Neutrophil gelatinase-associated lipocalin (NGAL): a promising biomarker of contrast-induced nephropathy after computed tomography

Contrast-induced nephropathy (CIN) is a common cause of hospital-acquired acute kidney injury (AKI) and a source of significantly increased short- and long-term mortality. Studies of large cohorts have revealed that more than half of these cases are in subjects undergoing cardiac catheterization and intra-arterial coronary angiography, and nearly a third follow computed tomography (CT) scans. Neutrophil gelatinase-associated lipocalin (NGAL) represents an early predictive troponin-like biomarker for AKI. Its role in the timely diagnosis of CIN has already been examined in adults and children undergoing coronary angiography and a meta-analysis revealed a very good performance of plasma or urine NGAL in the prediction of CIN. Much of these data have been extrapolated to patients receiving intravenous (IV) contrast agent for CT scans, although major differences in patient populations, contrast volume administered and intra-procedural complications between the two settings exist. In this context, a recent prospective study by our group evaluated plasma NGAL, measured using standardized Τriage® NGAL test (Biosite Incorporated, San Diego, CA) at baseline and 6-h post-procedure, for early detection of CIN among hospitalized patients undergoing elective contrast-enhanced CT. CIN, defined as an increase in serum creatinine (SCr) of >25% or >0.5?mg/dL from baseline within 48-h post-procedure, was found in 8.51% of subjects. In contrast, significant elevation of plasma NGAL was found at 6-h post-procedure with excellent performance characteristics. This review presents the current status of NGAL in the prediction of CIN after IV contrast administration among hospitalized patients undergoing elective contrast-enhanced CT.     

Neutrophil gelatinase-associated lipocalin in patients with autosomal-dominant polycystic kidney disease

It is known that many tubular proteins are involved in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which causes 8-10% of the cases of end-stage renal disease (ESRD) worldwide. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein expressed on tubular cells of which the production is markedly increased in response to harmful stimuli such as ischemia or toxicity. In the present study, serum and urinary NGAL levels were evaluated in 26 ADPKD subjects. Both levels were significantly higher in patients than in controls (sNGAL 174 +/- 52 vs. 50 +/- 27 ng/ml, p < 0.05; uNGAL 119 +/- 42 vs. 7 +/- 6 ng/ml, p < 0.005) and a close correlation was also found between these parameters and the residual renal function (sNGAL/GFR: r = -0.8, p = 0.006; sNGAL/Creatinine: r = 0.9, p = 0.007; uNGAL/GFR: r = -0.49, p < 0.05; uNGAL/Creatinine: r = 0.84, p < 0.001). Patients were further divided into two groups according to the cystic development assessed with echotomography; subjects with higher cystic growth (HCG) presented higher sNGAL and uNGAL levels with respect to others (sNGAL: 242 +/- 89 vs. 88 +/- 34 ng/ml, p < 0.05; uNGAL: 158 +/- 45 vs. 73 +/- 27 ng/ml, p < 0.05). The strict correlation between NGAL levels and residual renal function is perfectly in accord with recent studies on patients with other ESRD-associated diseases. We can hypothesize that tubular cells produce big quantities of NGAL as a consequence of increased apoptosis following chronic damage or as a compensatory response, similar to that observed in acute stress conditions (ischemia, toxicity ...). Finally, our last finding that patients with HCG showed higher levels of NGAL suggests that this protein could be also involved in the cyst growth process, as previously reported about epithelial and tumoral expansion.     

Neutrophil gelatinase-associated lipocalin levels associated with cardiovascular disease in chronic kidney disease patients

Background

Elevated levels of neutrophil gelatinase-associated lipocalin (NGAL) have been reported in patients with cardiovascular disease (CVD), heart failure, and stroke. We assessed the relationships between serum levels of NGAL and the prevalence of CVD, and clarified the prognostic usefulness of systemic NGAL levels in hemodialysis (HD) patients.

Methods

Eighty-eight HD patients were followed up for 1 year. Logistic regression analyses were used to investigate the relationship between de novo CVD status and NGAL levels as well as other risk factors.

Results

During follow-up, CVD events occurred in 20 patients. Initial serum levels of NGAL and brain natriuretic peptide of HD patients with de novo CVD were significantly higher than those of HD patients without de novo CVD. Multivariate logistic regression analyses showed that initial serum levels of NGAL were independent risk factors for de novo CVD in HD patients. When patients were classified on the basis of NGAL quartiles, multiple logistic regression analyses demonstrated that the highest quartile of NGAL level showed an increased odds ratio for the prevalence of CVD.

Conclusion

These findings suggest that NGAL levels can be used to detect the prevalence of CVD in HD patients with or without diabetes.     

Undiagnosed renal impairment in patients with and without diabetes with normal serum creatinine undergoing percutaneous coronary intervention

HYPOTHESIS: The recent Dialysis Outcome Quality Initiative publication on the evaluation, classification and stratification of chronic kidney disease (CKD) states that individuals with a reduced glomerular filtration rate (GFR) is at greater risk for cardiovascular diseases and cardiac deaths. AIM: To determine the prevalence of kidney dysfunction in a cohort of 1390 patients with and without diabetes with normal serum creatinine undergoing percutaneous coronary intervention. METHODS: Kidney function was estimated using simplified MDRD, Cockcroft-Gault and Jeliffe formulas. RESULTS: Normal serum creatinine was observed in 93% patients. Mean estimated GFR in 1068 non-diabetic patients was significantly higher than in 322 diabetic patients (all formulas). Diabetic females had significantly lower creatinine and estimated GFR, higher high-density lipoprotein and platelet count than diabetic males. A very high prevalence of CKD up to 77% was found in studied diabetic patients. Clinically significant CKD (as defined by GFR < 60 mL/min) was found in 13.0-33.8% patients depending on the formula used to estimate GFR. CONCLUSION: The prevalence of CKD (stages 2-3) is high in diabetic patients undergoing percutaneous coronary intervention despite normal creatinine. The risk of contrast nephropathy with worse outcomes is enhanced in these patients, particularly in elderly and females. Evaluation of renal function is important in order to select the appropriate strategy to reduce the cardiovascular risk.     

血清半胱氨酸蛋白酶抑制剂C与血肌酐的匹配研究

研究发现,半胱氨酸蛋白酶抑制剂C(CysC)不易受体内、体外因素干扰[1,2];能更早期地反映出肾小球滤过率(GFR)的降低[1,2];对儿童GFR的变化反应敏感[3].因此,被认为是一种比Scr能更好反映肾小球滤过功能的理想指标.然而CysC只是近几年才应用于临床,目前尚缺乏大样本、多中心、长时间的临床验证,严重地限制了其在临床的实际应用.因此,需要建立Scr和CysC两者的平行分析,使其互为参照,为临床提供诊断信息,共同发挥各自的优势.     

Comparison of serum cystatin C and creatinine changes after cardiopulmonary bypass in patients with normal preoperative kidney function

Purpose

Serum creatinine is used ubiquitously to estimate glomerular filtration rate and to diagnose acute kidney injury after cardiac surgery. Serum cystatin C is a novel biomarker that has emerged as a possible diagnostic alternative to serum creatinine. It is unclear if the dynamic changes in serum cystatin C immediately following cardiopulmonary bypass (CPB) differ from those of serum creatinine in patients with normal preoperative kidney function.

Methods

We compared changes in serum levels of creatinine and cystatin C by measuring them serially in 19 patients undergoing CPB. Within-patient differences for serum creatinine and serum cystatin C were compared by repeated measures ANOVA.

Results

Serum creatinine and cystatin C levels showed significant correlation with each other. Both biomarkers showed a significant decrease after CPB, but their serum concentrations reverted to pre-CPB levels within 12 h. Serum levels of serum creatinine remained unchanged from baseline levels throughout 72-h post-CPB. In contrast, serum cystatin C levels rose further and became significantly higher compared to baseline within 48 h. Serum cystatin C remained significantly elevated at 48- and 72-h post-CPB.

Conclusions

Processes that determine the serum concentrations of serum creatinine and cystatin C in the post-CPB period affect the two biomarkers differently, suggesting that the two are not interchangeable as diagnostic markers of glomerular filtration rate. Future studies are needed to examine if these discrepancies are related to differences in their production rates, in their ability to detect small changes in glomerular filtration rate, or to a combination of these, and to determine the effect of such differences on the diagnostic and prognostic accuracy of the two biomarkers.     

High-dose aprotinin with gentamicin-vancomycin antibiotic prophylaxis increases blood concentrations of creatinine and cystatin C in patients undergoing coronary artery bypass grafting

Both aprotinin and gentamicin-vancomycin antibiotic prophylaxis have beenused widely in cardiac surgery to prevent bleeding and infections,respectively. As the drugs are excreted almost entirely by glomerularfiltration, we investigated their action on renal function whenadministered either separately or together. To increase consistency, wemeasured serum concentrations of creatinine and cystatin C, a new marker ofglomerular filtration rate, that many recent studies have shown to be moresensitive than serum creatinine. One hundred patients undergoing coronaryartery bypass surgery were allocated randomly to one of four groups: groupA received antibiotic prophylaxis with cefamandole and no aprotinin; groupB received cefamandole and high- dose aprotinin; group C receivedantibiotic prophylaxis with gentamicin and vancomycin, but no aprotinin;and group D received both high-dose aprotinin and gentamicin-vancomycinantibiotic prophylaxis. Data from 84 patients, for whom data collection wascomplete, were analysed. In the first week after operation, mean serumconcentrations of cystatin C and creatinine either remained constant ordecreased slowly in all groups, except for group D. In group D, bothmarkers increased gradually from postoperative day 2 onwards. The increasein cystatin C was significant on postoperative day 5 (from mean 1.02 (SD0.11) mg litre-1 before operation to 1.35 (0.32) mg litre-1; P < 0.05),reaching a peak on postoperative day 7 (1.45 (0.35) mg litre-1; P <0.05), while the increase in creatinine concentration was significant onpostoperative day 6 (from 1.05 (0.16) mg dl-1 before operation to 1.29(0.34) mg dl-1; P < 0.05). We conclude that simultaneous administrationof high-dose aprotinin and prophylactic use of gentamicin with vancomycinincreased serum concentrations of cystatin C and creatinine in the firstpostoperative week in patients undergoing cardiac surgery.     

肾移植患者血清胱抑素C与肌酐清除率相关性的研究

目的探讨肾移植患者血清胱抑素C（SCysC）浓度作为移植肾功能测定指标的可行性和临床应用价值。方法采用颗粒增强透射免疫比浊法（PETIA）分别检测39例初次肾移植患者在术前、术后1周和4周的SCysC水平,并与血清肌酐（Scr）、内生肌酐清除率（Ccr）进行比较分析。结果肾移植术前与术后,患者的SCysC与Scr、Ccr都具有很好的相关性。SCysC与Scr呈正相关（术前r=0.849;术后r=0.940）;与Ccr呈负相关（术前r=-0.857;术后r=-0.876）;按Ccr分组的统计分析结果显示：不同肾功能水平的SCysC与Ccr的相关性均较Scr与Ccr的相关性相似或更佳。当50≤Ccr〈80mL/（min.1.73m^2）时,SCysC与Ccr的相关性要明显优于Scr与Ccr的相关性（P〈0.05）。结论在肾移植患者中,SCysC浓度与Scr浓度和Ccr有较好的相关性,可成为评估移植肾功能的较理想指标。     

NGAL和Cys C对重型颅脑损伤并发急性肾损伤的早期诊断价值

目的探讨血清中性粒细胞明胶酶相关载脂蛋白（neutrophil gelatinase-associated li-pocalin,NGAL）和半胱氨酸蛋白酶抑制剂C（Cys C）对重型颅脑损伤后并发急性肾损伤（acute kidney injury,AKI）的预测价值。方法选取85例重型颅脑损伤患者（GCS≤8）,收集患者入院后即刻（〈15 min）、2、4、6、8、10、12、18、24、36、48及72 h时的血标本,根据是否发生AKI分为AKI组（39例）及非AKI组（46例）。同时以25名健康体检者作为正常对照组。采用双抗体夹心酶联免疫吸附法（ELISA）检测血清NGAL浓度;用肌氨酸氧化酶法测定SCr水平;用免疫投射比浊法测定血清Cys C水平。以各项目入院即刻检查值作为基线值。结果85例重型颅脑损伤患者中有39例发生 AKI,发生率为45.9%。AKI组SCr水平自入院36 h开始明显升高,各时间点的检测值均高于基线值和正常对照组（P〈0.01）。AKI组入院36、48及72h SCr水平明显高于无AKI组（P〈0.01）。非 AKI组各时间点的SCr水平与正常对照组比较,差异无统计学意义（P〉0.05）。AKI组血清 NGAL 水平在入院2 h时已明显高于基线值（P〈0.01）,以后各时间点呈逐渐升高趋势,均高于基线值和正常对照组（P〈0.01）。非AKI组血清NGAL水平自入院10 h时开始逐渐升高,与基线值和正常对照组比较,差异有统计学意义（P〈0.01）。AKI组各时间点NGAL水平均明显高于非AKI组（P〈0.01）。AKI组血清Cys C水平在入院8 h时已明显高于基线值（P〈0.01）,以后各时间点呈逐渐升高趋势,均高于基线值和正常对照组（P〈0.01）。非AKI组血清Cys C水平自入院12h时开始明显升高,与基线值和正常对照组比较,差异有统计学意义（P〈0.01）。结论重型颅脑损伤后2 h 血清 NGAL即可明显升高,血清Cys C 于8h开始升高,其诊断AKI的时间早于SCr。血清NGAL和Cys C可作为重型颅脑损伤后诊断 AKI的早期标志物。     

GFR estimates using cystatin C are superior to serum creatinine in adult patients with cystic fibrosis

BackgroundAccurate assessment of renal function in patients with cystic fibrosis (CF) is vital for determining the appropriate dose of medications and for early detection of renal disease. Cystatin C (CysC) is a new marker of GFR with reportedly improved accuracy and precision compared to methods incorporating serum creatinine. The purpose of this study is to evaluate the predictive performance of cystatin C in estimating GFR in adult patients with CF.MethodsIothalamate was administered to enable measurement of GFR in 38 adult patients with CF and control subjects. Creatinine clearance (C&G) and GFR estimates (cystatin C clearance [Cys C] and abbreviated modified diet in renal disease [aMDRD]) were compared using Bland–Altman and receiver operating characteristic (ROC) analysis. GFR cutoff values of 80 and 90 mL/min–1.73 m² were used in the analysis.ResultsThe measured GFR was similar in both the CF and healthy volunteers 104 (32.2) and 105 (29.9), P = 0.969 respectively. No significant difference in mean bias was noted between the predictive methods within the CF population. Cys C provided the most precise estimates of GFR in both populations. ROC curves demonstrated that CysC provided greater sensitivity and specificity compared to the aMDRD (AUC 0.93 vs. 0.54, P = 0.003) and C&G (AUC 0.93 vs. 0.56, P = 0.005) in CF at a cutoff GFR of 90 mL/min–1.73 m².ConclusionCystatin C clearance provides an improved marker of glomerular filtration rate in CF patients.     

Assessment of creatinine and cystatin C-based eGFR equations in Chinese older adults with chronic kidney disease

Introduction

Glomerular filtration rate (GFR) estimation equations using creatinine and Cystatin-C appear to be superior to those based on creatinine or Cystatin-C in older adults. We sought to compare the performances of those based on creatinine and Cystatin-C in Chinese older adults with chronic kidney disease (CKD).

Methods

A total of 368 Chinese elderly with CKD underwent the dynamic imaging with technetium-⁹⁹m diethylene-triamine-pentaacetic acid (⁹⁹mTc-DTPA), and serum creatinine and Cystatin-C were measured on the same day. The comparison of GFR equations which were creatinine and Cystatin-C-based including chronic kidney disease epidemiology collaboration (CKD-EPI) equation (CKD-EPI-Cr-Cys), Berlin Initiative Study (BIS) equation (BIS-Cr-Cys, also known as BIS-2), MA equation (MA-Cr-Cys), and FENG equation (FENG-Cr-Cys) was conducted.

Results

Four equations overestimated GFR except for BIS-2 equation in mGFR?≥?60 ml/min/1.73 m² (bias: ? 1.40, p?=?0.7) and CKD-EPI-Cr-Cys equation in mGFR?<?30 ml/min/1.73 m² (bias: ? 1.82, p?=?0.2) were unbiased. BIS-2 equation had the smallest interquartile range (IQR, ml/min/1.73 m²) from 12.73 in age?<?75 years group to 16.05 in age?≥?75 years group. BIS-2 equation achieved highest values of 79.1% in overall participants, and 80.77% in age?≥?75 years group, respectively, and CKD-EPI-Cr-Cys equation 82.26% in age?<?75 years group. Lowest values of root-mean-square error (RMSE, ml/min/1.73 m²) were seen in BIS-2 equation from 13.22 in age?<?75 years group to 16.18 in age?≥?75 years group. BIS-2 equation had the lowest misclassification rates of 41.76% in age?≥?75 years group and 34.41% in age?<?75 years group.

Conclusions

BIS-2 equation may be optimal for Chinese older adults with CKD especially in older adults?≥?75 years and with mGFR?≥?30 ml/min/1.73 m², while CKD-EPI-Cr-Cys equation could yield a better performance than BIS-2 equation, especially in those?<?75 years and mGFR?<?30 ml/min/1.73 m².

     

Nephrotoxicity of vancomycin in patients with normal serum creatinine

Sir, The reported rate of nephrotoxicity of vancomycin (VCM) hasbeen 7–16%. It can reach 35% with concurrent aminoglycosidesand is associated with serum concentration >40 µg/ml[     

尿液生物学标记物对肝移植患者术后急性肾损伤早期诊断的价值

目的 探讨尿液中乳酸脱氢酶(lactate dehydrogenase,LDH)、胱抑素C(cystatin C,Cys-C)、中性粒细胞明胶酶相关脂质运载蛋白(neutrophil gelatinase-associated lipocalin,NGAL)对于肝移植患者术后急性肾损伤(acute kindey injury,AKI)早期诊断价值.方法 收集2011年1月～2011年10月在南方医院接受同种异体肝移植术的45例终末期肝病患者术前及手术结束时的静脉血液及尿液标本,检测血清肌酐( serum creatinine,SCr)、胱抑素、LDH及总胆红素,检测尿液中LDH、胱抑素、NGAL.根据AKI网络标准中的SCr标准将患者分为AKI组和非AKI组.比较两组术前、术后尿液中LDH、Cys-C、NGAL的变化情况,并运用受试者工作曲线(receiver operating characteristic curve,ROC)评价LDH、Cys-C、NGAL的准确性.结果 45例患者中20例发生了术后AKI,两组患者的年龄、性别、术前的基本情况、术中手术情况比较差异无统计学意义.AKI组和非AKI组术后血清SCr的差异具有统计学意义[(140±54)比(81±20),P＜0.05].术后AKI组及非AKI组尿液中的LDH、Cys-C、NGAL均升高,AKI组增加明显高于非AKI组.AKI组尿液中LDH、Cys-C、NGAL高于非AKI组,且差异具有统计学意义[(6.50±2.86)比(3.21±1.63),P＜0.05]、[(1.55±0.54)比(0.86±0.31),P＜0.05]、[(107±59)比(43±11),P＜0.05].ROC下面积结果显示,尿液中的LDH、Cys-C、NGAL均显示出了较好的诊断意义,面积分别为0.853、0.833、0.880,大于0.8. 结论 LDH、Cys-C、NGAL均表现出了较好的敏感性和特异性.     

Comparison of cystatin C, creatinine and creatinine clearance vs. GFR for detection of renal failure in renal transplant patients

BACKGROUND: Serum cystatin C (Scyst) has been suggested as an alternative index of glomerular filtration rate (GFR) and could be useful in renal transplant patients. METHODS: In a 60-subject cohort (40 +/- 12 years old), we compared the simultaneous measurements of Scyst, serum creatinine (Screat), creatinine clearance (Ccreat), Cockcroft and Gault's estimated clearance (Ccg) and GFR measured using inulin clearance (Cin). Receiver operating characteristic (ROC) analysis was performed using two Cin cut-off (60 and 90 mL/min/1.73 m2). RESULTS: A significant correlation was found among Cin on one hand and 1/Scyst, Ccreat, 1/Screat and Ccg on the other hand. Best fits (sensitivity/specificity) at 90 mL/min/1.73 m2 were 1.18 mg/L (0.72/0.80) for Scyst, 1.32 mg/dL (0.67/0.90) for Screat, 77 mL/min (0.80/0.70) for Ccg and 104 mL/min (0.88/0.80) for Ccreat. The areas under the ROC curves were not significantly different. CONCLUSIONS: This study provides cut-off values for Screat and Ccg for detection of renal failure in renal transplant patients. However, the results also suggest that Scyst is not a more sensitive marker than Screat or Ccg for detecting renal failure in renal transplant patients.