicting the development of AKI in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).

Methods and Results

From March 2010 to September 2013, 189 STEMI patients were sequentially enrolled and serum samples were collected at presentation for BNP, sST2, NGAL and cystatin C analysis. 37 patients (19.6%) developed AKI of varying severity within 48 hours of presentation. Univariate analysis showed age, Killip class ≥2, hypertension, white blood cell counts, hemoglobin, estimated glomerular filtration rate, blood urea nitrogen, creatinine, and all the four biomarkers were predictive of AKI. Serum levels of the biomarkers were correlated with risk of AKI and the Acute Kidney Injury Network (AKIN) stage and all significantly discriminated AKI (area under the receiver operating characteristic [ROC] curve: BNP: 0.86, sST2: 0.74, NGAL: 0.75, cystatin C: 0.73; all P < 0.05). Elevation of ≥2 of the biomarkers higher than the cutoff values derived from the ROC analysis improved AKI risk stratification, regardless of the creatine level (creatinine < 1.24 mg/dL: odds ratio [OR] 11.25, 95% confidence interval [CI] 1.63-77.92, P = 0.014; creatinine ≥ 1.24: OR 15.0, 95% CI 1.23-183.6, P = 0.034).

Conclusions

In this study of STEMI patients undergoing primary PCI, the biomarkers of heart failure (BNP and sST2) and renal injury (NGAL and cystatin C) at presentation were predictive of AKI. High serum levels of the biomarkers were associated with an elevated risk and more advanced stage of AKI. Regardless of the creatinine level, elevation of ≥2 of the biomarkers higher than the cutoff values indicated a further rise in AKI risk. Combined biomarker approach may assist in risk stratification of AKI in patients with STEMI.     

急性肾损伤患者血清胱抑素-C及尿NGAL 水平的变化及其临床意义

目的:观察急性肾损伤(Acute kidney injury,AKI)患者血清胱抑素-C(Cystatin-C,CysC)及尿中性粒细胞明胶酶相关脂质运载蛋白(Neutrophil gelatinase-associated lipocalin,NGAL)水平的变化及其临床意义。方法:选择60例AKI患者为实验组,50例正常健康人作为对照组,应用酶联免疫吸附法测定两组人群血清胱抑素-C和尿NGAL水平。结果:实验组与对照组相比血清胱抑素-C和尿NGAL水平显著升高,差异有统计学意义(P<0.05)。实验组尿NGAL检出率高于血清胱抑素-C、血肌酐,差异有统计学意义(P<0.05)。结论:急性肾损伤患者血清胱抑素-C和尿NGAL均升高,其中尿NGAL是反映AKI较敏感的生物学标志物,值得临床进一步研究。     

Urine/Plasma Neutrophil Gelatinase Associated Lipocalin Ratio Is a Sensitive and Specific Marker of Subclinical Acute Kidney Injury in Mice

Background

Detection of acute kidney injury (AKI) is still a challenge if conventional markers of kidney function are within reference range. We studied the sensitivity and specificity of NGAL as an AKI marker at different degrees of renal ischemia.

Methods

Male C57BL/6J mice were subjected to 10-, 20- or 30-min unilateral renal ischemia, to control operation or no operation, and AKI was evaluated 1 day later by histology, immunohistochemistry, BUN, creatinine, NGAL (plasma and urine) and renal NGAL mRNA expression.

Results

A short (10-min) ischemia did not alter BUN or kidney histology, but elevated plasma and urinary NGAL level and renal NGAL mRNA expression although to a much smaller extent than longer ischemia. Surprisingly, control operation elevated plasma NGAL and renal NGAL mRNA expression to a similar extent as 10-min ischemia. Further, the ratio of urine to plasma NGAL was the best parameter to differentiate a 10-min ischemic injury from control operation, while it was similar in the non and control-operated groups.

Conclusions

These results suggest that urinary NGAL excretion and especially ratio of urine to plasma NGAL are sensitive and specific markers of subclinical acute kidney injury in mice.     

先天性心脏病患儿术后急性肾损伤的影响因素及尿NGAL、KIM-1的诊断价值分析

摘要 目的：探讨影响先天性心脏病患儿术后急性肾损伤（AKI）的影响因素及尿中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、肾损伤分子1（KIM-1）的诊断价值。方法：选择2018年1月至2019年12月我院心胸外科收治的60例先天性心脏病术后并发AKI患儿（AKI组）和同期收治的172例先天性心脏病术后未发生AKI患儿（NAKI组）作为研究对象。收集患儿临床基线资料,检测尿NGAL、KIM-1水平,采用Logistic回归分析先天性心脏病患儿术后发生AKI的影响因素,受试者工作特征曲线（ROC）分析尿NGAL、KIM-1诊断先天性心脏病患儿术后发生AKI的价值。结果：AKI组年龄、体重低于NAKI组（P＜0.05）,手术时间、心肺转流（CPB）时间、主动脉阻断（ACT）时间、机械通气时间、重症监护室（ICU）住院时间长于NAKI组（P＜0.05）,术后平均动脉压（MAP）、尿素氮（BUN）、血肌酐（Scr）、NGAL、KIM-1高于NAKI组（P＜0.05）。Logistic回归分析结果显示低龄、低体重、CPB时间长、高NGAL、KIM-1水平是先天性心脏病患儿术后发生AKI的危险因素（P＜0.05）。ROC分析显示尿NGAL、KIM-1诊断先天性心脏病患儿术后发生AKI的灵敏度分别为81.67%,83.33%,特异度分别为84.30%,87.79%。结论：低龄、低体重、CPB时间长、高NGAL、KIM-1水平是先天性心脏病患儿术后发生AKI的危险因素,尿NGAL、KIM-1诊断先天性心脏病术后AKI具有较高价值。     

建立NGAL诊断阈值有利于临床判断和发现急性肾功能损伤

为探讨中性粒细胞相关载脂蛋白(neutrophil gelatinase-associated lipocalin, NGAL)检测在肝胆疾病患者继发急性肾功能损伤(acute kidney injury, AKI)中的诊断性能,本研究回顾性收集了476例肝胆疾病患者与225例健康受试者作为实验组,根据血清中性粒细胞相关载脂蛋白(NGAL)、血清肌酐(serum creatinine,s Cr)、尿素(Urea)、半胱氨酸蛋白酶抑制剂C (cystatin C, CysC)、估算肾小球滤过率(estimating glomerular filtration rate, eGFR)水平和尿量,分为急性肾功能损伤(AKI)组和高风险(high-risk, HR)组、低风险(low-risk,LR)组和对照(health control, HC)组,进而建立上述血清指标在急性肾功能损伤(AKI)诊断性能最大时的判断界值;随后,选取145例肝胆疾病患者作为验证组,以评估各观察指标对肝胆疾病继发急性肾功能损伤(AKI)的诊断性能。结果表明:本实验组中各亚组间所观察指标之血清水平均有统计学差异(p<0.05)。中性粒细胞相关载脂蛋白(NGAL)诊断性能最大时的判断界值为205.2μg/L。验证组患者各指标阳性检出率,在低风险(LR)亚组中中性粒细胞相关载脂蛋白(NGAL)均高于其它指标(p<0.05),但在高风险(HR)亚组中中性粒细胞相关载脂蛋白(NGAL)仅高于血清肌酐(sCr)(p<0.05),而与半胱氨酸蛋白酶抑制剂C (CysC)和估算肾小球滤过率(eGFR)无统计学差异(p>0.05);再经分层风险分析各指标预测高风险(HR)亚组患者急性肾功能损伤(AKI)发生的能力,中性粒细胞相关载脂蛋白(NGAL)的优势比(OR=21.0 (2.3, 192.8)),是半胱氨酸蛋白酶抑制剂C(CysC)或估算肾小球滤过率(eGFR)(OR (95%CI)=3.3 (0.7, 15.3))的6.4倍。本研究初步结论表明,肝胆疾病患者诊断急性肾功能损伤(AKI)时应考虑中性粒细胞相关载脂蛋白(NGAL)肝脏合成代谢的作用。因此实验室应建立适宜的中性粒细胞相关载脂蛋白(NGAL)诊断阈值以有利于临床准确判断及早期发现急性肾功能损伤(AKI)。     

Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass

The purpose of this study was to compare the performance of six candidate urinary biomarkers, kidney injury molecule (KIM)-1, N-acetyl-β-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, cystatin C and α-1 microglobulin, measured 2?h following cardiopulmonary bypass (CPB) for the early detection of acute kidney injury (AKI) in a prospective cohort of patients undergoing cardiac surgery. A total of 103 subjects were enrolled; AKI developed in 13%. Urinary KIM-1 achieved the highest area under-the-receiver-operator-characteristic curve (AUC 0.78, 95% confidence interval 0.64–0.91), followed by IL-18 and NAG. Only urinary KIM-1 remained independently associated with AKI after adjustment for a preoperative AKI prediction score (Cleveland Clinic Foundation score; p?=?0.02), or CPB perfusion time (p?=?0.006). In this small pilot cohort, KIM-1 performed best as an early biomarker for AKI. Larger studies are needed to explore further the role of biomarkers for early detection of AKI following cardiac surgery.     

联合检测血清NGAL、KIM-1和SCr可有效提高慢性肾病分期诊断

为了探讨中性粒细胞明胶酶相关脂质运载蛋白(neutrophil gelatinase-associated lipocalin, NGAL)和肾损伤分子-1 (kidney injury molecule-1, KIM-1)以及血肌酐(serum creatinine, SCr)联合检测对慢性肾病(chronic kidney disease, CKD)的早期诊断价值,本研究收集260例肾病患者和85例健康体检者,检测其血清NGAL、KIM-1和SCr水平。依据肾功能分级标准,CKD患者分为CKD 1期(53例),CKD 2期(68例),CKD 3期(71例),CKD 4期(46例)和CKD 5期(22例),并分析以上指标在各组间的含量差异,及其联合测定对CKD早期的敏感性。与健康对照组相比较,CKD 1期、CKD 2期、3期、4期和5期患者的NGAL、KIM-1水平均明显升高(p<0.001)。血清SCr含量在CKD 3期、4期和5期组较健康对照组显著增加(p<0.001)。以上3项指标均随着CKD严重程度增加而升高。各组指标阳性率分析显示,3项联合检测阳性率高于单项检测阳性率。ROC曲线分析NGAL、KIM-1、SCr对CKD诊断的AUC值F分别是为0.824、0.805、0.856。相关性分析结果显示,GFR和NGAL、KIM-1、SCr相关系数分别是r=-0.784、-0.756、-0.728 (p<0.05)。NGAL与KIM-1、SCr的相关系数分别是r=0.932、0.764 (p<0.05);KIM-1与SCr的相关系数r分别是0.791 (p<0.05)。本研究初步得出结论:血清NGAL、Kim-1可作为CKD早期诊断的重要指标,联合检测血清NGAL、Kim-1、SCr可有效提高CKD早期肾损伤诊断的敏感度,对CKD的分期诊断和治疗具有极其重要的临床价值。     

Urinary Neutrophil Gelatinase-Associated Lipocalin: A Useful Biomarker for Tacrolimus-Induced Acute Kidney Injury in Liver Transplant Patients

Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication of liver transplantation. For early detection of AKI, various urinary biomarkers such as monocyte chemotactic protein-1, liver-type fatty acid-binding protein, interleukin-18, osteopontin, cystatin C, clusterin and neutrophil gelatinase-associated lipocalin (NGAL) have been identified. Here, we attempt to identify urinary biomarkers for the early detection of tacrolimus-induced AKI in liver transplant patients. Urine samples were collected from 31 patients after living-donor liver transplantation (LDLT). Twenty recipients developed tacrolimus-induced AKI. After the initiation of tacrolimus therapy, urine samples were collected on postoperative days 7, 14, and 21. In patients who experienced AKI during postoperative day 21, additional spot urine samples were collected on postoperative days 28, 35, 42, 49, and 58. The 8 healthy volunteers, whose renal and liver functions were normal, were asked to collect their blood and spot urine samples. The urinary levels of NGAL, monocyte chemotactic protein-1 and liver-type fatty acid-binding protein were significantly higher in patients with AKI than in those without, while those of interleukin-18, osteopontin, cystatin C and clusterin did not differ between the 2 groups. The area under the receiver operating characteristics curve of urinary NGAL was 0.876 (95% confidence interval, 0.800–0.951; P<0.0001), which was better than those of the other six urinary biomarkers. In addition, the urinary levels of NGAL at postoperative day 1 (p = 0.0446) and day 7 (p = 0.0006) can be a good predictive marker for tacrolimus-induced AKI within next 6 days, respectively. In conclusion, urinary NGAL is a sensitive biomarker for tacrolimus-induced AKI, and may help predict renal event caused by tacrolimus therapy in liver transplant patients.     

Will urinary biomarkers provide a breakthrough in diagnosing cardiac surgery-associated AKI? – A systematic review

Abstract

Introduction: Acute kidney injury following cardiac surgery is a dreaded complication contributing to early mortality. Diagnosing AKI using serum creatinine usually results in a delay. To combat this, certain kidney damage specific biomarkers were investigated to identify if they can serve as early predictors of cardiac surgery-associated AKI (CSA-AKI). This study systematically reviews three such biomarkers; NGAL, tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP7) to identify if they can serve as early predictors of CSA-AKI.

Methods: Systematic search was carried out on literature reporting the diagnostic ability of the three biomarkers from databases in accordance with PRISMA guidelines.

Results: We found 43 articles reporting urinary-NGAL levels (n?=?34 in adults, n?=?9 in children) and 10 studies reporting TIMP-2 and IGFBP7 levels among adults. Interestingly, NGAL showed high diagnostic value in predicting AKI in children (seven among nine studies with AUROC?>?0.8). The cell cycle arrest biomarkers, namely TIMP-2 and IGFBP7, showed high diagnostic value in predicting AKI in adults (five among ten studies with AUROC?>?0.8).

Conclusion: In predicting CSA-AKI; the diagnostic value of NGAL is high in the paediatric population while the diagnostic value of TIMP-2 and IGFBP7 is high in adults.     

Semaphorin 3A Is a New Early Diagnostic Biomarker of Experimental and Pediatric Acute Kidney Injury

Background

Semaphorin 3A is a secreted protein that regulates cell motility and attachment in axon guidance, vascular growth, immune cell regulation and tumor progression. However, nothing is known about its role in kidney pathophysiology. Here, we determined whether semaphorin3A is induced after acute kidney injury (AKI) and whether urinary semaphorin 3A can predict AKI in humans undergoing cardiopulmonary bypass (CPB).

Methods and Principal Findings

In animals, semaphorin 3A is localized in distal tubules of the kidney and excretion increased within 3 hr after reperfusion of the kidney whereas serum creatinine was significantly raised at 24 hr. In humans, using serum creatinine, AKI was detected on average only 48 hours after CPB. In contrast, urine semaphorin increased at 2 hours after CPB, peaked at 6 hours (2596±591 pg/mg creatinine), and was no longer significantly elevated 12 hours after CPB. The predictive power of semaphorin 3A as demonstrated by area under the receiver-operating characteristic curve for diagnosis of AKI at 2, 6, and 12 hours after CPB was 0.88, 0.81, and 0.74, respectively. The 2-hour urine semaphorin measurement strongly correlated with duration and severity of AKI, as well as length of hospital stay. Adjusting for CPB time and gender, the 2-hour semaphorin remained an independent predictor of AKI, with an odds ratio of 2.19.

Conclusion

Our results suggest that semaphorin 3A is an early, predictive biomarker in experimental and pediatric AKI, and may allow for the reliable early diagnosis and prognosis of AKI after CPB, much before the rise in serum creatinine.     

Update on biomarkers of acute kidney injury: moving closer to clinical impact?

Acute kidney injury (AKI) represents a common disorder in hospitalized patients, and its incidence is rising at an alarming rate. Despite significant improvements in critical care and renal replacement therapies (RRT), the outcome of critically ill patients with AKI necessitating RRT remains unacceptably dismal. In current clinical practice, the diagnosis and severity classification of AKI is based on a rise in serum creatinine levels, which may occur 2-3 days after the initiating renal insult and delay potentially effective therapies that are limited to the early stage. The emergence of numerous renal tubular damage-specific biomarkers offers an opportunity to diagnose AKI at an early timepoint, to facilitate differential diagnosis of structural and functional AKI, and to predict the outcome of established AKI. The purposes of this review are to summarize and to discuss the performance of these novel AKI biomarkers in various clinical settings. The most promising AKI biomarkers include plasma and urinary neutrophil gelatinase-associated lipocalin (NGAL), urinary interleukin (IL)-18, urinary liver-type fatty acid binding protein (L-FABP), urinary cystatin C, and urinary kidney injury molecule (KIM)-1. However, enthusiasm about their usefulness in the emergency department seems unwarranted at present. There is little doubt that urinary biomarkers of nephron damage may enable prospective diagnostic and prognostic stratification in the emergency department. However, comparison of the areas under the receiver-operating characteristic curves of these biomarkers with clinical and/or routine biochemical outcome parameters reveals that none of these biomarkers has a clear advantage beyond the traditional approach in clinical decision making in patients with AKI. The performance of various biomarkers for predicting AKI in patients with sepsis or with acute-on-chronic kidney disease is poor. The inability of biomarkers to improve classification of 'unclassifiable' (structural or functional) AKI, in which accurate differential diagnosis of pre-renal versus intrinsic renal AKI has the most value, illustrates another problem. Future research is necessary to clarify whether serial measurements of a specific biomarker or the use of a panel of biomarkers may be more useful in critically ill patients at risk of AKI. Whether or not the use of AKI biomarkers revolutionizes critical care medicine by early diagnosis of severe AKI and individualizes the management of AKI patients remains to be shown. Currently, the place of biomarkers in this decision-making process is still uncertain. Indiscriminate use of various biomarkers may distract clinicians from adequate clinical evaluation, may result in worse instead of better patient outcomes, and may waste money. Future large randomized studies are necessary to demonstrate the association between biomarker levels and clinical outcomes, such as dialysis, clinical events, or death. It needs to be shown whether assignment to earlier treatment for AKI on the basis of generally accepted biomarker cut-off levels results in a reduction in mortality and an improvement in recovery of renal function.     

Analysis of a Urinary Biomarker Panel for Clinical Outcomes Assessment in Cirrhosis

Background

Biomarkers are potentially useful in assessment of outcomes in patients with cirrhosis, but information is very limited. Given the large number of biomarkers, adequate choice of which biomarker(s) to investigate first is important.

Aim

Analysis of potential usefulness of a panel of urinary biomarkers in outcome assessment in cirrhosis.

Patients and Methods

Fifty-five patients with acute decompensation of cirrhosis were studied: 39 had Acute Kidney Injury (AKI) (Prerenal 12, type-1 HRS (hepatorenal syndrome) 15 and Acute Tubular Necrosis (ATN) 12) and 16 acute decompensation without AKI. Thirty-four patients had Acute-on-chronic liver failure (ACLF). A panel of 12 urinary biomarkers was assessed, using a multiplex assay, for their relationship with ATN, ACLF and mortality.

Results

Biomarker with best accuracy for ATN diagnosis was NGAL (neutrophil-gelatinase associated lipocalin): 36 [26-125], 104 [58-208] and 1807 [494-3,716] μg/g creatinine in Prerenal-AKI, type-1 HRS and ATN, respectively; p<0.0001 (AUROC 0.957). Other attractive biomarkers for ATN diagnosis were IL-18, albumin, trefoil-factor-3 (TFF-3) and glutathione-S-transferase-π (GST-π) Biomarkers with less accuracy for ATN AUCROC<0.8 were β2-microglobulin, calbindin, cystatin-C, clusterin and KIM-1 (kidney injury molecule-1). For ACLF, the biomarker with the best accuracy was NGAL (ACLF vs. No-ACLF: 165 [67-676] and 32 [19-40] μg/g creatinine; respectively; p<0.0001; AUROC 0.878). Interestingly, other biomarkers with high accuracy for ACLF were osteopontin, albumin, and TFF-3. Biomarkers with best accuracy for prognosis were those associated with ACLF.

Conclusions

A number of biomarkers appear promising for differential diagnosis between ATN and other types of AKI. The most interesting biomarkers for ACLF and prognosis are NGAL, osteopontin, albumin, and TFF-3. These results support the role of major inflammatory reaction in the pathogenesis of ACLF.     

Acute kidney injury biomarkers for patients in a coronary care unit: a prospective cohort study

Background

Renal dysfunction is an established predictor of all-cause mortality in intensive care units. This study analyzed the outcomes of coronary care unit (CCU) patients and evaluated several biomarkers of acute kidney injury (AKI), including neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and cystatin C (CysC) on the first day of CCU admission.

Methodology/Principal Findings

Serum and urinary samples collected from 150 patients in the coronary care unit of a tertiary care university hospital between September 2009 and August 2010 were tested for NGAL, IL-18 and CysC. Prospective demographic, clinical and laboratory data were evaluated as predictors of survival in this patient group. The most common cause of CCU admission was acute myocardial infarction (80%). According to Acute Kidney Injury Network criteria, 28.7% (43/150) of CCU patients had AKI of varying severity. Cumulative survival rates at 6-month follow-up following hospital discharge differed significantly (p<0.05) between patients with AKI versus those without AKI. For predicting AKI, serum CysC displayed an excellent areas under the receiver operating characteristic curve (AUROC) (0.895±0.031, p<0.001). The overall 180-day survival rate was 88.7% (133/150). Multiple Cox logistic regression hazard analysis revealed that urinary NGAL, serum IL-18, Acute Physiology, Age and Chronic Health Evaluation II (APACHE II) and sodium on CCU admission day one were independent risk factors for 6-month mortality. In terms of 6-month mortality, urinary NGAL had the best discriminatory power, the best Youden index, and the highest overall correctness of prediction.

Conclusions

Our data showed that serum CysC has the best discriminative power for predicting AKI in CCU patients. However, urinary NGAL and serum IL-18 are associated with short-term mortality in these critically ill patients.     

Association between urinary indicators of renal dysfunction and metal concentrations in workers chronically co-exposed to cadmium,zinc and lead

The study was carried out in 31 workers co-exposed to cadmium, lead and zinc fumes and dusts in a zinc ore refinery. Urinary cadmium, lead, zinc, β₂-M levels and NAG activities were determined to evaluate the possible dose-effect relationship between these parameters. A correlation was found between urinary cadmium, lead and zinc concentrations, and urinary β₂-M levels and NAG activities of the exposed group. A statistically significant increase was also observed for urinary NAG activity in exposed workers who had urinary cadmium concentrations > 2 μg g^?1 creatinine. However, in the same exposed group, the increment of β₂-M was not statistically significant. In conclusion, the present study thus confirms the earlier observations and may suggest the notion that the urinary NAG seems to be a more sensitive indicator than urinary β₂-M level in early stages of renal injury of moderately cadmium co-exposure with lead and zinc even at urinary cadmium concentration as low as 2 μg g^?1 creatinine. When the earlier studies on the irreversibility of cadmium-induced tubular dysfunction and the present results were taken into consideration, the present health-based biological limit proposed by the WHO (5 μg g^?1 creatinine) seems to be high for the occupational exposure to cadmium.     

Association of plasma neutrophil gelatinase-associated lipocalin with acute kidney injury and clinical outcome in cardiac arrest survivors depends on the time of measurement

Purpose: The optimal timing for measurement of neutrophil gelatinase-associated lipocalin (NGAL) level to predict acute kidney injury (AKI) and prognosis in cardiac arrest (CA) survivors has not been elucidated. We aimed to compare the diagnostic and prognostic performance of NGAL levels after return of spontaneous circulation (ROSC) and at 48?h after CA.

Methods: We included 231 adult cardiac arrest survivors who underwent targeted temperature management between May 2013 and December 2016. The primary outcome was stage 2 and 3 AKI (high stage AKI), and the secondary outcomes were in-hospital mortality and neurologic outcome. Sixty-one (26.4%) developed high stage AKI, 50 (21.6%) died, and 152 (65.8%) had a poor neurologic outcome.

Results: NGAL level at 48?h (0.876; 95% confidence interval [CI], 0.826–0.916) had a higher area under receiver operating characteristic curve than NGAL level after ROSC (0.694; 95% CI, 0.631–0.753). Both NGAL levels were independently associated with high stage AKI. NGAL level at 48?h (1.001; 95% CI, 1.000–1.002) remained a significant predictor for in-hospital mortality, while neither of the NGAL levels were independently associated with neurologic outcome.

Conclusions: NGAL at 48?h after CA seems to be a robust predictor for high stage AKI and in-hospital mortality.