Early biomarkers of acute kidney failure after heart angiography or heart surgery in patients with acute coronary syndrome or acute heart failure.

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INCLIVA, Valencia, " "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Nefrología, Hospital Clínico Universitario de Valencia, Valencia, Spain, " "etiqueta" => "c" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Unidad Coronaria, Hospital Clínico Universitario de Valencia, Valencia, " "etiqueta" => "d" "identificador" => "affd" ] 4 => array:3 [ "entidad" => "Laboratorio, Hospital Clínico Universitario de Valencia, Valencia, " "etiqueta" => "e" "identificador" => "affe" ] 5 => array:3 [ "entidad" => " Fundación Investigación Hospital Clínico Universitario de Valencia. INCLIVA, Valencia, Spain, " "etiqueta" => "f" "identificador" => "afff" ] 6 => array:3 [ "entidad" => "Nefrología, Hospital Clínico Universitario de Valencia. Universidad de Valencia, Valencia, " "etiqueta" => "g" "identificador" => "affg" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Biomarcadores precoces de fracaso renal agudo tras angiografía coronaria o cirugía cardíaca en pacientes con síndrome coronario o fallo cardíaco agudos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10988_108_23959_en_10988t1.jpg" "Alto" => 458 "Ancho" => 600 "Tamanyo" => 166694 ] ] "descripcion" => array:1 [ "en" => "Clinical and demographic characteristics of patients that underwent coronary angiography" ] ] ] "textoCompleto" => "IntroductionAcute kidney injury (AKI) is a common complication following cardiovascular surgery, with varying incidence rates evidenced in the medical literature that depend both on the definition of AKI used and the population studied, but most estimates are close to 30%.1-3 AKI prolongs the duration of hospital stays and increases the risk of mortality by three to nine times, depending on its severity.2,3 Even small increases in creatinine levels worsen the situation for these patients.4 The mechanisms that contribute to kidney injury include exogenous and endogenous toxins, metabolic factors, ischaemia and reperfusion, neurohumoral activation, inflammation, and oxidative stress.5 The diagnosis of AKI is based on the detection of increased serum creatinine levels, which is delayed and does not properly show glomerular filtration rates in acute patients.6 However, experimental studies have demonstrated that although AKI can be prevented or treated with several different therapies, it should be started immediately after the renal damage is produced.7 The ineffectiveness of these interventions in clinical trials with humans has been attributed to significant delays in diagnosing AKI. As such, it is clear that in order to be effective, the treatment of AKI must start as early as possible.The incidence of AKI following percutaneous coronary operations can be placed between 5% and 20%, according to the definition of AKI and the population studied, and constitutes a potentially serious complication.8,9 Peak serum creatinine values tend to arise within the first 5 days following the surgery, and return to baseline values within 3 weeks (although permanent damage can be caused). As in AKI following heart surgery, increased serum creatinine values are late markers of kidney damage.To try and resolve these problems, different research groups have attempted in recent years to identify new markers for the early diagnosis and stratification of the AKI risk. Despite the effort invested and the progress made, the actual usefulness of these markers has yet to be established in the different clinical contexts of AKI.10,11 The most commonly studied markers are cystatin-C, which is not a marker of kidney damage but rather glomerular filtration rate, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and liver fatty acid-binding protein (L-FABP), in serum or urine samples.The objective of this study is to evaluate the sensitivity and specificity of IL-18 in urine, NGAL in urine (uNGAL), and serum cystatin for the early detection of acute kidney injury in a population of patients with acute coronary syndrome or heart failure and undergoing heart surgery or catheterization.MATERIAL AND METHODStudy sampleOur study included 135 patients admitted between May 2008 and December 2009 to the intensive care unit of the Valencia University Clinical Hospital for acute coronary syndrome or heart failure due to coronary or valvular pathologies, and who underwent a heart angiography with or without angioplasty and/or an implanted endoprosthesis (group 1, n=89), or cardiac surgery involving revascularization or valve replacement (group 2, n=46). The exclusion criteria were: being younger than 18 years of age, pre-existing chronic kidney disease on renal replacement therapy with dialysis or transplant, and acute renal failure due to cardiogenic shock upon hospitalisation. We also excluded patients that had consecutively undergone both angiography and surgery in order to avoid confusion.All patients were monitored prospectively starting at their inclusion in the study. We monitored creatinine levels from the day prior to the procedure to six days after, and followed the clinical evolution of each patient until they were discharged from the hospital. We also took serum and urine samples 12 hours after the procedure for assessing the biomarkers. Baseline creatinine levels were established as the value measured the day before the intervention.Blood and urine samples were centrifuged for 10 minutes at 1500g. Several 0.5ml aliquots were taken from each serum and urine sample for storage at -80ºC for later analysis. We took urine samples from 20 healthy volunteers in order to obtain normal urine NGAL values.The following information was also collected from each patient: demographic variables and comorbidities, parameters of the surgical procedure, and complications during or after the catheter placement or heart surgery (Table 1 and Table 2). The endpoint used for evaluating our patients was the appearance of AKI, defined as creatinine levels increasing by 50% or more, in keeping with the RIFLE (Risk, Injury, Failure, Loss, End-stage renal disease) classification system.12 The secondary criteria were in-hospital mortality rates and duration of stays in the ICU and hospital.Measurements of biomarkersNGAL and IL-18 in urineNGAL was measured from urine samples using ELISA kits (Human NGAL ELISA, Hycult biotechnology b.v.). The urine samples were diluted at 1:20 in a dilution buffer provided by the manufacturing laboratory, and 0.1ml aliquots were taken for analysis. The minimum detection level for this test is 0.4ng/ml.We measured IL-18 levels from urine samples using ELISA kits (Human IL-18 ELISA, Bender MedSystems), and used 50µl of each urine sample for the analysis. The detection limit for this test was 9pg/ml.Cystatin-C in serumWe measured cystatin-C in serum samples using a standardised immunonephelometry analysis using a BNII nephelometer (Siemens Healthcare Diagnostics).Statistical analysisWe analysed the results using SPSS (version 17.0) and GraphPad PRISM (version 4.0) software. The Kolmogorov-Smirnov tests were used for verifying that the variables had a normal distribution. We compared the means of more than two variables using a one-way ANOVA test with post-hoc Bonferroni analysis, and used Student’s t-tests for comparing two means, or Mann-Whitney U-tests in the case of non-normal distributions. We used Pearson’s correlation coefficients to analyse the relationship between the different variables. The significance level was set at P<.05. We evaluated the sensitivity and specificity of each marker using ROC (Receiver Operating Characteristic) curves.RESULTSClinical characteristicsThe clinical and demographic characteristics of our study patients are summarised in Table 1 and Table 2. A total of 26 patients developed AKI, 12 of which were in the angiography group (13%, 12/89) and 14 were from the cardiac surgery group (30%, 14/46). Six patients that underwent catheterization died, three of which had developed AKI, and four patients died from the cardiac surgery group, all of which had AKI. The patients with AKI had a longer mean hospital stay than those that did not in both groups of patients.In the group of patients that underwent catheterization, creatinine values prior to the procedure were significantly higher in patients with AKI (P<.001) (Table 1), and we did not observe any significant differences in the group of patients that underwent cardiac surgery.NGAL values in urine samples from healthy controls and patientsWe observed a significant difference in the values of NGAL from urine samples between patients that developed AKI and those that did not, allowing us to clearly distinguish between the two groups (P<.001) (Figure 1).The mean urine level of NGAL in the control group (healthy volunteers) was 18 (5) ng/ml. We observed a significant difference in NGAL (P<.001) between patients with AKI and the control group (catheters: 96 [24]; cardiac surgery: 129 [28]) (Figure 1A, Figure 1B, and Table 3).The NGAL values in the group of patients without AKI were not significantly different from the control group (catheter: 17.4 [1.5]; cardiac surgery: 27.4 [3.7]) (Figure 1A, Figure 1B, and Table 3). Figure 1C shows how patients without AKI did not have significantly different urine NGAL values from the control group.Cystatin-C serum valuesThe cystatin-C serum values were significantly different (P<.001) between AKI and non-AKI patients. In the catheter group, the mean value for patients with AKI was 1.22 (0.16) mg/dl, and 0.71 (0.02) mg/dl in patients without AKI. In the cardiac surgery group, the values for patients with and without AKI were 1 (0.1) mg/dl and 0.78 (0.04) mg/dl, respectively. The overall results were 1.1 (0.09) mg/dl and 0.7 (0.02) mg/dl in patients with and without AKI, respectively (Table 3).Urine IL-18 valuesIn the case of the IL-18 inflammatory marker, AKI patients had significantly higher values than those without AKI (Table 3).In both the catheter and cardiac surgery groups, we observed a significant difference between patients with and without AKI (P<.05). This significant difference was greater when we analysed all values together (P<.001).Relationship between cystatin, IL-18, and NGALWe tested for correlations between these parameters and observed a significant correlation between NGAL in urine samples and cystatin in serum samples (r=0.311; P=.001) and between NGAL and IL-18 in urine samples (r=0.448; P<.001).ROC curves for NGAL, cystatin-C, and IL-18In order to determine whether these markers are good predictors for the appearance of AKI in patients that undergo catheterization or cardiac revascularisation surgery, we carried out a sensitivity/specificity analysis using ROC curves (Figure 2). Figure 2A shows the ROC curve of the three markers that were analysed in the catheter group. NGAL, cystatin-C, and IL-18 were good markers for AKI, and NGAL was the best predictor, with an area under the curve (AUC) of 0.983, followed by cystatin-C (0.869) and IL-18 (0.727) (Table 4). For a cut-off point of urine NGAL at 31.9ng/ml, sensitivity was 100% and specificity was 91%. For cystatin-C, the cut-off point of 0.8mg/l in serum samples yielded a sensitivity of 89% and specificity of 76%. The cut-off point of 202pg/ml for IL-18 yielded a sensitivity of 67% and a specificity of 73%.The ROC curve for patients that underwent cardiac surgery is displayed in Figure 2B. In these patients, although the incidence of AKI was higher than in the catheter group (Table 1 and Table 2), the ROC AUC were lower for all three markers (Table 4). NGAL continued to be the best predictor (AUC: 0.773) with sensitivity and specificity values of 64% and 80% respectively, considering 31.9ng/ml as the cut-off point for urine NGAL. Cystatin-C produced an AUC of 0.675, with sensitivity and specificity of 64% for the cut-off point of 0.8mg/l, and the ROC curve for IL-18 produced an AUC of 0.676, with the best cut-off point for urine IL-18 at 249pg/ml, with a sensitivity of 64% and specificity of 60% (Table 4).Figure 2C shows the ROC curve for the three markers, considering the two groups of patients studied. NGAL produced an AUC of 0.881, and was capable of detecting 80% of AKI cases with a specificity of 86%, considering the cut-off point for urine NGAL to be 31.9ng/ml. Cystatin-C produced an AUC of 0.774, detecting 75% of AKI cases with a specificity of 71% for a cut-off point of 0.8mg/l of cystatin-C in serum samples. The cut-off point for IL-18 was 201pg/ml, with sensitivity and specificity values lower than the other markers (70% and 61%, respectively) and an AUC of 0.722 (Table 4).DISCUSSIONIn this study we evaluated the usefulness of NGAL and IL-18 in urine samples and cystatin-C in serum samples for the early (within 12 hours of the intervention) detection of AKI in a group of emergency patients in the ICU with acute coronary syndrome or heart failure, who underwent cardiac surgery or coronary angiography with or without angioplasty or endoprosthesis implantation with the following results:uNGAL is useful for the early detection of AKI with an AUC of 0.881.Cystatin in serum samples and IL-18 in urine samples also offer good options, although not quite as strong (AUC of 0.774 and 0.722, respectively).Of the 46 patients that underwent cardiac surgery, 14 (30%) developed AKI, 9 of which had a status of R on the RIFLE classification system, and five of which were I. This 30% is in accordance with the data previously published on the subject. Of the 89 patients that underwent angiography, 12 (13%) developed AKI, six of which were stage R, two were I, and one was F. These results were also within expected ranges. The delay for AKI diagnosis using creatinine took 3 (1) days in the cardiac surgery group and 4 (3) days in the angiography group.Of all the biomarker for AKI that are being studied, NGAL has probably inspired the greatest amount of interest. NGAL is a 25 kD protein that is covalently bound to neutrophil gelatinase. It is normally expressed in very low concentrations in several different tissues such as the kidneys, lungs, stomach, and colon, but is found at very high levels in kidneys with ischaemic or toxic damage.13-15 It has been most heavily researched as a marker for AKI following cardiac surgery. In a study published in The Lancet in 2005,16 Mishra et al carried out a study using paediatric patients that underwent cardiac surgery with extracorporeal circulation, and showed that NGAL is useful both in serum and urine samples for the early (in the first few hours following the procedure) detection of patients that will develop AKI in the coming days, with extremely high sensitivity and specificity levels. The usefulness of NGAL (in blood or urine samples) for the early detection of AKI following cardiac surgery was later confirmed both in children17,18 and adults,19-24 although the results are more varied and are clearly worse in adults. In other studies, however, NGAL was predictive for AKI in urine samples, but not in serum,25,26 and some studies have even produced negative results from using urine NGAL.27 Probably, the reason for the lower specificity observed in adults than in children is related to the existence of other associated conditions. For instance, it has been shown that NGAL values are higher in hypertensive28 and diabetic29 patients, and that they also increase with age.30 Sepsis can also affect NGAL values.31 It has also been shown that the relationship between NGAL and AKI after cardiac surgery varies according to baseline glomerular filtration rate, and the predictive capacity of NGAL is lost in patients with an estimated glomerular filtration rate (eGFR) below 60ml/min.32 Although the strength of the results are variable in both urine and blood tests, it appears that urine samples are generally superior.25,26 The best time to obtain and analyse the samples has not been defined yet.  NGAL has also been shown to be useful for the early diagnosis of AKI following coronary angiography,33-38 although fewer studies have been published in support, and the predictive power of this analysis, the cut-off point, and the optimal time for measurement are not well established.In our study, the results from the overall group of patients were very positive for the measurement of uNGAL 12 hours after the procedure, with an AUC of 0.881. In the cardiac surgery group, AUC was 0.773, somewhat higher than the results published in other studies with adult cardiac surgery patients (0.62-0.72).19-25 The AUC for patients that underwent coronary angiography was higher too (0.983). The cut-off point for better sensitivity and specificity in the overall group was 31.9ng/ml, with a sensitivity of 80% and a specificity of 86%.Urine IL-18 has also been studied as a possible early marker for the detection of AKI in patients that undergo cardiac surgery, yielding both positive39 and negative40 results, as well as following coronary angiography,36 although this measurement has inspired less interest as a possible biomarker for AKI.In contrast to NGAL and IL-18, cystatin is not a marker of kidney damage, but rather glomerular filtration rate. Cystatin-C is a small endogenous protein that is freely filtered in the glomerulus, and is reabsorbed and catabolised in the proximal tubule, such that only a small quantity is excreted in the urine. Its usefulness as a possible substitute for creatinine as a method of measuring glomerular filtration rate has been examined in recent years, both in chronic and acute kidney disease, because of its lower dependence on muscle mass. However, its value does depend on other variables such as age, sex, race, and the presence of diabetes or inflammation.41 The results using this measure are also variable in patients that undergo cardiac surgery, with positive,21 modest,42 and negative results,26 although in this latter study, urine cystatin was capable of predicting the appearance of AKI, compared to serum samples. The published studies with cardiac catheters are also inconsistent, with varying and occasionally contrasting results.35, 43-45 In our study, the AUC for cystatin was 0.774 in all patients, 0.869 in the coronary angiography group, and 0.675 in the cardiac surgery group. The results for IL-18 were quite similar (Table 4).Therefore, the search for the ideal biological marker for the early detection of AKI still has the following important questions pending:1. The best biomarker (or combination of biomarkers) and cut-off point that offers optimal sensitivity and specificity.2. Whether blood or urine samples should be used, and the optimal moment for obtaining the sample.3. Extrinsic factors that may influence the results and viability of the measurements in different clinical contexts.4. The prognostic power in addition to the diagnostic capacity.In this study, we have attempted to contribute a response to some of these questions. This study differs from those previously published by including both cardiac surgery and catheter patients, as well as the fact that all patients were admitted to intensive care units for coronary syndrome or acute heart failure, making them unstable patients. This is important because we need to know how these biomarkers work in large groups of the population with different characteristics, not just in homogeneous groups, and also because of the need to observe how other factors influence these measurements.We took all of our samples 12 hours after the procedure. We were interested in testing the usefulness of samples at this time since it is the simplest option for collecting and processing samples in a normal clinical context (if the procedure takes place in the afternoon, the samples would be taken first thing the next morning).We decided not to take samples for the biomarkers before the procedure, since the ultimate objective is to have a reliable marker in a specific situation, regardless of baseline values. For instance, when troponin or D-dimer are measured in clinical practice, it is without a baseline value for comparison. In any case, NGAL was measured in a population of healthy individuals with normal renal function in order to provide a reference value for comparison with the study groups.The results from the markers in urine samples were not adjusted to urinary creatinine levels since, although some authors do defend this normalisation, the majority of studies have preferred not to do so because the evidence is not clear.We preferred to measure NGAL in urine samples over serum samples since, although currently there are rapid methods for determining NGAL in blood samples with a good correlation with the results obtained in blood samples by ELISA,16 the results from previously published studies show a better yield in urine samples.In conclusion, urine NGAL taken 12 hours after the procedure is a good marker for the early detection of AKI in adult patients with acute heart failure or coronary syndrome that undergo cardiac surgery or coronary angiography, with a predictive power superior to cystatin and IL-18.<a href="grande/10988_108_23959_en_10988t1.jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23959_en_10988t1.jpg" alt="Clinical and demographic characteristics of patients that underwent coronary angiography"></img></a>Table 1. Clinical and demographic characteristics of patients that underwent coronary angiography<a href="grande/10988_108_23960_en_10988t2.jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23960_en_10988t2.jpg" alt="Clinical and demographic characteristics of patients that underwent cardiac surgery"></img></a>Table 2. Clinical and demographic characteristics of patients that underwent cardiac surgery<a href="grande/10988_108_23961_en_10988t3.jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23961_en_10988t3.jpg" alt="Values for the three markers analysed"></img></a>Table 3. Values for the three markers analysed<a href="grande/10988_108_23962_en_10988t4.jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23962_en_10988t4.jpg" alt="Diagnostic capacity of the markers analysed for the detection of acute kidney injury in the different study groups"></img></a>Table 4. Diagnostic capacity of the markers analysed for the detection of acute kidney injury in the different study groups<a href="grande/10988_108_23963_en_10988f1.jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23963_en_10988f1.jpg" alt="Measurements of NGAL in urine samples from controls, patients without acute kidney injury (no AKI), and patients with acute kidney injury (AKI) in the different study groups"></img></a>Figure 1. Measurements of NGAL in urine samples from controls, patients without acute kidney injury (no AKI), and patients with acute kidney injury (AKI) in the different study groups<a href="grande/10988_108_23964_en_10988f2.jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23964_en_10988f2.jpg" alt="ROC curves for the different markers analysed in each patient group"></img></a>Figure 2. ROC curves for the different markers analysed in each patient group" "pdfFichero" => "P1-E532-S3377-A10988-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:8 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439067" "palabras" => array:1 [ 0 => "Angiografía coronaria" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439069" "palabras" => array:1 [ 0 => "Síndrome coronario agudo" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439071" "palabras" => array:1 [ 0 => "Cirugía cardíaca" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439073" "palabras" => array:1 [ 0 => "Cistatina-C" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439075" "palabras" => array:1 [ 0 => "Interleukina-18" ] ] 5 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439077" "palabras" => array:1 [ 0 => "NGAL" ] ] 6 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439079" "palabras" => array:1 [ 0 => "Fracaso renal agudo" ] ] 7 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec439081" "palabras" => array:1 [ 0 => "Fallo cardíaco" ] ] ] "en" => array:8 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439068" "palabras" => array:1 [ 0 => "Coronary angiography" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439070" "palabras" => array:1 [ 0 => "Acute coronary syndrome" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439072" "palabras" => array:1 [ 0 => "Cardiac surgery" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439074" "palabras" => array:1 [ 0 => "Cystatin C" ] ] 4 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439076" "palabras" => array:1 [ 0 => "Interleukin-18" ] ] 5 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439078" "palabras" => array:1 [ 0 => "NGAL" ] ] 6 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439080" "palabras" => array:1 [ 0 => "Acute kidney injury" ] ] 7 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec439082" "palabras" => array:1 [ 0 => "Heart failure" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "Antecedentes: El fracaso renal agudo (FRA) es una complicación frecuente tras la cirugía cardíaca y la angiografía coronaria que ensombrece el pronóstico de estos pacientes. El diagnóstico se basa en el ascenso de la creatinina sérica, que es tardío. Es necesaria la identificación y validación de nuevos biomarcadores precoces que permitan intervenciones más tempranas y eficaces. Objetivos: Evaluar la sensibilidad y especificidad de interleuquina-18 (IL-18) en orina, neutrophil gelatinase-associated lipocalin en orina (uNGAL) y cistatina C en suero para la detección precoz del FRA en una población de pacientes con síndrome coronario agudo o fallo cardíaco y sometidos a cirugía cardíaca o cateterismo. Métodos: Se incluyeron en el estudio 135 pacientes ingresados en una unidad de cuidados intensivos por síndrome coronario agudo o fallo cardíaco por patología coronaria o valvular y a los que se realizaron una angiografía cardíaca o una cirugía cardíaca de revascularización o recambio valvular. Se determinaron los biomarcadores a las 12 horas de la intervención y se monitorizó la creatinina sérica durante los siguientes seis días para el diagnóstico del FRA. Resultados: Para NGAL se obtuvo un área bajo la curva ROC (AUC) de 0,983 y para cistatina C e IL-18 de 0,869 y 0,727, respectivamente. Para un punto de corte de NGAL en orina de 31,9 ng/ml la sensibilidad fue del 100% y la especificidad del 91%. Conclusiones: uNGAL es un marcador precoz de FRA en pacientes con síndrome coronario o fallo cardíaco agudo y sometidos a cirugía cardíaca y angiografía cardíaca, con una capacidad predictiva superior a cistatina o a IL-18." ] "en" => array:1 [ "resumen" => "Background: Acute kidney injury (AKI) is a common complication in cardiac surgery and coronary angiography, which worsens patients’ prognosis. The diagnosis is based on the increase in serum creatinine, which is delayed. It is necessary to identify and validate new biomarkers that allow for early and effective interventions. Aims: To assess the sensitivity and specificity of neutrophil gelatinase-associated lipocalin in urine (uNGAL), interleukin-18 (IL-18) in urine and cystatin C in serum for the early detection of AKI in patients with acute coronary syndrome or heart failure, and who underwent cardiac surgery or catheterization. Methods: The study included 135 patients admitted to the intensive care unit for acute coronary syndrome or heart failure due to coronary or valvular pathology and who underwent coronary angiography or cardiac bypass surgery or valvular replacement. The biomarkers were determined 12 hours after surgery and serum creatinine was monitored during the next six days for the diagnosis of AKI. Results: The area under the ROC curve (AUC) for NGAL was 0.983, and for cystatin C and IL-18 the AUCs were 0.869 and 0.727, respectively. At a cut-off of 31.9ng/ml for uNGAL the sensitivity was 100% and the specificity was 91%. Conclusions: uNGAL is an early marker of AKI in patients with acute coronary syndrome or heart failure and undergoing cardiac surgery and coronary angiography, with a higher predictive value than cystatin C or IL-18." ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10988_108_23959_en_10988t1.jpg" "Alto" => 458 "Ancho" => 600 "Tamanyo" => 166694 ] ] "descripcion" => array:1 [ "en" => "Clinical and demographic characteristics of patients that underwent coronary angiography" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10988_108_23960_en_10988t2.jpg" "Alto" => 613 "Ancho" => 600 "Tamanyo" => 197438 ] ] "descripcion" => array:1 [ "en" => "Clinical and demographic characteristics of patients that underwent cardiac surgery" ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10988_108_23961_en_10988t3.jpg" "Alto" => 113 "Ancho" => 600 "Tamanyo" => 64138 ] ] "descripcion" => array:1 [ "en" => "Values for the three markers analysed" ] ] 3 => array:8 [ "identificador" => "fig4" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10988_108_23962_en_10988t4.jpg" "Alto" => 155 "Ancho" => 600 "Tamanyo" => 74172 ] ] "descripcion" => array:1 [ "en" => "Diagnostic capacity of the markers analysed for the detection of acute kidney injury in the different study groups" ] ] 4 => array:8 [ "identificador" => "fig5" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10988_108_23963_en_10988f1.jpg" "Alto" => 1250 "Ancho" => 600 "Tamanyo" => 177374 ] ] "descripcion" => array:1 [ "en" => "Measurements of NGAL in urine samples from controls, patients without acute kidney injury (no AKI), and patients with acute kidney injury (AKI) in the different study groups" ] ] 5 => array:8 [ "identificador" => "fig6" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10988_108_23964_en_10988f2.jpg" "Alto" => 1634 "Ancho" => 600 "Tamanyo" => 231680 ] ] "descripcion" => array:1 [ "en" => "ROC curves for the different markers analysed in each patient group" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Rosner MH, Okusa MD. 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Biomarcadores precoces de fracaso renal agudo tras angiografía coronaria o cirugía cardíaca en pacientes con síndrome coronario o fallo cardíaco agudos

Isidro Torregrosaa, Carmina Montoliub, Amparo Uriosb, Isabel Juanc, Nisrin ElMlilib, María Jesús Puchadesa, Miguel Angel Solísa, Rafael Sanjuánd, Maria Luisa Blascod, Carmen Ramosa, Patricia Tomása, José Ribesa, Arturo Carrataláe, Nisrin ElMlilif, Isabel Juana, Alfonso Miguelg

a Nefrología, Hospital Clínico Universitario de Valencia, Valencia,

b Fundación Investigación Hospital Clínico Universitario de Valencia. INCLIVA, Valencia,

c Nefrología, Hospital Clínico Universitario de Valencia, Valencia, Spain,

d Unidad Coronaria, Hospital Clínico Universitario de Valencia, Valencia,

e Laboratorio, Hospital Clínico Universitario de Valencia, Valencia,

f Fundación Investigación Hospital Clínico Universitario de Valencia. INCLIVA, Valencia, Spain,

g Nefrología, Hospital Clínico Universitario de Valencia. Universidad de Valencia, Valencia,

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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction</span></p><p class="elsevierStylePara">Acute kidney injury &#40;AKI&#41; is a common complication following cardiovascular surgery&#44; with varying incidence rates evidenced in the medical literature that depend both on the definition of AKI used and the population studied&#44; but most estimates are close to 30&#37;&#46;<span class="elsevierStyleSup">1-3</span> AKI prolongs the duration of hospital stays and increases the risk of mortality by three to nine times&#44; depending on its severity&#46;<span class="elsevierStyleSup">2&#44;3</span> Even small increases in creatinine levels worsen the situation for these patients&#46;<span class="elsevierStyleSup">4</span> The mechanisms that contribute to kidney injury include exogenous and endogenous toxins&#44; metabolic factors&#44; ischaemia and reperfusion&#44; neurohumoral activation&#44; inflammation&#44; and oxidative stress&#46;<span class="elsevierStyleSup">5</span> The diagnosis of AKI is based on the detection of increased serum creatinine levels&#44; which is delayed and does not properly show glomerular filtration rates in acute patients&#46;<span class="elsevierStyleSup">6</span> However&#44; experimental studies have demonstrated that although AKI can be prevented or treated with several different therapies&#44; it should be started immediately after the renal damage is produced&#46;<span class="elsevierStyleSup">7</span> The ineffectiveness of these interventions in clinical trials with humans has been attributed to significant delays in diagnosing AKI&#46; As such&#44; it is clear that in order to be effective&#44; the treatment of AKI must start as early as possible&#46;</p><p class="elsevierStylePara">The incidence of AKI following percutaneous coronary operations can be placed between 5&#37; and 20&#37;&#44; according to the definition of AKI and the population studied&#44; and constitutes a potentially serious complication&#46;<span class="elsevierStyleSup">8&#44;9</span> Peak serum creatinine values tend to arise within the first 5 days following the surgery&#44; and return to baseline values within 3 weeks &#40;although permanent damage can be caused&#41;&#46; As in AKI following heart surgery&#44; increased serum creatinine values are late markers of kidney damage&#46;</p><p class="elsevierStylePara">To try and resolve these problems&#44; different research groups have attempted in recent years to identify new markers for the early diagnosis and stratification of the AKI risk&#46; Despite the effort invested and the progress made&#44; the actual usefulness of these markers has yet to be established in the different clinical contexts of AKI&#46;<span class="elsevierStyleSup">10&#44;11</span> The most commonly studied markers are cystatin-C&#44; which is not a marker of kidney damage but rather glomerular filtration rate&#44; neutrophil gelatinase-associated lipocalin &#40;NGAL&#41;&#44; interleukin-18 &#40;IL-18&#41;&#44; kidney injury molecule-1 &#40;KIM-1&#41;&#44; and liver fatty acid-binding protein &#40;L-FABP&#41;&#44; in serum or urine samples&#46;</p><p class="elsevierStylePara">The objective of this study is to evaluate the sensitivity and specificity of IL-18 in urine&#44; NGAL in urine &#40;uNGAL&#41;&#44; and serum cystatin for the early detection of acute kidney injury in a population of patients with acute coronary syndrome or heart failure and undergoing heart surgery or catheterization&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">MATERIAL AND METHOD</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Study sample</span></p><p class="elsevierStylePara">Our study included 135 patients admitted between May 2008 and December 2009 to the intensive care unit of the Valencia University Clinical Hospital for acute coronary syndrome or heart failure due to coronary or valvular pathologies&#44; and who underwent a heart angiography with or without angioplasty and&#47;or an implanted endoprosthesis &#40;group 1&#44; n&#61;89&#41;&#44; or cardiac surgery involving revascularization or valve replacement &#40;group 2&#44; n&#61;46&#41;&#46; The exclusion criteria were&#58; being younger than 18 years of age&#44; pre-existing chronic kidney disease on renal replacement therapy with dialysis or transplant&#44; and acute renal failure due to cardiogenic shock upon hospitalisation&#46; We also excluded patients that had consecutively undergone both angiography and surgery in order to avoid confusion&#46;</p><p class="elsevierStylePara">All patients were monitored prospectively starting at their inclusion in the study&#46; We monitored creatinine levels from the day prior to the procedure to six days after&#44; and followed the clinical evolution of each patient until they were discharged from the hospital&#46; We also took serum and urine samples 12 hours after the procedure for assessing the biomarkers&#46; Baseline creatinine levels were established as the value measured the day before the intervention&#46;</p><p class="elsevierStylePara">Blood and urine samples were centrifuged for 10 minutes at 1500g&#46; Several 0&#46;5ml aliquots were taken from each serum and urine sample for storage at -80&#186;C for later analysis&#46; We took urine samples from 20 healthy volunteers in order to obtain normal urine NGAL values&#46;</p><p class="elsevierStylePara">The following information was also collected from each patient&#58; demographic variables and comorbidities&#44; parameters of the surgical procedure&#44; and complications during or after the catheter placement or heart surgery &#40;Table 1 and Table 2&#41;&#46; The endpoint used for evaluating our patients was the appearance of AKI&#44; defined as creatinine levels increasing by 50&#37; or more&#44; in keeping with the RIFLE &#40;Risk&#44; Injury&#44; Failure&#44; Loss&#44; End-stage renal disease&#41; classification system&#46;<span class="elsevierStyleSup">12</span> The secondary criteria were in-hospital mortality rates and duration of stays in the ICU and hospital&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Measurements of biomarkers</span></p><p class="elsevierStylePara">NGAL and IL-18 in urine</p><p class="elsevierStylePara">NGAL was measured from urine samples using ELISA kits &#40;Human NGAL ELISA&#44; Hycult biotechnology b&#46;v&#46;&#41;&#46; The urine samples were diluted at 1&#58;20 in a dilution buffer provided by the manufacturing laboratory&#44; and 0&#46;1ml aliquots were taken for analysis&#46; The minimum detection level for this test is 0&#46;4ng&#47;ml&#46;</p><p class="elsevierStylePara">We measured IL-18 levels from urine samples using ELISA kits &#40;Human IL-18 ELISA&#44; Bender MedSystems&#41;&#44; and used 50&#181;l of each urine sample for the analysis&#46; The detection limit for this test was 9pg&#47;ml&#46;</p><p class="elsevierStylePara">Cystatin-C in serum</p><p class="elsevierStylePara">We measured cystatin-C in serum samples using a standardised immunonephelometry analysis using a BNII nephelometer &#40;Siemens Healthcare Diagnostics&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Statistical analysis</span></p><p class="elsevierStylePara">We analysed the results using SPSS &#40;version 17&#46;0&#41; and GraphPad PRISM &#40;version 4&#46;0&#41; software&#46; The Kolmogorov-Smirnov tests were used for verifying that the variables had a normal distribution&#46; We compared the means of more than two variables using a one-way ANOVA test with post-hoc Bonferroni analysis&#44; and used Student&#8217;s t-tests for comparing two means&#44; or Mann-Whitney U-tests in the case of non-normal distributions&#46; We used Pearson&#8217;s correlation coefficients to analyse the relationship between the different variables&#46; The significance level was set at <span class="elsevierStyleItalic">P</span>&#60;&#46;05&#46; We evaluated the sensitivity and specificity of each marker using ROC &#40;Receiver Operating Characteristic&#41; curves&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Clinical characteristics</span></p><p class="elsevierStylePara">The clinical and demographic characteristics of our study patients are summarised in Table 1 and Table 2&#46; A total of 26 patients developed AKI&#44; 12 of which were in the angiography group &#40;13&#37;&#44; 12&#47;89&#41; and 14 were from the cardiac surgery group &#40;30&#37;&#44; 14&#47;46&#41;&#46; Six patients that underwent catheterization died&#44; three of which had developed AKI&#44; and four patients died from the cardiac surgery group&#44; all of which had AKI&#46; The patients with AKI had a longer mean hospital stay than those that did not in both groups of patients&#46;</p><p class="elsevierStylePara">In the group of patients that underwent catheterization&#44; creatinine values prior to the procedure were significantly higher in patients with AKI &#40;<span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41; &#40;Table 1&#41;&#44; and we did not observe any significant differences in the group of patients that underwent cardiac surgery&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">NGAL values in urine samples from healthy controls and patients</span></p><p class="elsevierStylePara">We observed a significant difference in the values of NGAL from urine samples between patients that developed AKI and those that did not&#44; allowing us to clearly distinguish between the two groups &#40;<span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41; &#40;Figure 1&#41;&#46;</p><p class="elsevierStylePara">The mean urine level of NGAL in the control group &#40;healthy volunteers&#41; was 18 &#40;5&#41; ng&#47;ml&#46; We observed a significant difference in NGAL &#40;<span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41; between patients with AKI and the control group &#40;catheters&#58; 96 &#91;24&#93;&#59; cardiac surgery&#58; 129 &#91;28&#93;&#41; &#40;Figure 1A&#44; Figure 1B&#44; and Table 3&#41;&#46;</p><p class="elsevierStylePara">The NGAL values in the group of patients without AKI were not significantly different from the control group &#40;catheter&#58; 17&#46;4 &#91;1&#46;5&#93;&#59; cardiac surgery&#58; 27&#46;4 &#91;3&#46;7&#93;&#41; &#40;Figure 1A&#44; Figure 1B&#44; and Table 3&#41;&#46; Figure 1C shows how patients without AKI did not have significantly different urine NGAL values from the control group&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Cystatin-C serum values</span></p><p class="elsevierStylePara">The cystatin-C serum values were significantly different &#40;<span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41; between AKI and non-AKI patients&#46; In the catheter group&#44; the mean value for patients with AKI was 1&#46;22 &#40;0&#46;16&#41; mg&#47;dl&#44; and 0&#46;71 &#40;0&#46;02&#41; mg&#47;dl in patients without AKI&#46; In the cardiac surgery group&#44; the values for patients with and without AKI were 1 &#40;0&#46;1&#41; mg&#47;dl and 0&#46;78 &#40;0&#46;04&#41; mg&#47;dl&#44; respectively&#46; The overall results were 1&#46;1 &#40;0&#46;09&#41; mg&#47;dl and 0&#46;7 &#40;0&#46;02&#41; mg&#47;dl in patients with and without AKI&#44; respectively &#40;Table 3&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Urine IL-18 values</span></p><p class="elsevierStylePara">In the case of the IL-18 inflammatory marker&#44; AKI patients had significantly higher values than those without AKI &#40;Table 3&#41;&#46;</p><p class="elsevierStylePara">In both the catheter and cardiac surgery groups&#44; we observed a significant difference between patients with and without AKI &#40;<span class="elsevierStyleItalic">P</span>&#60;&#46;05&#41;&#46; This significant difference was greater when we analysed all values together &#40;<span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Relationship between cystatin&#44; IL-18&#44; and NGAL</span></p><p class="elsevierStylePara">We tested for correlations between these parameters and observed a significant correlation between NGAL in urine samples and cystatin in serum samples &#40;r&#61;0&#46;311&#59; <span class="elsevierStyleItalic">P</span>&#61;&#46;001&#41; and between NGAL and IL-18 in urine samples &#40;r&#61;0&#46;448&#59; <span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">ROC curves for NGAL&#44; cystatin-C&#44; and IL-18</span></p><p class="elsevierStylePara">In order to determine whether these markers are good predictors for the appearance of AKI in patients that undergo catheterization or cardiac revascularisation surgery&#44; we carried out a sensitivity&#47;specificity analysis using ROC curves &#40;Figure 2&#41;&#46; Figure 2A shows the ROC curve of the three markers that were analysed in the catheter group&#46; NGAL&#44; cystatin-C&#44; and IL-18 were good markers for AKI&#44; and NGAL was the best predictor&#44; with an area under the curve &#40;AUC&#41; of 0&#46;983&#44; followed by cystatin-C &#40;0&#46;869&#41; and IL-18 &#40;0&#46;727&#41; &#40;Table 4&#41;&#46; For a cut-off point of urine NGAL at 31&#46;9ng&#47;ml&#44; sensitivity was 100&#37; and specificity was 91&#37;&#46; For cystatin-C&#44; the cut-off point of 0&#46;8mg&#47;l in serum samples yielded a sensitivity of 89&#37; and specificity of 76&#37;&#46; The cut-off point of 202pg&#47;ml for IL-18 yielded a sensitivity of 67&#37; and a specificity of 73&#37;&#46;</p><p class="elsevierStylePara">The ROC curve for patients that underwent cardiac surgery is displayed in Figure 2B&#46; In these patients&#44; although the incidence of AKI was higher than in the catheter group &#40;Table 1 and Table 2&#41;&#44; the ROC AUC were lower for all three markers &#40;Table 4&#41;&#46; NGAL continued to be the best predictor &#40;AUC&#58; 0&#46;773&#41; with sensitivity and specificity values of 64&#37; and 80&#37; respectively&#44; considering 31&#46;9ng&#47;ml as the cut-off point for urine NGAL&#46; Cystatin-C produced an AUC of 0&#46;675&#44; with sensitivity and specificity of 64&#37; for the cut-off point of 0&#46;8mg&#47;l&#44; and the ROC curve for IL-18 produced an AUC of 0&#46;676&#44; with the best cut-off point for urine IL-18 at 249pg&#47;ml&#44; with a sensitivity of 64&#37; and specificity of 60&#37; &#40;Table 4&#41;&#46;</p><p class="elsevierStylePara">Figure 2C shows the ROC curve for the three markers&#44; considering the two groups of patients studied&#46; NGAL produced an AUC of 0&#46;881&#44; and was capable of detecting 80&#37; of AKI cases with a specificity of 86&#37;&#44; considering the cut-off point for urine NGAL to be 31&#46;9ng&#47;ml&#46; Cystatin-C produced an AUC of 0&#46;774&#44; detecting 75&#37; of AKI cases with a specificity of 71&#37; for a cut-off point of 0&#46;8mg&#47;l of cystatin-C in serum samples&#46; The cut-off point for IL-18 was 201pg&#47;ml&#44; with sensitivity and specificity values lower than the other markers &#40;70&#37; and 61&#37;&#44; respectively&#41; and an AUC of 0&#46;722 &#40;Table 4&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara">In this study we evaluated the usefulness of NGAL and IL-18 in urine samples and cystatin-C in serum samples for the early &#40;within 12 hours of the intervention&#41; detection of AKI in a group of emergency patients in the ICU with acute coronary syndrome or heart failure&#44; who underwent cardiac surgery or coronary angiography with or without angioplasty or endoprosthesis implantation with the following results&#58;</p><p class="elsevierStylePara">uNGAL is useful for the early detection of AKI with an AUC of 0&#46;881&#46;</p><p class="elsevierStylePara">Cystatin in serum samples and IL-18 in urine samples also offer good options&#44; although not quite as strong &#40;AUC of 0&#46;774 and 0&#46;722&#44; respectively&#41;&#46;</p><p class="elsevierStylePara">Of the 46 patients that underwent cardiac surgery&#44; 14 &#40;30&#37;&#41; developed AKI&#44; 9 of which had a status of R on the RIFLE classification system&#44; and five of which were I&#46; This 30&#37; is in accordance with the data previously published on the subject&#46; Of the 89 patients that underwent angiography&#44; 12 &#40;13&#37;&#41; developed AKI&#44; six of which were stage R&#44; two were I&#44; and one was F&#46; These results were also within expected ranges&#46; The delay for AKI diagnosis using creatinine took 3 &#40;1&#41; days in the cardiac surgery group and 4 &#40;3&#41; days in the angiography group&#46;</p><p class="elsevierStylePara">Of all the biomarker for AKI that are being studied&#44; NGAL has probably inspired the greatest amount of interest&#46; NGAL is a 25 kD protein that is covalently bound to neutrophil gelatinase&#46; It is normally expressed in very low concentrations in several different tissues such as the kidneys&#44; lungs&#44; stomach&#44; and colon&#44; but is found at very high levels in kidneys with ischaemic or toxic damage&#46;<span class="elsevierStyleSup">13-15</span> It has been most heavily researched as a marker for AKI following cardiac surgery&#46; In a study published in <span class="elsevierStyleItalic">The Lancet </span>in 2005&#44;<span class="elsevierStyleSup">16</span> Mishra et al carried out a study using paediatric patients that underwent cardiac surgery with extracorporeal circulation&#44; and showed that NGAL is useful both in serum and urine samples for the early &#40;in the first few hours following the procedure&#41; detection of patients that will develop AKI in the coming days&#44; with extremely high sensitivity and specificity levels&#46; The usefulness of NGAL &#40;in blood or urine samples&#41; for the early detection of AKI following cardiac surgery was later confirmed both in children<span class="elsevierStyleSup">17&#44;18</span> and adults&#44;<span class="elsevierStyleSup">19-24</span> although the results are more varied and are clearly worse in adults&#46; In other studies&#44; however&#44; NGAL was predictive for AKI in urine samples&#44; but not in serum&#44;<span class="elsevierStyleSup">25&#44;26</span> and some studies have even produced negative results from using urine NGAL&#46;<span class="elsevierStyleSup">27</span> Probably&#44; the reason for the lower specificity observed in adults than in children is related to the existence of other associated conditions&#46; For instance&#44; it has been shown that NGAL values are higher in hypertensive<span class="elsevierStyleSup">28</span> and diabetic<span class="elsevierStyleSup">29</span> patients&#44; and that they also increase with age&#46;<span class="elsevierStyleSup">30</span> Sepsis can also affect NGAL values&#46;<span class="elsevierStyleSup">31</span> It has also been shown that the relationship between NGAL and AKI after cardiac surgery varies according to baseline glomerular filtration rate&#44; and the predictive capacity of NGAL is lost in patients with an estimated glomerular filtration rate &#40;eGFR&#41; below 60ml&#47;min&#46;<span class="elsevierStyleSup">32</span> Although the strength of the results are variable in both urine and blood tests&#44; it appears that urine samples are generally superior&#46;<span class="elsevierStyleSup">25&#44;26</span> The best time to obtain and analyse the samples has not been defined yet&#46; &#160;</p><p class="elsevierStylePara">NGAL has also been shown to be useful for the early diagnosis of AKI following coronary angiography&#44;<span class="elsevierStyleSup">33-38</span> although fewer studies have been published in support&#44; and the predictive power of this analysis&#44; the cut-off point&#44; and the optimal time for measurement are not well established&#46;</p><p class="elsevierStylePara">In our study&#44; the results from the overall group of patients were very positive for the measurement of uNGAL 12 hours after the procedure&#44; with an AUC of 0&#46;881&#46; In the cardiac surgery group&#44; AUC was 0&#46;773&#44; somewhat higher than the results published in other studies with adult cardiac surgery patients &#40;0&#46;62-0&#46;72&#41;&#46;<span class="elsevierStyleSup">19-25</span> The AUC for patients that underwent coronary angiography was higher too &#40;0&#46;983&#41;&#46; The cut-off point for better sensitivity and specificity in the overall group was 31&#46;9ng&#47;ml&#44; with a sensitivity of 80&#37; and a specificity of 86&#37;&#46;</p><p class="elsevierStylePara">Urine IL-18 has also been studied as a possible early marker for the detection of AKI in patients that undergo cardiac surgery&#44; yielding both positive<span class="elsevierStyleSup">39</span> and negative<span class="elsevierStyleSup">40</span> results&#44; as well as following coronary angiography&#44;<span class="elsevierStyleSup">36</span> although this measurement has inspired less interest as a possible biomarker for AKI&#46;</p><p class="elsevierStylePara">In contrast to NGAL and IL-18&#44; cystatin is not a marker of kidney damage&#44; but rather glomerular filtration rate&#46; Cystatin-C is a small endogenous protein that is freely filtered in the glomerulus&#44; and is reabsorbed and catabolised in the proximal tubule&#44; such that only a small quantity is excreted in the urine&#46; Its usefulness as a possible substitute for creatinine as a method of measuring glomerular filtration rate has been examined in recent years&#44; both in chronic and acute kidney disease&#44; because of its lower dependence on muscle mass&#46; However&#44; its value does depend on other variables such as age&#44; sex&#44; race&#44; and the presence of diabetes or inflammation&#46;<span class="elsevierStyleSup">41</span> The results using this measure are also variable in patients that undergo cardiac surgery&#44; with positive&#44;<span class="elsevierStyleSup">21</span> modest&#44;<span class="elsevierStyleSup">42</span> and negative results&#44;<span class="elsevierStyleSup">26</span> although in this latter study&#44; urine cystatin was capable of predicting the appearance of AKI&#44; compared to serum samples&#46; The published studies with cardiac catheters are also inconsistent&#44; with varying and occasionally contrasting results&#46;<span class="elsevierStyleSup">35&#44; 43-45 In our study&#44; the AUC for cystatin was 0&#46;774 in all patients&#44; 0&#46;869 in the coronary angiography group&#44; and 0&#46;675 in the cardiac surgery group&#46; The results for IL-18 were quite similar &#40;Table 4&#41;&#46;</span></p><p class="elsevierStylePara">Therefore&#44; the search for the ideal biological marker for the early detection of AKI still has the following important questions pending&#58;</p><p class="elsevierStylePara">1&#46; The best biomarker &#40;or combination of biomarkers&#41; and cut-off point that offers optimal sensitivity and specificity&#46;</p><p class="elsevierStylePara">2&#46; Whether blood or urine samples should be used&#44; and the optimal moment for obtaining the sample&#46;</p><p class="elsevierStylePara">3&#46; Extrinsic factors that may influence the results and viability of the measurements in different clinical contexts&#46;</p><p class="elsevierStylePara">4&#46; The prognostic power in addition to the diagnostic capacity&#46;</p><p class="elsevierStylePara">In this study&#44; we have attempted to contribute a response to some of these questions&#46; This study differs from those previously published by including both cardiac surgery and catheter patients&#44; as well as the fact that all patients were admitted to intensive care units for coronary syndrome or acute heart failure&#44; making them unstable patients&#46; This is important because we need to know how these biomarkers work in large groups of the population with different characteristics&#44; not just in homogeneous groups&#44; and also because of the need to observe how other factors influence these measurements&#46;</p><p class="elsevierStylePara">We took all of our samples 12 hours after the procedure&#46; We were interested in testing the usefulness of samples at this time since it is the simplest option for collecting and processing samples in a normal clinical context &#40;if the procedure takes place in the afternoon&#44; the samples would be taken first thing the next morning&#41;&#46;</p><p class="elsevierStylePara">We decided not to take samples for the biomarkers before the procedure&#44; since the ultimate objective is to have a reliable marker in a specific situation&#44; regardless of baseline values&#46; For instance&#44; when troponin or D-dimer are measured in clinical practice&#44; it is without a baseline value for comparison&#46; In any case&#44; NGAL was measured in a population of healthy individuals with normal renal function in order to provide a reference value for comparison with the study groups&#46;</p><p class="elsevierStylePara">The results from the markers in urine samples were not adjusted to urinary creatinine levels since&#44; although some authors do defend this normalisation&#44; the majority of studies have preferred not to do so because the evidence is not clear&#46;</p><p class="elsevierStylePara">We preferred to measure NGAL in urine samples over serum samples since&#44; although currently there are rapid methods for determining NGAL in blood samples with a good correlation with the results obtained in blood samples by ELISA&#44;<span class="elsevierStyleSup">16</span> the results from previously published studies show a better yield in urine samples&#46;</p><p class="elsevierStylePara">In conclusion&#44; urine NGAL taken 12 hours after the procedure is a good marker for the early detection of AKI in adult patients with acute heart failure or coronary syndrome that undergo cardiac surgery or coronary angiography&#44; with a predictive power superior to cystatin and IL-18&#46;</p><p class="elsevierStylePara"><a href="grande&#47;10988&#95;108&#95;23959&#95;en&#95;10988t1&#46;jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23959_en_10988t1.jpg" alt="Clinical and demographic characteristics of patients that underwent coronary angiography"></img></a></p><p class="elsevierStylePara">Table 1&#46; Clinical and demographic characteristics of patients that underwent coronary angiography</p><p class="elsevierStylePara"><a href="grande&#47;10988&#95;108&#95;23960&#95;en&#95;10988t2&#46;jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23960_en_10988t2.jpg" alt="Clinical and demographic characteristics of patients that underwent cardiac surgery"></img></a></p><p class="elsevierStylePara">Table 2&#46; Clinical and demographic characteristics of patients that underwent cardiac surgery</p><p class="elsevierStylePara"><a href="grande&#47;10988&#95;108&#95;23961&#95;en&#95;10988t3&#46;jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23961_en_10988t3.jpg" alt="Values for the three markers analysed"></img></a></p><p class="elsevierStylePara">Table 3&#46; Values for the three markers analysed</p><p class="elsevierStylePara"><a href="grande&#47;10988&#95;108&#95;23962&#95;en&#95;10988t4&#46;jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23962_en_10988t4.jpg" alt="Diagnostic capacity of the markers analysed for the detection of acute kidney injury in the different study groups"></img></a></p><p class="elsevierStylePara">Table 4&#46; Diagnostic capacity of the markers analysed for the detection of acute kidney injury in the different study groups</p><p class="elsevierStylePara"><a href="grande&#47;10988&#95;108&#95;23963&#95;en&#95;10988f1&#46;jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23963_en_10988f1.jpg" alt="Measurements of NGAL in urine samples from controls&#44; patients without acute kidney injury &#40;no AKI&#41;&#44; and patients with acute kidney injury &#40;AKI&#41; in the different study groups"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Measurements of NGAL in urine samples from controls&#44; patients without acute kidney injury &#40;no AKI&#41;&#44; and patients with acute kidney injury &#40;AKI&#41; in the different study groups</p><p class="elsevierStylePara"><a href="grande&#47;10988&#95;108&#95;23964&#95;en&#95;10988f2&#46;jpg" class="elsevierStyleCrossRefs"><img src="10988_108_23964_en_10988f2.jpg" alt="ROC curves for the different markers analysed in each patient group"></img></a></p><p class="elsevierStylePara">Figure 2&#46; ROC curves for the different markers analysed in each patient group</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Antecedentes&#58;</span><span class="elsevierStyleBold"> </span>El fracaso renal agudo &#40;FRA&#41; es una complicaci&#243;n frecuente tras la cirug&#237;a card&#237;aca y la angiograf&#237;a coronaria que ensombrece el pron&#243;stico de estos pacientes&#46; El diagn&#243;stico se basa en el ascenso de la creatinina s&#233;rica&#44; que es tard&#237;o&#46; Es necesaria la identificaci&#243;n y validaci&#243;n de nuevos biomarcadores precoces que permitan intervenciones m&#225;s tempranas y eficaces&#46; <span class="elsevierStyleBold">Objetivos&#58; </span>Evaluar la sensibilidad y especificidad de interleuquina-18 &#40;IL-18&#41; en orina&#44;&#160;<span class="elsevierStyleItalic">neutrophil gelatinase-associated lipocalin</span> en orina &#40;uNGAL&#41; y cistatina C&#160;en suero para la detecci&#243;n precoz del FRA en una poblaci&#243;n de pacientes con s&#237;ndrome coronario agudo o fallo card&#237;aco y sometidos a cirug&#237;a card&#237;aca o cateterismo&#46; <span class="elsevierStyleBold">M&#233;todos&#58; </span>Se incluyeron en el estudio 135 pacientes ingresados en una unidad de cuidados intensivos por s&#237;ndrome coronario agudo o fallo card&#237;aco por patolog&#237;a coronaria o valvular y a los que se realizaron una angiograf&#237;a card&#237;aca o una cirug&#237;a card&#237;aca de revascularizaci&#243;n o recambio valvular&#46; Se determinaron los biomarcadores a las 12 horas de la intervenci&#243;n y se monitoriz&#243; la creatinina s&#233;rica durante los siguientes seis d&#237;as para el diagn&#243;stico del FRA&#46; <span class="elsevierStyleBold">Resultados&#58; </span>Para<span class="elsevierStyleBold"> </span>NGAL se obtuvo un &#225;rea bajo la curva ROC &#40;AUC&#41; de 0&#44;983 y para cistatina C e IL-18 de 0&#44;869 y 0&#44;727&#44; respectivamente&#46; Para un punto de corte de NGAL en orina de 31&#44;9 ng&#47;ml la sensibilidad fue del 100&#37; y la especificidad del 91&#37;&#46; <span class="elsevierStyleBold">Conclusiones&#58; </span>uNGAL es un marcador precoz de FRA en pacientes con s&#237;ndrome coronario o fallo card&#237;aco agudo y sometidos a cirug&#237;a card&#237;aca y angiograf&#237;a card&#237;aca&#44; con una capacidad predictiva superior a cistatina o a&#160;IL-18&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Background&#58;</span> Acute kidney injury &#40;AKI&#41; is a common complication in cardiac surgery and coronary angiography&#44; which worsens patients&#8217; prognosis&#46; The diagnosis is based on the increase in serum creatinine&#44; which is delayed&#46; It is necessary to identify and validate new biomarkers that allow for early and effective interventions&#46; <span class="elsevierStyleBold">Aims&#58; </span>To assess the sensitivity and specificity of neutrophil gelatinase-associated lipocalin in urine &#40;uNGAL&#41;&#44; interleukin-18 &#40;IL-18&#41; in urine and cystatin C&#160;in&#160;serum for the early detection of AKI in patients with acute coronary syndrome or heart failure&#44; and who underwent cardiac surgery or catheterization&#46; <span class="elsevierStyleBold">Methods&#58; </span>The study included 135 patients admitted to the intensive care unit for acute coronary syndrome or heart failure due to coronary or valvular pathology and who underwent coronary angiography or cardiac bypass surgery or valvular replacement&#46; The biomarkers were determined 12 hours after surgery and serum creatinine was monitored during the next six days for the diagnosis of AKI&#46; <span class="elsevierStyleBold">Results&#58;</span> The area under the ROC curve &#40;AUC&#41; for NGAL was 0&#46;983&#44; and for cystatin C and IL-18 the AUCs were 0&#46;869 and 0&#46;727&#44; respectively&#46; At a cut-off of 31&#46;9ng&#47;ml for uNGAL the sensitivity was 100&#37; and the specificity was 91&#37;&#46; <span class="elsevierStyleBold">Conclusions&#58; </span>uNGAL is an early marker of AKI in patients with acute coronary syndrome or heart failure and undergoing cardiac surgery and coronary angiography&#44; with a higher predictive value than cystatin C or IL-18&#46;</span></p>"
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Article information

ISSN: 20132514
Original language: English

DOI:10.3265/Nefrologia.pre2011.Sep.10988

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	9	10	19
2024 October	58	35	93
2024 September	60	29	89
2024 August	80	59	139
2024 July	71	36	107
2024 June	81	57	138
2024 May	69	50	119
2024 April	66	45	111
2024 March	70	27	97
2024 February	42	41	83
2024 January	62	19	81
2023 December	48	37	85
2023 November	53	33	86
2023 October	69	36	105
2023 September	52	31	83
2023 August	51	31	82
2023 July	55	36	91
2023 June	57	43	100
2023 May	56	38	94
2023 April	50	17	67
2023 March	69	29	98
2023 February	40	27	67
2023 January	41	29	70
2022 December	66	29	95
2022 November	64	31	95
2022 October	69	45	114
2022 September	60	40	100
2022 August	81	46	127
2022 July	49	46	95
2022 June	61	65	126
2022 May	51	31	82
2022 April	45	43	88
2022 March	72	54	126
2022 February	56	46	102
2022 January	50	28	78
2021 December	49	50	99
2021 November	35	39	74
2021 October	69	51	120
2021 September	50	40	90
2021 August	49	41	90
2021 July	95	39	134
2021 June	78	41	119
2021 May	71	31	102
2021 April	175	104	279
2021 March	103	45	148
2021 February	80	28	108
2021 January	55	17	72
2020 December	43	18	61
2020 November	40	17	57
2020 October	50	14	64
2020 September	51	12	63
2020 August	46	15	61
2020 July	50	10	60
2020 June	40	14	54
2020 May	45	14	59
2020 April	36	29	65
2020 March	36	18	54
2020 February	62	26	88
2020 January	56	23	79
2019 December	58	17	75
2019 November	63	28	91
2019 October	35	16	51
2019 September	51	37	88
2019 August	48	18	66
2019 July	39	31	70
2019 June	61	33	94
2019 May	56	21	77
2019 April	109	54	163
2019 March	58	31	89
2019 February	48	22	70
2019 January	39	21	60
2018 December	115	53	168
2018 November	128	23	151
2018 October	112	34	146
2018 September	120	23	143
2018 August	78	29	107
2018 July	74	19	93
2018 June	78	23	101
2018 May	64	18	82
2018 April	84	23	107
2018 March	103	20	123
2018 February	62	12	74
2018 January	66	7	73
2017 December	68	16	84
2017 November	78	18	96
2017 October	61	14	75
2017 September	45	16	61
2017 August	55	31	86
2017 July	71	28	99
2017 June	69	24	93
2017 May	108	28	136
2017 April	64	28	92
2017 March	65	22	87
2017 February	142	20	162
2017 January	50	21	71
2016 December	107	12	119
2016 November	141	12	153
2016 October	239	14	253
2016 September	345	18	363
2016 August	354	8	362
2016 July	223	5	228
2016 June	173	0	173
2016 May	168	0	168
2016 April	159	0	159
2016 March	141	0	141
2016 February	143	0	143
2016 January	141	0	141
2015 December	148	0	148
2015 November	128	0	128
2015 October	119	0	119
2015 September	105	0	105
2015 August	99	0	99
2015 July	106	0	106
2015 June	44	0	44
2015 May	83	0	83
2015 April	5	0	5

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