Urinary Klotho measured by ELISA as an early biomarker of acute kidney injury in patients after cardiac surgery or coronary angiography

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Giménez-Garzó, Patricia Tomás, Miguel Ángel Solís, Carmen Ramos, Isabel Juan, María Jesús Puchades, Guillermo Sáez, María Luisa Blasco, Alfonso Miguel" "autores" => array:12 [ 0 => array:3 [ "nombre" => "Isidro" "apellidos" => "Torregrosa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 1 => array:3 [ "nombre" => "Carmina" "apellidos" => "Montoliu" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 2 => array:3 [ "nombre" => "Amparo" "apellidos" => "Urios" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 3 => array:3 [ "nombre" => "Carla" "apellidos" => "Giménez-Garzó" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 4 => array:3 [ "nombre" => "Patricia" "apellidos" => "Tomás" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 5 => array:3 [ "nombre" => "Miguel Ángel" "apellidos" => "Solís" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 6 => array:3 [ "nombre" => "Carmen" "apellidos" => "Ramos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 7 => array:3 [ "nombre" => "Isabel" "apellidos" => "Juan" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 8 => array:3 [ "nombre" => "María Jesús" "apellidos" => "Puchades" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] 9 => array:3 [ "nombre" => "Guillermo" "apellidos" => "Sáez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] 10 => array:3 [ "nombre" => "María Luisa" "apellidos" => "Blasco" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "affe" ] ] ] 11 => array:3 [ "nombre" => "Alfonso" "apellidos" => "Miguel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Nephrology, Hospital Clínico Universitario de Valencia [University Clinical Hospital of Valencia], Valencia, Valencia (Spain)" "etiqueta" => "a" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Fundación Investigación Clínico de Valencia Instituto de Investigación Sanitaria – INCLIVA [Valencia Clinical Research Foundation, Health Research Institute], Valencia, Valencia (Spain)" "etiqueta" => "b" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Neurobiology Laboratory. Centro Investigación Príncipe Felipe [Príncipe Felipe Research Centre]. Valencia, Valencia (Spain)" "etiqueta" => "c" "identificador" => "affc" ] 3 => array:3 [ "entidad" => "Coordinator of International Relations and Mobility Programs, Health Area of Universidad de Valencia [Valencia University], Biochemistry and Molecular Biology Department, Valencia, Valencia (Spain)" "etiqueta" => "d" "identificador" => "affd" ] 4 => array:3 [ "entidad" => "Coronary Care Unit, Hospital Clínico Universitario de Valencia, Valencia, Valencia (Spain)" "etiqueta" => "e" "identificador" => "affe" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Klotho urinario determinado por ELISA como biomarcador precoz de fracaso renal agudo en pacientes sometidos a cirugía cardiaca o angiografía coronaria" ] ] "textoCompleto" => "Introduction Acute kidney injury (AKI) is a common complication following cardiac surgery and percutaneous coronary interventions, with an estimated incidence around 30% in the former1-3 and between 5 and 20% in the latter4-6. The onset of AKI significantly worsens prognosis in these patients2,3,7. AKI increases mortality in different clinical contexts and, additionally, patients often develop chronic kidney disease (CKD) after AKI8-9. The mechanisms involved in AKI include both endogenous and exogenous toxins, metabolic factors, ischaemia and reperfusion, neurohumoral activation, inflammation and oxidative stress10. The diagnosis of AKI is based on detecting increased serum creatinine, which occurs late and does not adequately reflect the glomerular filtration in acute patients11. However, experimental studies show that AKI can only be prevented or treated by means of early interventions12. New early biomarkers of AKI, such as NGAL (Neutrophil Gelatinase-Associated Lipocaline), KIM-1 (Kidney Injury Molecule 1), L-FABP (Liver Fatty Acid-Binding Protein), Cystatin C or IL-18 (Interleukin 18), have been identified in recent years, but many important aspects remain to be solved in the search for the ideal biomarker13. The study of these molecules has also provided a greater understanding of AKI pathogenesis. The Klotho gene was identified in 1997 as an anti-aging gene14. This gene is expressed in multiple tissues, the kidney being the organ where it is expressed more markedly,15 especially in the distal tubule, but also in the proximal tubule16 and the collecting duct17,18. Klotho is a transmembrane protein that acts as a co-receptor for fibroblast growth factor-23 (FGF-23)19,20. The ectodomain may be cut and released into the extracellular space by the proteases anchored to ADAM10 and ADAM1721 membrane. This results in soluble Klotho, which is present in blood, cerebrospinal fluid22 and urine23. There is another soluble Klotho protein which is shorter, but its function is not well known24. Soluble Klotho is a pleiotropic protein that acts as a paracrine and endocrine hormonal factor, both in the kidney and in other organs25. In the renal tubule, Klotho modulates sodium-phosphate cotransporters23, calcium channels26 and potassium channels27. Finally, Klotho is also present at nuclear and cytoplasmic levels, where it functions as an anti-aging protein28,29. Klotho’s role in aging and in phosphocalcic metabolism continues to become more understood16,30,31. Its implications in the progression of CKD and its non-renal complications have also been the focus of intense study in recent years25,32-34, as well as the relationship existing among its circulating levels, glomerular filtration and CKD prognosis35 or its potential use as an anti-fibrotic agent36. With respect to AKI, the presence of decreased Klotho levels has been shown in various animal models of AKI induced by ischaemia-reperfusion, ureteral obstruction or nephrotoxic agents23,37-43. In 2010, Hu et al.23 measured urinary Klotho in 17 AKI patients and found decreased levels compared to the values obtained in 14 healthy volunteers. No other studies have been published about Klotho as an AKI biomarker in humans. The objective of this paper was to assess the usefulness of measuring urinary Klotho for the early detection of AKI in patients with acute coronary syndrome or heart failure undergoing cardiac surgery or coronary angiography.MethodsPatients Sixty patients were enrolled from a cohort of 193 patients admitted to the intensive care unit (ICU) of the Hospital Clínico Universitario de Valencia with acute coronary syndrome (ACS) or heart failure secondary to coronary or valvular disease. All patients had undergone coronary angiography with or without angioplasty or cardiac surgery. The coronary angiography group was made up of 30 patients: 18 had AKI after the intervention and 12 did not. Another 30 patients were also selected in the cardiac surgery group: 15 with AKI and 15 without AKI (Table 1).<img alt="Table 1 – Clinical and demographic characteristics of patients" src="498v35n02-90412347fig1.jpg"></img> The exclusion criteria were: age younger than 18 years; CKD on replacement therapy and AKI secondary to cardiogenic shock during hospitalisation. All patients were prospectively monitored since their enrolment in the study. Serum creatinine was measured from before the procedure up to six days after it, and the clinical progress of each patient was monitored until discharge. The first value of serum creatinine obtained on admission was used as the baseline creatinine value. Urine samples for Klotho measurement were collected 12 hours after the intervention and processed immediately thereafter. We also obtained urine samples from 10 healthy volunteers to determine the normal values. Additionally, the following information was collected from each patient: demographic variables and comorbidities, parameters of the surg ical procedure and complicat ions dur ing or after interventions (Table 1). The primary endpoint was the onset of AKI, defined as an increase of creatinine of 50% or more based on the RIFLE (Risk, Injury, Failure, Loss, End-stage renal disease) classification44. This study was approved by the Hospital Clínico Universitario de Valencia Ethics Committee and it was conducted in compliance with the principles of the Declaration of Helsinki45.Processing of urine samples Urine samples were centrifuged for 10 minutes at 1500 g immediately after being collected, and the supernatant was stored in 0.5-mL aliquots at –80ºC for later use.Measurement of urinary Klotho levels Human Klotho levels were determined in urine, both in patients and in controls, using two commercial ELISA assays: one from Shanghai Sunred Biological Technology Co., Ltd, with a sensitivity of 0.05 ng/mL and an assay range of 0.1–20 ng/mL, and the other assay from IBL International (Human soluble α-Klotho Assay Kit – IBL, Immuno-Biolog ical Laboratories Co., Ltd), with a sensitivity of 0.006 ng/mL and an assay range of 0.093–6 ng/mL. The values obtained were adjusted to urine creatinine. Creatinine was measured in serum and urine using standard techniques.Statistical analysis We analysed our results with GraphPad PRISM (version 4.0) software. A Kolmogorov-Smirnov test was conducted to verify that the variables followed a normal distribution. For the comparison of means with more than two variables, a one-factor ANOVA was performed with a post-hoc Bonferroni analysis, and for the comparison of two means, a Student’s or Mann-Whitney test was used in case of non-normal distribution. The correlations between the presence of AKI and urinary Klotho levels were conducted by Spearman’s correlation. The correlations between the Klotho levels measured with the two ELISA assays, and between the Klotho level (ng/ mg creatinine) and the serum delta creatinine (maximum serum creatinine – baseline creatinine), were conducted by Pearson’s bivariate correlation, with the SPSS vs. 19 analysis program. The significance level was set at p < 0.05.Results Patients characteristics The clinical and demographic characteristics of patients are shown in Table 1. The diagnosis of AKI using creatinine required 3 ± 1 days in cardiac surgery patients and 4 ± 2 days in angiography patients. With respect to mortality, eight patients died: four from the cardiac surgery group and the other four from the angiography group, all of whom had developed AKI. AKI patients had a mean hospital stay longer than patients who did not develop AKI in both groups of patients, although the differences were non-significant. In the angiography group, pre-intervention serum creatinine was significantly higher (p < 0.05) in AKI patients than in non-AKI patients, whereas the baseline estimated glomerular filtration rate (eGFR) was significantly lower in AKI patients (p < 0.01). No significant differences were found in these values in the group of patients with cardiac surgery (Table 1). In this group, the patients who developed AKI had been on extracorporeal circulation (ECC) for a longer period (p < 0.05) than patients who did not develop AKI (Table 1).Urinary Klotho values Urinary Klotho protein levels were significantly elevated in AKI patients both in the angiography group and the cardiac surgery group, when compared to the control group (p < 0.05) (Table 2). When correcting Klotho concentrations based on urine creatinine levels, only the AKI patients from the surgery group differed from the controls (p < 0.01), but there were no significant differences with respect to non-AKI patients (Table 2). If the patients from both groups are considered together, urinary Klotho levels (corrected for creatinine) were significantly higher in AKI patients than in healthy controls (p < 0.05), but there were no significant differences compared to non-AKI patients (Table 2). A correlation was not found between Klotho levels and the presence of AKI (r = 0.182, p = 0.67) when the Spearman’s test was conducted. Additionally, we examined whether there was a correlation between the Klotho level (ng/mg of urine creatinine) and delta serum creatinine (maximum serum creatinine – baseline creatinine) for both ELISA assays. No significant correlations were found when the patients from both groups were considered together or separately, regardless of the assay used.<img alt="Table 2 – Urinary Klotho values using two commercial ELISA kits" src="498v35n02-90412347fig2.jpg"></img> There was no significant correlation between urinary Klotho levels (ng/mL) measured by the two ELISA assays (r = –0.079; p = 0.614) or after correction based on urine creatinine (r = –0.043; p = 0.792).Discussion In this study, we assessed the usefulness of measuring Klotho protein in urine samples by ELISA for the early (12 hours post-intervention) detection of AKI in a group of patients with acute coronary syndrome or heart failure who had undergone cardiac surgery or coronary angiography, either with or without angioplasty or stenting. We found no significant differences in Klotho levels between the patients who developed AKI and those who did not. We also found a small but significant increase in urinary Klotho levels in AKI patients following cardiac surgery compared to healthy control subjects. The Klotho protein was measured in urine with two different ELISA kits for human Klotho. In the literature, there are no other studies testing urinary Klotho as an early biomarker of AKI in humans. There is only one study23 in which urinary Klotho was measured in 17 AKI patients by immunoblotting using anti-Klotho antibodies, and the authors reported decreased Klotho in AKI patients compared to 14 healthy controls, although the urine samples were collected at a late stage of renal failure progression. It has been shown in animal models that Klotho is underexpressed in the renal tissue in AKI secondary to ischaemia-reperfusion, ureteral obstruction, sepsis or nephrotoxic agents23,37-43, and that the overexpression of the transmembrane protein or the administration of soluble protein has a protective effect against the renal damage induced by ischaemia and reperfusion23,28 or nephrotoxins42. In 2010, Hu et al.23 measured Klotho expression in renal tissue as well as the levels of Klotho protein in plasma and urine in an animal model of ischaemia/reperfusion-induced AKI and found that Klotho was decreased at all levels. We had already studied the usefulness of different bio-markers as early predictors of AKI in this cohort of patients and had shown that NGAL46,47 was a strong predictor. Based on the evidence obtained in animal models of AKI, we expected to find decreased levels of Klotho protein in the urine of patients with AKI. There are several explanations for these dissimilar results. Firstly, all the experiments have been conducted in rats and mice. It is obvious that animal experiment conditions are not comparable to those in a clinical context and that the results obtained cannot be directly extrapolated. Moreover, it is possible that Klotho protein does not behave in the same manner in humans as in animal models. Another possible explanation lies in sample collection time. Hu et al.23 found decreased Klotho levels in urine one day after ischaemia-reperfusion, but in our study the samples were collected 12 hours after the intervention. They also measured urinary Klotho in 17 patients with AKI and found that the levels were much lower than those obtained from healthy volunteers. However, the population in their study was very heterogeneous (including prerenal AKI and sepsis-induced AKI, lupus, obstruction, liver failure, transplantation, uremic haemolytic syndrome and pregnancy) and data about the sample collection time were not provided. Notwithstanding, when the samples were collected, serum creatinine was 3.76 ± 0.58 mg/dL, so they were collected very late. It is also possible that urinary Klotho levels do not reflect Klotho expression well at renal tissue level. We know that the circulating levels do not relate to the expression in renal tissue in CKD. Data from animal experimentation clearly indicate the existence of Klotho deficit at renal level in CKD48. However, the measurement of Klotho protein in plasma provides dissimilar results. Hu et al.48 found very low Klotho levels in renal tissue, plasma and urine in mice with CKD, whereas Sugiura et al.49 found elevated levels in plasma from patients with CKD. Devaraj et al.50 reported decreased levels in diabetic patients and high levels in CKD patients and, furthermore, those values correlated with plasma creatinine. They hypothesised that the Klotho protein could be synthesised at an extrarenal level to provide renal protection by anti-oxidant and anti-inflammatory mechanisms. Nevertheless, Seiler et al.35 measured plasma Klotho levels in a cohort of 312 patients with Stage 2–4 CKD and did not find a correlation with glomerular filtration. Plasma Klotho levels did not correlate with renal function and did not predict progression in patients with CKD. It is possible that, in patients with AKI, the Klotho protein is also being synthesised at the extrarenal level to provide renal protection and that it is appearing in the urine due to the glomerular filtration. Hu et al.23 and Moreno et al.40 found decreased Klotho levels in plasma from animal models of AKI. So far, no study has measured Klotho in plasma from humans with AKI. Even if Klotho levels were not increased in plasma, it is possible that it could be synthesised at the extrarenal level and pass into ur ine. Therefore, plasma or urine levels may not reflect what is going on at tissue level. Further studies would be required to clarify this issue. Obviously, another possible explanation for the results is the existence of methodological differences. To obtain more robust results, two different human ELISA kits from different manufacturers were used to measure urinary Klotho levels, but no differences were found in patients with or without acute kidney injury using either kit. The little consistency between both assays is also notable. It is possible that different assays recognise different parts of the molecule and that some assays recognise the entire molecule while others recognise fragments. Heijboer et al.51 assessed three different ELISA assays, including the IBL one, and found major quality differences among them, IBL being clearly superior to the other two evaluated assays.Conclusion Despite the evidence in animal experimentation that Klotho is underexpressed in the kidney after either toxic or ischaemic AKI, in this study we did not find any correlation between the presence of AKI and urinary Klotho levels 12 hours after the intervention in a group of patients admitted to the ICU for acute coronary syndrome or heart failure who had undergone cardiac surgery or coronary angiography, either with or without angioplasty or stenting. Although these results need to be confirmed, urinary Klotho measured by ELISA does not seem to be a good candidate to be used as an early biomarker of AKI.Acknowledgments This research has received contributions from the Ministry of Science and Innovation [PS09/00806 (CM), PI10/01434 (AM) and PI12/00884 (CM)], co-funded by the European Regional Development Fund (ERDF), as well as contributions from the Conselleria de Educación de la Generalitat Valenciana (ACOMP/2009/191 and ACOMP/2012/056 to CM) and Sanitat (AP-028/10, AP-087/11 to CM).<hr></hr> Sent for review: 2 July 2014 Accepted on: 3 Dec. 2014<a href="http://dx.doi.org/10.3265/Nefrologia.pre2014.Dec.12663" class="elsevierStyleCrossRefs">http://dx.doi.org/10.3265/Nefrologia.pre2014.Dec.12663</a> * Corresponding author. Isidro Torregrosa, Nephrology, Hospital Clínico Universitario de Valencia, Avda Blasco Ibáñez 17, 46010, Valencia, Valencia, Spain E-mail:<a href="mailto:isist67@gmail.com" class="elsevierStyleCrossRefs">isist67@gmail.com</a>" "pdfFichero" => "498v35n02a90412347pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec503493" "palabras" => array:8 [ 0 => "Fracaso" 1 => "Renal" 2 => "Agudo" 3 => "Biomarcadores" 4 => "Cirugía cardiaca" 5 => "Angiografía coronaria" 6 => "Klotho" 7 => "ELISA" ] ] ] "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec503494" "palabras" => array:6 [ 0 => "Acute kidney injury" 1 => "Biomarkers" 2 => "Cardiac surgery" 3 => "Coronary angiography" 4 => "Klotho" 5 => "ELISA" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => " Introducción y objetivos: El fracaso renal agudo (FRA) es una complicación frecuente tras la cirugía cardiaca y las intervenciones percutáneas coronarias cuya aparición empeora el pronóstico de manera marcada. En los últimos años se han identificado nuevos biomarcadores precoces de FRA, pero aún quedan muchos aspectos importantes por resolver. Klotho es una proteína pleiotrópica que actúa como un factor paracrino y endocrino en múltiples órganos. En diversos modelos animales de FRA se ha demostrado niveles disminuidos de Klotho renal. No se ha publicado ningún estudio en el que se haya probado Klotho como marcador precoz de FRA en humanos. El objetivo de este trabajo es investigar la utilidad de la determinación de Klotho en orina para el diagnóstico precoz del FRA en pacientes con síndrome coronario agudo o fallo cardiaco sometidos a cirugía cardiaca o angiografía coronaria. Métodos: Se midió Klotho urinario 12 horas tras la intervención en 60 pacientes ingresados en la unidad de cuidados intensivos por síndrome coronario agudo o fallo cardiaco secundarios a enfermedad coronaria o valvular y a los que se realizó angiografía coronaria (30 pacientes) o cirugía cardiaca de recambio valvular o bypass (30 pacientes). El criterio de valoración primario fue la aparición de FRA según la clasificación RIFLE. Los niveles de Klotho humano se midieron utilizando un ensayo ELISA. Resultados: No encontramos diferencias en los niveles de Klotho en orina entre los pacientes que desarrollaron FRA y aquellos que no. Además, no había correlación significativa entre niveles de klotho en orina y presencia de FRA. Conclusión: Klotho urinario medido por ELISA no parece ser un buen candidato para ser usado como biomarcador precoz de FRA." ] "en" => array:1 [ "resumen" => " Background. Acute kidney injury (AKI) is a common complication after cardiac surgery and percutaneous coronary interventions which markedly worsens prognosis. In recent years, new early biomarkers of AKI have been identified, but many important aspects still remain to be solved. Klotho is a pleiotropic protein that acts as a paracrine and endocrine factor in multiple organs. Reduced renal Klotho levels have been show in several animal models of AKI. No study has been published in which Klotho was tested in humans as an early marker of AKI. The aim of this work is to assess the usefulness of measuring urinary Klotho for the early diagnosis of AKI in patients with acute coronary syndrome or heart failure undergoing cardiac surgery or coronary angiography. Methods. Urinary Klotho was measured 12 hours after intervention in 60 patients admitted to the Intensive Care Unit with acute coronary syndrome or heart failure secondary to coronary or valvular conditions, who underwent coronary angiography (30 patients) or cardiac bypass surgery or heart valve replacement (30 patients). The primary endpoint used was the onset of AKI according to the RIFLE classification system. Human Klotho levels were measured using an ELISA assay. Results. We found no differences in urinary Klotho levels between AKI patients and those who did not develop AKI. Moreover, there was not significant correlation between urinary Klotho levels and the presence of AKI. Conclusion. Urinary Klotho measured by ELISA does not seem to be a good candidate to be used as an early biomarker of AKI." ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "tbl1" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "498v35n02-90412347fig1.jpg" "imagenAlto" => 1758 "imagenAncho" => 1050 "imagenTamanyo" => 273679 ] ] ] ] ] "descripcion" => array:1 [ "en" => "– Clinical and demographic characteristics of patients" ] ] 1 => array:8 [ "identificador" => "tbl2" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tablaImagen" => array:1 [ 0 => array:4 [ "imagenFichero" => "498v35n02-90412347fig2.jpg" "imagenAlto" => 791 "imagenAncho" => 2100 "imagenTamanyo" => 252506 ] ] ] ] ] "descripcion" => array:1 [ "en" => "– Urinary Klotho values using two commercial ELISA kits" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:51 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Acute kidney injury associated with cardiac surgery. 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Klotho urinario determinado por ELISA como biomarcador precoz de fracaso renal agudo en pacientes sometidos a cirugía cardiaca o angiografía coronaria

Isidro Torregrosaa, Carmina Montoliub, Amparo Uriosb, Carla Giménez-Garzóc, Patricia Tomása, Miguel Ángel Solísa, Carmen Ramosa, Isabel Juana, María Jesús Puchadesa, Guillermo Sáezd, María Luisa Blascoe, Alfonso Miguela

a Nephrology, Hospital Clínico Universitario de Valencia [University Clinical Hospital of Valencia], Valencia, Valencia (Spain)

b Fundación Investigación Clínico de Valencia Instituto de Investigación Sanitaria INCLIVA [Valencia Clinical Research Foundation, Health Research Institute], Valencia, Valencia (Spain)

c Neurobiology Laboratory. Centro Investigación Príncipe Felipe [Príncipe Felipe Research Centre]. Valencia, Valencia (Spain)

d Coordinator of International Relations and Mobility Programs, Health Area of Universidad de Valencia [Valencia University], Biochemistry and Molecular Biology Department, Valencia, Valencia (Spain)

e Coronary Care Unit, Hospital Clínico Universitario de Valencia, Valencia, Valencia (Spain)

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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 cardiac surgery and percutaneous coronary interventions&#44; with an estimated incidence around 30&#37; in the former<span class="elsevierStyleSup">1-3</span> and between 5 and 20&#37; in the latter<span class="elsevierStyleSup">4-6</span>&#46; The onset of AKI significantly worsens prognosis in these patients<span class="elsevierStyleSup">2&#44;3&#44;7</span>&#46; AKI increases mortality in different clinical contexts and&#44; additionally&#44; patients often develop chronic kidney disease &#40;CKD&#41; after AKI<span class="elsevierStyleSup">8-9</span>&#46; The mechanisms involved in AKI include both endogenous and exogenous toxins&#44; metabolic factors&#44; ischaemia and reperfusion&#44; neurohumoral activation&#44; inflammation and oxidative stress<span class="elsevierStyleSup">10</span>&#46; The diagnosis of AKI is based on detecting increased serum creatinine&#44; which occurs late and does not adequately reflect the glomerular filtration in acute patients<span class="elsevierStyleSup">11</span>&#46; However&#44; experimental studies show that AKI can only be prevented or treated by means of early interventions<span class="elsevierStyleSup">12</span>&#46; New early biomarkers of AKI&#44; such as NGAL &#40;Neutrophil Gelatinase-Associated Lipocaline&#41;&#44; KIM-1 &#40;Kidney Injury Molecule 1&#41;&#44; L-FABP &#40;Liver Fatty Acid-Binding Protein&#41;&#44; Cystatin C or IL-18 &#40;Interleukin 18&#41;&#44; have been identified in recent years&#44; but many important aspects remain to be solved in the search for the ideal biomarker<span class="elsevierStyleSup">13</span>&#46; The study of these molecules has also provided a greater understanding of AKI pathogenesis&#46;</p><p class="elsevierStylePara"> The Klotho gene was identified in 1997 as an anti-aging gene<span class="elsevierStyleSup">14</span>&#46; This gene is expressed in multiple tissues&#44; the kidney being the organ where it is expressed more markedly&#44;<span class="elsevierStyleSup">15</span> especially in the distal tubule&#44; but also in the proximal tubule<span class="elsevierStyleSup">16</span> and the collecting duct<span class="elsevierStyleSup">17&#44;18</span>&#46; Klotho is a transmembrane protein that acts as a co-receptor for fibroblast growth factor-23 &#40;FGF-23&#41;<span class="elsevierStyleSup">19&#44;20</span>&#46; The ectodomain may be cut and released into the extracellular space by the proteases anchored to ADAM10 and ADAM17<span class="elsevierStyleSup">21</span> membrane&#46; This results in soluble Klotho&#44; which is present in blood&#44; cerebrospinal fluid<span class="elsevierStyleSup">22</span> and urine23&#46; There is another soluble Klotho protein which is shorter&#44; but its function is not well known<span class="elsevierStyleSup">24</span>&#46; Soluble Klotho is a pleiotropic protein that acts as a paracrine and endocrine hormonal factor&#44; both in the kidney and in other organs<span class="elsevierStyleSup">25</span>&#46; In the renal tubule&#44; Klotho modulates sodium-phosphate cotransporters<span class="elsevierStyleSup">23</span>&#44; calcium channels<span class="elsevierStyleSup">26</span> and potassium channels27&#46; Finally&#44; Klotho is also present at nuclear and cytoplasmic levels&#44; where it functions as an anti-aging protein<span class="elsevierStyleSup">28&#44;29</span>&#46;</p><p class="elsevierStylePara"> Klotho&#8217;s role in aging and in phosphocalcic metabolism continues to become more understood<span class="elsevierStyleSup">16&#44;30&#44;31</span>&#46; Its implications in the progression of CKD and its non-renal complications have also been the focus of intense study in recent years<span class="elsevierStyleSup">25&#44;32-34</span>&#44; as well as the relationship existing among its circulating levels&#44; glomerular filtration and CKD prognosis<span class="elsevierStyleSup">35</span> or its potential use as an anti-fibrotic agent<span class="elsevierStyleSup">36</span>&#46; With respect to AKI&#44; the presence of decreased Klotho levels has been shown in various animal models of AKI induced by ischaemia-reperfusion&#44; ureteral obstruction or nephrotoxic agents<span class="elsevierStyleSup">23&#44;37-43</span>&#46; In 2010&#44; Hu et al&#46;<span class="elsevierStyleSup">23</span> measured urinary Klotho in 17 AKI patients and found decreased levels compared to the values obtained in 14 healthy volunteers&#46; No other studies have been published about Klotho as an AKI biomarker in humans&#46; The objective of this paper was to assess the usefulness of measuring urinary Klotho for the early detection of AKI in patients with acute coronary syndrome or heart failure undergoing cardiac surgery or coronary angiography&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Methods</span></p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Patients </span></span></p><p class="elsevierStylePara"> Sixty patients were enrolled from a cohort of 193 patients admitted to the intensive care unit &#40;ICU&#41; of the Hospital Cl&#237;nico Universitario de Valencia with acute coronary syndrome &#40;ACS&#41; or heart failure secondary to coronary or valvular disease&#46; All patients had undergone coronary angiography with or without angioplasty or cardiac surgery&#46; The coronary angiography group was made up of 30 patients&#58; 18 had AKI after the intervention and 12 did not&#46; Another 30 patients were also selected in the cardiac surgery group&#58; 15 with AKI and 15 without AKI &#40;Table 1&#41;&#46;</p><p class="elsevierStylePara"><img alt="Table 1 – Clinical and demographic characteristics of patients" src="498v35n02-90412347fig1.jpg"></img></p><p class="elsevierStylePara"> The exclusion criteria were&#58; age younger than 18 years&#59; CKD on replacement therapy and AKI secondary to cardiogenic shock during hospitalisation&#46; All patients were prospectively monitored since their enrolment in the study&#46; Serum creatinine was measured from before the procedure up to six days after it&#44; and the clinical progress of each patient was monitored until discharge&#46; The first value of serum creatinine obtained on admission was used as the baseline creatinine value&#46; Urine samples for Klotho measurement were collected 12 hours after the intervention and processed immediately thereafter&#46; We also obtained urine samples from 10 healthy volunteers to determine the normal values&#46; Additionally&#44; the following information was collected from each patient&#58; demographic variables and comorbidities&#44; parameters of the surg ical procedure and complicat ions dur ing or after interventions &#40;Table 1&#41;&#46; The primary endpoint was the onset of AKI&#44; defined as an increase of creatinine of 50&#37; or more based on the RIFLE &#40;Risk&#44; Injury&#44; Failure&#44; Loss&#44; End-stage renal disease&#41; classification<span class="elsevierStyleSup">44</span>&#46; This study was approved by the Hospital Cl&#237;nico Universitario de Valencia Ethics Committee and it was conducted in compliance with the principles of the Declaration of Helsinki<span class="elsevierStyleSup">45</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Processing of urine samples </span></span></p><p class="elsevierStylePara"> Urine samples were centrifuged for 10 minutes at 1500 g immediately after being collected&#44; and the supernatant was stored in 0&#46;5-mL aliquots at &#8211;80&#186;C for later use&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Measurement of urinary Klotho levels </span></span></p><p class="elsevierStylePara"> Human Klotho levels were determined in urine&#44; both in patients and in controls&#44; using two commercial ELISA assays&#58; one from Shanghai Sunred Biological Technology Co&#46;&#44; Ltd&#44; with a sensitivity of 0&#46;05 ng&#47;mL and an assay range of 0&#46;1&#8211;20 ng&#47;mL&#44; and the other assay from IBL International &#40;Human soluble &#945;-Klotho Assay Kit &#8211; IBL&#44; Immuno-Biolog ical Laboratories Co&#46;&#44; Ltd&#41;&#44; with a sensitivity of 0&#46;006 ng&#47;mL and an assay range of 0&#46;093&#8211;6 ng&#47;mL&#46; The values obtained were adjusted to urine creatinine&#46; Creatinine was measured in serum and urine using standard techniques&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Statistical analysis </span></span></p><p class="elsevierStylePara"> We analysed our results with GraphPad PRISM &#40;version 4&#46;0&#41; software&#46; A Kolmogorov-Smirnov test was conducted to verify that the variables followed a normal distribution&#46; For the comparison of means with more than two variables&#44; a one-factor ANOVA was performed with a post-hoc Bonferroni analysis&#44; and for the comparison of two means&#44; a Student&#8217;s or Mann-Whitney test was used in case of non-normal distribution&#46; The correlations between the presence of AKI and urinary Klotho levels were conducted by Spearman&#8217;s correlation&#46; The correlations between the Klotho levels measured with the two ELISA assays&#44; and between the Klotho level &#40;ng&#47; mg creatinine&#41; and the serum delta creatinine &#40;maximum serum creatinine &#8211; baseline creatinine&#41;&#44; were conducted by Pearson&#8217;s bivariate correlation&#44; with the SPSS vs&#46; 19 analysis program&#46; The significance level was set at p &#60; 0&#46;05&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Results </span></p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Patients characteristics </span></span></p><p class="elsevierStylePara"> The clinical and demographic characteristics of patients are shown in Table 1&#46; The diagnosis of AKI using creatinine required 3 &#177; 1 days in cardiac surgery patients and 4 &#177; 2 days in angiography patients&#46; With respect to mortality&#44; eight patients died&#58; four from the cardiac surgery group and the other four from the angiography group&#44; all of whom had developed AKI&#46; AKI patients had a mean hospital stay longer than patients who did not develop AKI in both groups of patients&#44; although the differences were non-significant&#46; In the angiography group&#44; pre-intervention serum creatinine was significantly higher &#40;p &#60; 0&#46;05&#41; in AKI patients than in non-AKI patients&#44; whereas the baseline estimated glomerular filtration rate &#40;eGFR&#41; was significantly lower in AKI patients &#40;p &#60; 0&#46;01&#41;&#46; No significant differences were found in these values in the group of patients with cardiac surgery &#40;Table 1&#41;&#46; In this group&#44; the patients who developed AKI had been on extracorporeal circulation &#40;ECC&#41; for a longer period &#40;p &#60; 0&#46;05&#41; than patients who did not develop AKI &#40;Table 1&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Urinary Klotho values </span></span></p><p class="elsevierStylePara"> Urinary Klotho protein levels were significantly elevated in AKI patients both in the angiography group and the cardiac surgery group&#44; when compared to the control group &#40;p &#60; 0&#46;05&#41; &#40;Table 2&#41;&#46; When correcting Klotho concentrations based on urine creatinine levels&#44; only the AKI patients from the surgery group differed from the controls &#40;p &#60; 0&#46;01&#41;&#44; but there were no significant differences with respect to non-AKI patients &#40;Table 2&#41;&#46; If the patients from both groups are considered together&#44; urinary Klotho levels &#40;corrected for creatinine&#41; were significantly higher in AKI patients than in healthy controls &#40;p &#60; 0&#46;05&#41;&#44; but there were no significant differences compared to non-AKI patients &#40;Table 2&#41;&#46; A correlation was not found between Klotho levels and the presence of AKI &#40;r &#61; 0&#46;182&#44; p &#61; 0&#46;67&#41; when the Spearman&#8217;s test was conducted&#46; Additionally&#44; we examined whether there was a correlation between the Klotho level &#40;ng&#47;mg of urine creatinine&#41; and delta serum creatinine &#40;maximum serum creatinine &#8211; baseline creatinine&#41; for both ELISA assays&#46; No significant correlations were found when the patients from both groups were considered together or separately&#44; regardless of the assay used&#46;</p><p class="elsevierStylePara"><img alt="Table 2 – Urinary Klotho values using two commercial ELISA kits" src="498v35n02-90412347fig2.jpg"></img></p><p class="elsevierStylePara"> There was no significant correlation between urinary Klotho levels &#40;ng&#47;mL&#41; measured by the two ELISA assays &#40;r &#61; &#8211;0&#46;079&#59; p &#61; 0&#46;614&#41; or after correction based on urine creatinine &#40;r &#61; &#8211;0&#46;043&#59; p &#61; 0&#46;792&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Discussion </span></p><p class="elsevierStylePara"> In this study&#44; we assessed the usefulness of measuring Klotho protein in urine samples by ELISA for the early &#40;12 hours post-intervention&#41; detection of AKI in a group of patients with acute coronary syndrome or heart failure who had undergone cardiac surgery or coronary angiography&#44; either with or without angioplasty or stenting&#46; We found no significant differences in Klotho levels between the patients who developed AKI and those who did not&#46; We also found a small but significant increase in urinary Klotho levels in AKI patients following cardiac surgery compared to healthy control subjects&#46; The Klotho protein was measured in urine with two different ELISA kits for human Klotho&#46;</p><p class="elsevierStylePara"> In the literature&#44; there are no other studies testing urinary Klotho as an early biomarker of AKI in humans&#46; There is only one study<span class="elsevierStyleSup">23</span> in which urinary Klotho was measured in 17 AKI patients by immunoblotting using anti-Klotho antibodies&#44; and the authors reported decreased Klotho in AKI patients compared to 14 healthy controls&#44; although the urine samples were collected at a late stage of renal failure progression&#46; It has been shown in animal models that Klotho is underexpressed in the renal tissue in AKI secondary to ischaemia-reperfusion&#44; ureteral obstruction&#44; sepsis or nephrotoxic agents<span class="elsevierStyleSup">23&#44;37-43</span>&#44; and that the overexpression of the transmembrane protein or the administration of soluble protein has a protective effect against the renal damage induced by ischaemia and reperfusion<span class="elsevierStyleSup">23&#44;28</span> or nephrotoxins42&#46; In 2010&#44; Hu et al&#46;<span class="elsevierStyleSup">23</span> measured Klotho expression in renal tissue as well as the levels of Klotho protein in plasma and urine in an animal model of ischaemia&#47;reperfusion-induced AKI and found that Klotho was decreased at all levels&#46;</p><p class="elsevierStylePara"> We had already studied the usefulness of different bio-markers as early predictors of AKI in this cohort of patients and had shown that NGAL<span class="elsevierStyleSup">46&#44;47</span> was a strong predictor&#46; Based on the evidence obtained in animal models of AKI&#44; we expected to find decreased levels of Klotho protein in the urine of patients with AKI&#46; There are several explanations for these dissimilar results&#46; Firstly&#44; all the experiments have been conducted in rats and mice&#46; It is obvious that animal experiment conditions are not comparable to those in a clinical context and that the results obtained cannot be directly extrapolated&#46; Moreover&#44; it is possible that Klotho protein does not behave in the same manner in humans as in animal models&#46; Another possible explanation lies in sample collection time&#46; Hu et al&#46;<span class="elsevierStyleSup">23</span> found decreased Klotho levels in urine one day after ischaemia-reperfusion&#44; but in our study the samples were collected 12 hours after the intervention&#46; They also measured urinary Klotho in 17 patients with AKI and found that the levels were much lower than those obtained from healthy volunteers&#46; However&#44; the population in their study was very heterogeneous &#40;including prerenal AKI and sepsis-induced AKI&#44; lupus&#44; obstruction&#44; liver failure&#44; transplantation&#44; uremic haemolytic syndrome and pregnancy&#41; and data about the sample collection time were not provided&#46; Notwithstanding&#44; when the samples were collected&#44; serum creatinine was 3&#46;76 &#177; 0&#46;58 mg&#47;dL&#44; so they were collected very late&#46; It is also possible that urinary Klotho levels do not reflect Klotho expression well at renal tissue level&#46; We know that the circulating levels do not relate to the expression in renal tissue in CKD&#46; Data from animal experimentation clearly indicate the existence of Klotho deficit at renal level in CKD<span class="elsevierStyleSup">48</span>&#46; However&#44; the measurement of Klotho protein in plasma provides dissimilar results&#46; Hu et al&#46;<span class="elsevierStyleSup">48</span> found very low Klotho levels in renal tissue&#44; plasma and urine in mice with CKD&#44; whereas Sugiura et al&#46;<span class="elsevierStyleSup">49</span> found elevated levels in plasma from patients with CKD&#46; Devaraj et al&#46;<span class="elsevierStyleSup">50</span> reported decreased levels in diabetic patients and high levels in CKD patients and&#44; furthermore&#44; those values correlated with plasma creatinine&#46; They hypothesised that the Klotho protein could be synthesised at an extrarenal level to provide renal protection by anti-oxidant and anti-inflammatory mechanisms&#46; Nevertheless&#44; Seiler et al&#46;<span class="elsevierStyleSup">35</span> measured plasma Klotho levels in a cohort of 312 patients with Stage 2&#8211;4 CKD and did not find a correlation with glomerular filtration&#46; Plasma Klotho levels did not correlate with renal function and did not predict progression in patients with CKD&#46; It is possible that&#44; in patients with AKI&#44; the Klotho protein is also being synthesised at the extrarenal level to provide renal protection and that it is appearing in the urine due to the glomerular filtration&#46; Hu et al&#46;<span class="elsevierStyleSup">23</span> and Moreno et al&#46;<span class="elsevierStyleSup">40</span> found decreased Klotho levels in plasma from animal models of AKI&#46; So far&#44; no study has measured Klotho in plasma from humans with AKI&#46; Even if Klotho levels were not increased in plasma&#44; it is possible that it could be synthesised at the extrarenal level and pass into ur ine&#46; Therefore&#44; plasma or urine levels may not reflect what is going on at tissue level&#46; Further studies would be required to clarify this issue&#46;</p><p class="elsevierStylePara"> Obviously&#44; another possible explanation for the results is the existence of methodological differences&#46; To obtain more robust results&#44; two different human ELISA kits from different manufacturers were used to measure urinary Klotho levels&#44; but no differences were found in patients with or without acute kidney injury using either kit&#46; The little consistency between both assays is also notable&#46; It is possible that different assays recognise different parts of the molecule and that some assays recognise the entire molecule while others recognise fragments&#46; Heijboer et al&#46;<span class="elsevierStyleSup">51</span> assessed three different ELISA assays&#44; including the IBL one&#44; and found major quality differences among them&#44; IBL being clearly superior to the other two evaluated assays&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conclusion </span></p><p class="elsevierStylePara"> Despite the evidence in animal experimentation that Klotho is underexpressed in the kidney after either toxic or ischaemic AKI&#44; in this study we did not find any correlation between the presence of AKI and urinary Klotho levels 12 hours after the intervention in a group of patients admitted to the ICU for acute coronary syndrome or heart failure who had undergone cardiac surgery or coronary angiography&#44; either with or without angioplasty or stenting&#46; Although these results need to be confirmed&#44; urinary Klotho measured by ELISA does not seem to be a good candidate to be used as an early biomarker of AKI&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Acknowledgments </span></p><p class="elsevierStylePara"> This research has received contributions from the Ministry of Science and Innovation &#91;PS09&#47;00806 &#40;CM&#41;&#44; PI10&#47;01434 &#40;AM&#41; and PI12&#47;00884 &#40;CM&#41;&#93;&#44; co-funded by the European Regional Development Fund &#40;ERDF&#41;&#44; as well as contributions from the Conselleria de Educaci&#243;n de la Generalitat Valenciana &#40;ACOMP&#47;2009&#47;191 and ACOMP&#47;2012&#47;056 to CM&#41; and Sanitat &#40;AP-028&#47;10&#44; AP-087&#47;11 to CM&#41;&#46;</p><hr></hr><p class="elsevierStylePara"> Sent for review&#58; 2 July 2014 <br></br> Accepted on&#58; 3 Dec&#46; 2014</p><p class="elsevierStylePara"><a href="http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;3265&#47;Nefrologia&#46;pre2014&#46;Dec&#46;12663" class="elsevierStyleCrossRefs">http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;3265&#47;Nefrologia&#46;pre2014&#46;Dec&#46;12663</a></p><p class="elsevierStylePara"> &#42; <span class="elsevierStyleItalic">Corresponding author</span>&#46;<br></br> Isidro Torregrosa&#44; Nephrology&#44; <br></br> Hospital Cl&#237;nico Universitario de Valencia&#44; <br></br> Avda Blasco Ib&#225;&#241;ez 17&#44; 46010&#44; Valencia&#44; Valencia&#44; Spain <br></br><span class="elsevierStyleItalic">E-mail&#58;</span><a href="mailto&#58;isist67&#64;gmail&#46;com" class="elsevierStyleCrossRefs">isist67&#64;gmail&#46;com</a></p>"
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        "resumen" => "<p class="elsevierStylePara"> <span class="elsevierStyleItalic">Introducci&#243;n y objetivos&#58;</span> El fracaso renal agudo &#40;FRA&#41; es una complicaci&#243;n frecuente tras la cirug&#237;a cardiaca y las intervenciones percut&#225;neas coronarias cuya aparici&#243;n empeora el pron&#243;stico de manera marcada&#46; En los &#250;ltimos a&#241;os se han identificado nuevos biomarcadores precoces de FRA&#44; pero a&#250;n quedan muchos aspectos importantes por resolver&#46; Klotho es una prote&#237;na pleiotr&#243;pica que act&#250;a como un factor paracrino y endocrino en m&#250;ltiples &#243;rganos&#46; En diversos modelos animales de FRA se ha demostrado niveles disminuidos de Klotho renal&#46; No se ha publicado ning&#250;n estudio en el que se haya probado Klotho como marcador precoz de FRA en humanos&#46; El objetivo de este trabajo es investigar la utilidad de la determinaci&#243;n de Klotho en orina para el diagn&#243;stico precoz del FRA en pacientes con s&#237;ndrome coronario agudo o fallo cardiaco sometidos a cirug&#237;a cardiaca o angiograf&#237;a coronaria&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">M&#233;todos&#58;</span> Se midi&#243; Klotho urinario 12 horas tras la intervenci&#243;n en 60 pacientes ingresados en la unidad de cuidados intensivos por s&#237;ndrome coronario agudo o fallo cardiaco secundarios a enfermedad coronaria o valvular y a los que se realiz&#243; angiograf&#237;a coronaria &#40;30 pacientes&#41; o cirug&#237;a cardiaca de recambio valvular o bypass &#40;30 pacientes&#41;&#46; El criterio de valoraci&#243;n primario fue la aparici&#243;n de FRA seg&#250;n la clasificaci&#243;n RIFLE&#46; Los niveles de Klotho humano se midieron utilizando un ensayo ELISA&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Resultados&#58; </span>No encontramos diferencias en los niveles de Klotho en orina entre los pacientes que desarrollaron FRA y aquellos que no&#46; Adem&#225;s&#44; no hab&#237;a correlaci&#243;n significativa entre niveles de klotho en orina y presencia de FRA&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Conclusi&#243;n&#58;</span> Klotho urinario medido por ELISA no parece ser un buen candidato para ser usado como biomarcador precoz de FRA&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"> <span class="elsevierStyleItalic">Background&#46;</span> Acute kidney injury &#40;AKI&#41; is a common complication after cardiac surgery and percutaneous coronary interventions which markedly worsens prognosis&#46; In recent years&#44; new early biomarkers of AKI have been identified&#44; but many important aspects still remain to be solved&#46; Klotho is a pleiotropic protein that acts as a paracrine and endocrine factor in multiple organs&#46; Reduced renal Klotho levels have been show in several animal models of AKI&#46; No study has been published in which Klotho was tested in humans as an early marker of AKI&#46; The aim of this work is to assess the usefulness of measuring urinary Klotho for the early diagnosis of AKI in patients with acute coronary syndrome or heart failure undergoing cardiac surgery or coronary angiography&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Methods&#46;</span> Urinary Klotho was measured 12 hours after intervention in 60 patients admitted to the Intensive Care Unit with acute coronary syndrome or heart failure secondary to coronary or valvular conditions&#44; who underwent coronary angiography &#40;30 patients&#41; or cardiac bypass surgery or heart valve replacement &#40;30 patients&#41;&#46; The primary endpoint used was the onset of AKI according to the RIFLE classification system&#46; Human Klotho levels were measured using an ELISA assay&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Results&#46;</span> We found no differences in urinary Klotho levels between AKI patients and those who did not develop AKI&#46; Moreover&#44; there was not significant correlation between urinary Klotho levels and the presence of AKI&#46;</p> <p class="elsevierStylePara"> <span class="elsevierStyleItalic">Conclusion&#46;</span> Urinary Klotho measured by ELISA does not seem to be a good candidate to be used as an early biomarker of AKI&#46;</p>"
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Article information

ISSN: 20132514
Original language: English

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Year/Month	Html	Pdf	Total

2024 November	6	7	13
2024 October	59	29	88
2024 September	50	23	73
2024 August	67	34	101
2024 July	51	26	77
2024 June	57	32	89
2024 May	63	27	90
2024 April	46	30	76
2024 March	43	21	64
2024 February	38	33	71
2024 January	31	25	56
2023 December	24	29	53
2023 November	50	35	85
2023 October	39	23	62
2023 September	26	19	45
2023 August	42	22	64
2023 July	43	22	65
2023 June	37	13	50
2023 May	49	31	80
2023 April	28	13	41
2023 March	45	22	67
2023 February	24	14	38
2023 January	34	27	61
2022 December	57	29	86
2022 November	41	36	77
2022 October	50	26	76
2022 September	43	21	64
2022 August	46	51	97
2022 July	20	40	60
2022 June	32	27	59
2022 May	29	28	57
2022 April	35	34	69
2022 March	32	38	70
2022 February	33	40	73
2022 January	27	21	48
2021 December	37	40	77
2021 November	27	34	61
2021 October	27	43	70
2021 September	34	34	68
2021 August	26	37	63
2021 July	34	32	66
2021 June	27	20	47
2021 May	29	27	56
2021 April	62	48	110
2021 March	43	23	66
2021 February	41	12	53
2021 January	54	25	79
2020 December	45	14	59
2020 November	35	12	47
2020 October	24	17	41
2020 September	30	12	42
2020 August	50	18	68
2020 July	32	9	41
2020 June	29	11	40
2020 May	42	15	57
2020 April	46	17	63
2020 March	37	12	49
2020 February	30	16	46
2020 January	60	19	79
2019 December	55	28	83
2019 November	41	23	64
2019 October	34	15	49
2019 September	46	12	58
2019 August	47	18	65
2019 July	53	34	87
2019 June	37	15	52
2019 May	36	19	55
2019 April	110	28	138
2019 March	37	16	53
2019 February	26	8	34
2019 January	42	24	66
2018 December	84	36	120
2018 November	108	13	121
2018 October	105	15	120
2018 September	70	15	85
2018 August	44	15	59
2018 July	65	18	83
2018 June	53	16	69
2018 May	64	15	79
2018 April	62	9	71
2018 March	42	8	50
2018 February	33	10	43
2018 January	29	10	39
2017 December	42	10	52
2017 November	58	10	68
2017 October	40	7	47
2017 September	43	7	50
2017 August	54	8	62
2017 July	61	15	76
2017 June	68	9	77
2017 May	78	12	90
2017 April	59	5	64
2017 March	57	8	65
2017 February	64	21	85
2017 January	42	14	56
2016 December	123	26	149
2016 November	125	15	140
2016 October	139	21	160
2016 September	162	7	169
2016 August	249	0	249
2016 July	206	0	206
2016 June	156	0	156
2016 May	158	0	158
2016 April	174	0	174
2016 March	134	0	134
2016 February	237	0	237
2016 January	174	0	174
2015 December	188	1	189
2015 November	123	1	124
2015 October	150	5	155
2015 September	124	3	127
2015 August	162	36	198
2015 July	268	0	268
2015 June	174	0	174
2015 May	253	25	278
2015 April	33	0	33

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