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years&#46; The data were collected and evaluated by four observers&#46; Demographic variables &#40;age and sex&#41;&#44; personal medical history &#40;cardiovascular risk factors &#91;presence of diabetes&#44; dyslipidaemia&#44; smoking&#44; blood pressure levels and monitoring&#44; abdominal circumference&#93; and cardiovascular history prior to the study&#41; were collected at baseline and laboratory studies were ordered for cardiac markers &#40;troponin T&#44; brain natriuretic peptide &#91;BNP&#93;&#41;&#44; kidney disease &#40;creatinine&#44; albuminuria&#41;&#44; inflammation-nutritional markers &#40;ferritin&#44; fibrinogen&#44; C-reactive protein &#91;CRP&#93;&#44; albumin&#41;&#44; calcium-phosphorus metabolism markers &#40;parathyroid hormone &#91;PTH&#93;&#44; calcium&#44; phosphorus&#44; vitamin D&#41; as well as other variables that were considered relevant such as insulin&#44; homocystein and haemoglobin&#46; None of these measurements required more blood draws or office visits on the part of the patient&#46; Patients also provided verbal informed consent for inclusion in the study&#46;</p><p class="elsevierStylePara">We define dyslipidaemia according to the ATP III guidelines &#40;LDL greater than 160mg&#47;dl in patients with 0-1 risk factor&#59; greater than 130mg&#47;dl in patients with more than 1 risk factor&#59; greater than 100mg&#47;dl in patients with coronary artery disease or equivalent&#59; or those in treatment with lipid-lowering agents&#41;&#46;<span class="elsevierStyleSup">16</span> We define hypertension according to the criteria of the seventh report of the Joint National Committee &#40;blood pressure above 140&#47;90mmHg or in treatment with at least one antihypertensive agent&#41;&#46;<span class="elsevierStyleSup">17</span> We define progression according to the recently published &#8220;Consensus Document on Chronic Kidney Disease&#34;<span class="elsevierStyleSup">6</span> as loss of more than 5ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#47;year of glomerular filtration rate &#40;GFR&#41;&#44; GFR deterioration greater than 25&#37; or greater than 50&#37; increase in the urine albumin&#47;creatinine ratio&#46;</p><p class="elsevierStylePara">Routine methods were used to measure creatinine&#44; albumin&#44; haemoglobin&#44; uric acid&#44; fibrinogen&#44; PTH&#44; calcium&#44; phosphorus and vitamin D&#46;&#160; Ultrasensitive CRP was measured using turbidimetric immunoassay in the HITACHI automatic analyzer &#40;Sigma Chemical Co&#46;&#44; St&#46; Louis&#44; MO&#44; USA&#41;&#46; Albuminuria was measured as the albumin&#47;creatinine ratio with an immunonephelometric method&#46; Cardiac troponin T and BNP were measured using a third-generation electrochemiluminescence &#40;ECLIA&#41; immunoassay &#40;Roche Diagnostics&#44; Basel&#44; Switzerland&#41;&#46; Based on the estimated GFR by CKD-EPI&#44; we divided the patients into stages according to the K&#47;DOQI Guideline classification&#46;<span class="elsevierStyleSup">18</span></p><p class="elsevierStylePara">The first cardiovascular events &#40;fatal and non-fatal&#41; were recorded during follow-up &#40;median 38 &#91;37-39&#93; months&#41;&#58;</p><ul><li>Heart failure&#46;</li><li>Arrhythmia&#46;</li><li>Peripheral artery disease &#40;diagnosed as stenosis of the main arteries or arteries of the lower extremities confirmed by arteriogram&#59; or the need for amputation&#41;&#46;</li><li>Stroke&#46;</li><li>Coronary event&#46;</li></ul><p class="elsevierStylePara">In addition to deaths by other causes&#44; we defined a combined variable for all endpoint events &#40;composed of cardiovascular events and death due to any cause&#41;&#46;</p><p class="elsevierStylePara">A univariate analysis was done in order to corroborate the factors associated with an endpoint event&#46; Afterwards&#44; those factors that were independent predictors were analyzed using multivariate analysis&#46;</p><p class="elsevierStylePara">The variables are expressed as the mean &#40;standard deviation&#41; if they follow a normal distribution &#40;according the Kolmogorov-Smirnov test&#41;&#46; When the variables do not follow a normal distribution&#44; they are expressed as the median &#40;interquartile range&#41;&#46; Student&#8217;s t test or the &#967;<span class="elsevierStyleSup">2</span> test was used for variables with a normal distribution&#44; otherwise the Mann-Whitney U test was used&#46;&#160; Logistical regression analysis was performed to analyze what variables were predictive of endpoint events&#46; A survival analysis was performed using the Kaplan-Meier curves in order to confirm the link between albuminuria &#40;urine albumin&#47;creatinine ratio above or below 1000mg&#47;g&#41; and the events&#46; In addition&#44; linear regression was used to calculate the progression of CKD&#46; This cut-off point was chosen as it was sufficient data in the univariate analysis&#46; A value of <span class="elsevierStyleItalic">P</span>&#60;&#46;05 was considered to be statistically significant&#46; SPSS version 16&#174; &#40;Chicago&#44; IL&#44; USA&#41; was used for the statistical analysis&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The baseline characteristics of the population &#40;n&#61;218&#41; are shown in Table 1&#46; The baseline laboratory values are shown in Table 2&#46; Patients with CKD&#44; stages 1 to 4&#44; were included and distributed as follows&#58; stage 1&#44; 10&#37;&#59; stage 2&#44; 18&#37;&#59; stage 3&#44; 48&#37;&#59; stage 4&#44; 23&#37;&#46;</p><p class="elsevierStylePara">During follow-up &#40;38 &#91;37-39&#93; months&#41;&#44; 50 patients had an event&#58; 37 patients &#40;17&#37;&#41; had a cardiovascular event and 13 &#40;6&#37;&#41; died due to a non-cardiovascular cause&#46; The distribution of the events was the following&#58; 33&#37; coronary event&#44; 29&#37; died&#44; 17&#37; first episode of heart failure&#44; 8&#37; some type of arrhythmia&#44; 8&#37; stroke and 2&#37; peripheral artery disease&#46; 10&#37; of patients &#40;21&#41; were lost in follow-up because they stopped coming in to the outpatient clinic&#46; Among the lost patients and those who completed follow-up&#44; statistically significant differences were only found for sex &#40;more men lost&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;022&#41;&#46;</p><p class="elsevierStylePara">The univariate analysis revealed that factors that were associated with having an endpoint event &#40;cardiovascular event or death due to non-cardiovascular cause&#41; were male sex&#44; active smoking&#44; diabetes mellitus&#44; low diastolic blood pressure&#44; cardiovascular history&#44; lower GFR&#44; an urine albumin&#47;creatinine ratio greater than 1000mg&#47;g &#40;when we found 300mg&#47;g&#44; we obtained a value of <span class="elsevierStyleItalic">P</span>&#61;&#46;14&#41;&#44; troponin T levels greater than 0&#46;01ng&#47;l&#44; BNP levels greater than 34pg&#47;ml&#44; CRP levels greater than 2&#46;7mg&#47;dl and low haemoglobin levels &#40;Table 4&#41;&#46; A survival analysis was performed for the endpoint event with Kaplan-Meier curves in order to evaluate their associated with albuminuria levels &#40;Figure 1&#41;&#46; We found no significant differences between patients with and without progression of their CKD &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;566&#41;&#46;</p><p class="elsevierStylePara">Male sex&#44; diabetes mellitus&#44; cardiovascular history and reduced GFR maintained their independent predictive value on multivariate analysis by logical regression&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Classic cardiovascular risk factors such as being male&#44; diabetic&#44; having a higher stage of kidney disease or having a cardiovascular history are independent predictors of cardiovascular events and mortality in patients with CKD&#46;</p><p class="elsevierStylePara">The incidence of events in our population is around 5&#37; annually&#44; findings that are slightly lower than previously published series&#46;<span class="elsevierStyleSup">19&#44;20</span> This is probably due to a different distribution of patients by stages in our series &#40;with a greater number in stage 3&#41;&#44; the younger age of our patients and the lesser history of cardiovascular risk factors&#46; In addition&#44; the distribution of cardiovascular events increases with kidney disease stage&#46; However&#44; this progression disappears when mortality is combined in the endpoint event&#46; The reason is probably the same since an event in stages 1 and 2 leads to a significant increase in the total percentage&#46;</p><p class="elsevierStylePara">As in our case&#44; male sex has been shown to be an independent factor for cardiovascular events and mortality in populations with and without kidney disease&#46;<span class="elsevierStyleSup">21&#44;22</span> However&#44; age does not achieve a significant value between both groups&#46; This is probably because of the very narrow age range in our patients&#46; Conversely&#44; tobacco use&#44; which is associated with having an event&#44; loses its predictive value&#46; This is because the majority of smokers have a cardiovascular history&#46; In addition&#44; the percentage of smokers in our outpatient clinic is low compared to the general population&#46;<span class="elsevierStyleSup">23</span></p><p class="elsevierStylePara">The association between kidney disease and cardiovascular events is known and has been studied broadly&#46;<span class="elsevierStyleSup">4&#44;5</span> The element that contributes most to an increase in these events is probably endothelial dysfunction given that this is considered to be the first step in the development of atheromas&#46; This endothelial damage is not only explained by classic cardiovascular risk factors but also by the microinflammation environment in patients with CKD&#44; uraemia&#44; malnutrition&#44; volume overload or calcium-phosphorus metabolism alterations&#46;<span class="elsevierStyleSup">24-26</span> These data support the assertion that kidney disease itself is a cardiovascular risk factor and leads to the determination that&#44; despite carrying out exhaustive monitoring of these factors&#44; the population with CKD continues to be at an increased risk for an event&#46;<span class="elsevierStyleSup">27</span> The classic RENAAL and LIFE studies on cardiovascular risk&#44; which include diabetic and&#47;or hypertensive patients&#44; demonstrate that baseline creatinine is the most significant independent predictor for the development of cardiovascular events&#46;<span class="elsevierStyleSup">28-30</span></p><p class="elsevierStylePara">The association between elevated cardiac markers and cardiovascular events indicates the presence of these subclinical asymptomatic lesions in patients with CKD&#46;<span class="elsevierStyleSup">6</span> Several studies have demonstrated that both troponin and natriuretic peptide levels are elevated in patients with CKD&#59; however&#44; this situation does not seem to be related to the deterioration in GFR but instead is due to silent myocardial damage or volume overload&#46;<span class="elsevierStyleSup">7&#44;31&#44;32</span> Therefore&#44; it is not surprising that after adjusting the multivariate model for cardiovascular risk factors&#44; these variables lose their independent predictive ability&#46; This is because they are not effectors but simply cardiovascular risk markers and their baseline value should therefore be obtained in the nephrology department&#46;<span class="elsevierStyleSup">33</span></p><p class="elsevierStylePara">Diabetes mellitus is a cardiovascular risk factor on its own&#46; It causes an increase in cardiovascular events&#44; as is seen in our data&#46;<span class="elsevierStyleSup">34&#44;35</span> However&#44; although proteinuria shows an association with cardiovascular events&#44; we have not been able to demonstrate that it is an independent predictive factor&#46; This is probably due to the fact that diabetics make up the highest percentage of patients with a urine albumin&#47;creatinine ratio greater than 1000mg&#47;g&#44; which causes it to lose its significance in multivariate analysis that includes diabetic patients&#46; Conversely&#44; the presence of hypertension was not associated with the presence of events&#44; though low diastolic blood pressure was associated with having an event&#46; Both high and low systolic and diastolic blood pressure has been associated with the presence of cardiovascular events and mortality&#44; meaning that excessive control of hypertensive patients carries an increased risk that is similar to that seen in patients with high levels &#40;J-curve effect&#41;&#46;<span class="elsevierStyleSup">37&#44;38</span> As can be seen in the distribution of CKD aetiology in Table 1&#44; more than 40&#37; of patients have vascular disease or diabetes&#46; This confirms the high prevalence of these pathologies in patients with deteriorated kidney function&#46; This distribution coincides with the data in the Spanish Nephrology Society registry&#46;</p><p class="elsevierStylePara">We were not able to demonstrate an association between increased cardiovascular risk and the emerging factors mentioned previously&#46; In our cohort&#44; neither the presence of increased uric acid nor inflammation markers demonstrated an association with the combined endpoint event&#46; This is probably due to low baseline levels of these variables&#46; Therefore&#44; it would seem that monitoring these variables is less relevant in the prognosis of these patients when compared to the classic factors&#46; These data lead us to think that indiscriminate measurement of these variables in nephrology department is&#44; for the moment&#44; not justified when compared to the classic cardiovascular risk parameters&#46;</p><p class="elsevierStylePara">Our study has some limitations such as being a single-site study and it lacks the echocardiographic parameters necessary to perform a more exhaustive study of heart disease&#46; As these are consecutive patients&#44; the distribution of patients by stage is not homogeneous and above all the results are valid for the population studied &#40;patients in an outpatient nephrology clinic&#41;&#46; In addition&#44; the number of patients and the follow-up time are also limitations of the study&#46;</p><p class="elsevierStylePara">In conclusion&#44; male sex&#44; diabetes mellitus&#44; having a reduced GFR &#40;CKD-EPI&#41; and a history of cardiovascular risk are independent predictors of cardiovascular risk factors and mortality in patients with CKD &#40;stages 1-4&#41;&#46; In addition&#44; the presence of an albumin&#47;creatinine ratio greater than 1000mg&#47;g is associated with a greater number of events&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49223&#95;en&#95;t111895&#95;03&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49223_en_t111895_03.jpg" alt="Baseline characteristics of the study population"></img></a></p><p class="elsevierStylePara">Table 1&#46; Baseline characteristics of the study population</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49224&#95;en&#95;t211895&#95;03&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49224_en_t211895_03.jpg" alt="Variables measured at baseline in the study population"></img></a></p><p class="elsevierStylePara">Table 2&#46; Variables measured at baseline in the study population</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49225&#95;en&#95;t311895&#95;03&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49225_en_t311895_03.jpg" alt="Cardiovascular events and mortality distributed by stages&#46;"></img></a></p><p class="elsevierStylePara">Table 3&#46; Cardiovascular events and mortality distributed by stages&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49226&#95;en&#95;t411895&#95;03&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49226_en_t411895_03.jpg" alt="Univariate and multivariate analysis for combined event"></img></a></p><p class="elsevierStylePara">Table 4&#46; Univariate and multivariate analysis for combined event</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49227&#95;en&#95;f111895&#95;035&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49227_en_f111895_035.jpg" alt="Kaplan-Meier survival analysis between patients with a urine albumin&#47;creatinine ratio above or below 1 g&#47;g &#40;log-rank 5&#46;99&#44; p &#38;"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Kaplan-Meier survival analysis between patients with a urine albumin&#47;creatinine ratio above or below 1 g&#47;g &#40;log-rank 5&#46;99&#44; p &#38;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introducci&#243;n&#58; </span>Los eventos cardiovasculares &#40;CV&#41; son la primera causa de mortalidad en pacientes con enfermedad renal cr&#243;nica &#40;ERC&#41;&#46; El objetivo de nuestro estudio fue determinar los factores predictores de eventos CV y mortalidad en pacientes con ERC &#40;estadios 1-4&#41;&#46; <span class="elsevierStyleBold">Material y m&#233;todos&#58; </span>Realizamos un estudio prospectivo con 218 pacientes &#40;62&#160;&#37; varones&#41;&#44; con una mediana de edad de 69 a&#241;os &#40;rango intercuart&#237;lico 56-78&#41;&#46; Basalmente se recogieron variables demogr&#225;ficas&#44; antecedentes CV y par&#225;metros anal&#237;ticos&#46; Se recogieron los eventos CV y la mortalidad &#40;variable final&#41;&#46; <span class="elsevierStyleBold">Resultados&#58; </span>Durante el seguimiento &#40;38 &#91;37-39&#93; meses&#41;&#44; 50 pacientes tuvieron un evento&#58; 37 pacientes &#40;17&#160;&#37;&#41; tuvieron un evento CV y 13 &#40;6&#160;&#37;&#41; fallecieron de causa no CV&#46; Se asoci&#243; con la variable final ser var&#243;n&#44; ser fumador activo&#44; diabetes mellitus&#44; antecedentes CV&#44; presi&#243;n arterial diast&#243;lica baja&#44; menor filtrado glomerular&#44; un &#237;ndice alb&#250;mina&#47;creatinina en orina superior a 1000 mg&#47;g&#44; niveles de troponina T elevados&#44; niveles de p&#233;ptido natriur&#233;tico cerebral elevados&#44; niveles de prote&#237;na C reactiva elevados y niveles de hemoglobina bajos&#46; En el an&#225;lisis multivariante&#44; mantuvieron su poder predictivo independiente para el evento final ser var&#243;n&#44; diabetes mellitus&#44; antecedentes CV y menor filtrado glomerular&#46; <span class="elsevierStyleBold">Conclusi&#243;n&#58; </span>El sexo var&#243;n&#44; la diabetes mellitus&#44; tener menor filtrado glomerular y tener antecedentes de evento CV son predictores independientes de tener evento CV y de mortalidad en pacientes con ERC&#46; No hemos podido demostrar la superioridad de los marcadores emergentes de riesgo CV frente a los cl&#225;sicos&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">Introduction&#58;</span></span><span class="elsevierStyleItalic"> Cardiovascular events &#40;CV&#41; are the major cause of mortality in chronic kidney disease patients &#40;CKD&#41;&#46; The aim of the present study was to determine the independent predictors of CV and mortality in CKD patients &#40;stages 1-4&#41;&#46; <span class="elsevierStyleBold">Methods&#58; </span>A prospective study was conducted with 218 patients &#40;62&#37; male&#41;&#44; with a median age of 69 years &#40;interquartile range 56-78&#41;&#46; Basally&#44; demographic variables&#44; CV risk factors and biochemical values were collected&#46; During follow-up&#44; new CV events and deaths were collected &#40;final variable&#41;&#46; <span class="elsevierStyleBold">Results&#58;</span> During follow-up &#40;38 &#91;37-39&#93; months&#41;&#44; 50 patients suffered a final event&#58; 37 patients &#40;17&#37;&#41; had a CV and 13 &#40;6&#37;&#41; died due to a non-CV death&#46; Having a final event was associated to male sex&#44; smoker&#44; diabetes mellitus&#44; history of CV event&#44; low diastolic blood pressure values&#44; low glomerular filtration&#44; urine albumin&#47;creatinine higher than 1000 mg&#47;g&#44; higher troponin T levels&#44; higher BNP levels&#44; higher CRP levels and lower haemoglobin levels&#46; Multivariate analysis&#44; showed that only male sex&#44; diabetes mellitus&#44; previous CV event and lower glomerular filtration independently predicted having the final event&#46;<span class="elsevierStyleBold"> Conclusion&#58; </span>Male sex&#44; diabetes mellitus&#44; previous CV event and lower glomerular filtration independently predicted having a CV event or death in CKD patients&#46; We could not demonstrate the superiority of emerging CV risk markers compared to the classic ones&#46;</span></p>"
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Cardiovascular events and mortality in chronic kidney disease (stages I-IV)
Eventos cardiovasculares y mortalidad en pacientes con enfermedad renal crónica (estadios I a IV)
Borja Quirogaa, Borja Quirogab, Úrsula Verdallesb, Javier Requeb, Soledad García de Vinuesab, Marian Goicoecheab, José Luñob
a Nefrología, Hospital Gregorio Marañón, Madrid, Madrid, Spain,
b Servicio de Nefrología, Hospital Gregorio Marañón, Madrid,
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such as troponin or natriuretic peptide&#44; have been proposed for identifying those CKD patients with an increased cardiovascular risk&#46;<span class="elsevierStyleSup">7</span> It is known that an asymptomatic increase in these markers leads to a poor cardiovascular and overall prognosis in CKD patients&#46; This is due to silent myocardial damage and not to deterioration in renal function itself&#46;<span class="elsevierStyleSup">8</span></p><p class="elsevierStylePara">Other emerging markers have appeared in recent years that have also been associated with increased cardiovascular risk&#46; These include uric acid&#44; cytokines&#44; interleukins or adiponectins&#46;<span class="elsevierStyleSup">9&#44;10</span> These emerging markers have demonstrated their predictive value in several studies&#46; However&#44; they are still not included in routine clinical practice&#46; For this reason&#44; the classic factors continue to form the foundation for stratifying cardiovascular risk in CKD patients&#46;<span class="elsevierStyleSup">11-13</span> In addition&#44; different intrinsic factors of kidney disease itself are associated with a greater number of events&#46; These include proteinuria&#44; calcium-phosphorus metabolism alterations&#44; anaemia or water-electrolyte disorders&#46;<span class="elsevierStyleSup">14&#44;15</span></p><p class="elsevierStylePara">The focus of this study is to determine which risk factors are associated with suffering a cardiovascular event and death in the CKD population&#46; These include some emerging factors in order to corroborate their utility in stratifying cardiovascular risk in these patients&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">MATERIAL AND METHOD</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">We performed a prospective study over 6 months with 218 consecutive patients with stable CKD &#40;stages I-IV&#41; in outpatient nephrology follow-up&#44; of which 135 &#40;62&#37;&#41; were men and the median age was 69 &#40;56-78&#41; years&#46; The data were collected and evaluated by four observers&#46; Demographic variables &#40;age and sex&#41;&#44; personal medical history &#40;cardiovascular risk factors &#91;presence of diabetes&#44; dyslipidaemia&#44; smoking&#44; blood pressure levels and monitoring&#44; abdominal circumference&#93; and cardiovascular history prior to the study&#41; were collected at baseline and laboratory studies were ordered for cardiac markers &#40;troponin T&#44; brain natriuretic peptide &#91;BNP&#93;&#41;&#44; kidney disease &#40;creatinine&#44; albuminuria&#41;&#44; inflammation-nutritional markers &#40;ferritin&#44; fibrinogen&#44; C-reactive protein &#91;CRP&#93;&#44; albumin&#41;&#44; calcium-phosphorus metabolism markers &#40;parathyroid hormone &#91;PTH&#93;&#44; calcium&#44; phosphorus&#44; vitamin D&#41; as well as other variables that were considered relevant such as insulin&#44; homocystein and haemoglobin&#46; None of these measurements required more blood draws or office visits on the part of the patient&#46; Patients also provided verbal informed consent for inclusion in the study&#46;</p><p class="elsevierStylePara">We define dyslipidaemia according to the ATP III guidelines &#40;LDL greater than 160mg&#47;dl in patients with 0-1 risk factor&#59; greater than 130mg&#47;dl in patients with more than 1 risk factor&#59; greater than 100mg&#47;dl in patients with coronary artery disease or equivalent&#59; or those in treatment with lipid-lowering agents&#41;&#46;<span class="elsevierStyleSup">16</span> We define hypertension according to the criteria of the seventh report of the Joint National Committee &#40;blood pressure above 140&#47;90mmHg or in treatment with at least one antihypertensive agent&#41;&#46;<span class="elsevierStyleSup">17</span> We define progression according to the recently published &#8220;Consensus Document on Chronic Kidney Disease&#34;<span class="elsevierStyleSup">6</span> as loss of more than 5ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#47;year of glomerular filtration rate &#40;GFR&#41;&#44; GFR deterioration greater than 25&#37; or greater than 50&#37; increase in the urine albumin&#47;creatinine ratio&#46;</p><p class="elsevierStylePara">Routine methods were used to measure creatinine&#44; albumin&#44; haemoglobin&#44; uric acid&#44; fibrinogen&#44; PTH&#44; calcium&#44; phosphorus and vitamin D&#46;&#160; Ultrasensitive CRP was measured using turbidimetric immunoassay in the HITACHI automatic analyzer &#40;Sigma Chemical Co&#46;&#44; St&#46; Louis&#44; MO&#44; USA&#41;&#46; Albuminuria was measured as the albumin&#47;creatinine ratio with an immunonephelometric method&#46; Cardiac troponin T and BNP were measured using a third-generation electrochemiluminescence &#40;ECLIA&#41; immunoassay &#40;Roche Diagnostics&#44; Basel&#44; Switzerland&#41;&#46; Based on the estimated GFR by CKD-EPI&#44; we divided the patients into stages according to the K&#47;DOQI Guideline classification&#46;<span class="elsevierStyleSup">18</span></p><p class="elsevierStylePara">The first cardiovascular events &#40;fatal and non-fatal&#41; were recorded during follow-up &#40;median 38 &#91;37-39&#93; months&#41;&#58;</p><ul><li>Heart failure&#46;</li><li>Arrhythmia&#46;</li><li>Peripheral artery disease &#40;diagnosed as stenosis of the main arteries or arteries of the lower extremities confirmed by arteriogram&#59; or the need for amputation&#41;&#46;</li><li>Stroke&#46;</li><li>Coronary event&#46;</li></ul><p class="elsevierStylePara">In addition to deaths by other causes&#44; we defined a combined variable for all endpoint events &#40;composed of cardiovascular events and death due to any cause&#41;&#46;</p><p class="elsevierStylePara">A univariate analysis was done in order to corroborate the factors associated with an endpoint event&#46; Afterwards&#44; those factors that were independent predictors were analyzed using multivariate analysis&#46;</p><p class="elsevierStylePara">The variables are expressed as the mean &#40;standard deviation&#41; if they follow a normal distribution &#40;according the Kolmogorov-Smirnov test&#41;&#46; When the variables do not follow a normal distribution&#44; they are expressed as the median &#40;interquartile range&#41;&#46; Student&#8217;s t test or the &#967;<span class="elsevierStyleSup">2</span> test was used for variables with a normal distribution&#44; otherwise the Mann-Whitney U test was used&#46;&#160; Logistical regression analysis was performed to analyze what variables were predictive of endpoint events&#46; A survival analysis was performed using the Kaplan-Meier curves in order to confirm the link between albuminuria &#40;urine albumin&#47;creatinine ratio above or below 1000mg&#47;g&#41; and the events&#46; In addition&#44; linear regression was used to calculate the progression of CKD&#46; This cut-off point was chosen as it was sufficient data in the univariate analysis&#46; A value of <span class="elsevierStyleItalic">P</span>&#60;&#46;05 was considered to be statistically significant&#46; SPSS version 16&#174; &#40;Chicago&#44; IL&#44; USA&#41; was used for the statistical analysis&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The baseline characteristics of the population &#40;n&#61;218&#41; are shown in Table 1&#46; The baseline laboratory values are shown in Table 2&#46; Patients with CKD&#44; stages 1 to 4&#44; were included and distributed as follows&#58; stage 1&#44; 10&#37;&#59; stage 2&#44; 18&#37;&#59; stage 3&#44; 48&#37;&#59; stage 4&#44; 23&#37;&#46;</p><p class="elsevierStylePara">During follow-up &#40;38 &#91;37-39&#93; months&#41;&#44; 50 patients had an event&#58; 37 patients &#40;17&#37;&#41; had a cardiovascular event and 13 &#40;6&#37;&#41; died due to a non-cardiovascular cause&#46; The distribution of the events was the following&#58; 33&#37; coronary event&#44; 29&#37; died&#44; 17&#37; first episode of heart failure&#44; 8&#37; some type of arrhythmia&#44; 8&#37; stroke and 2&#37; peripheral artery disease&#46; 10&#37; of patients &#40;21&#41; were lost in follow-up because they stopped coming in to the outpatient clinic&#46; Among the lost patients and those who completed follow-up&#44; statistically significant differences were only found for sex &#40;more men lost&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;022&#41;&#46;</p><p class="elsevierStylePara">The univariate analysis revealed that factors that were associated with having an endpoint event &#40;cardiovascular event or death due to non-cardiovascular cause&#41; were male sex&#44; active smoking&#44; diabetes mellitus&#44; low diastolic blood pressure&#44; cardiovascular history&#44; lower GFR&#44; an urine albumin&#47;creatinine ratio greater than 1000mg&#47;g &#40;when we found 300mg&#47;g&#44; we obtained a value of <span class="elsevierStyleItalic">P</span>&#61;&#46;14&#41;&#44; troponin T levels greater than 0&#46;01ng&#47;l&#44; BNP levels greater than 34pg&#47;ml&#44; CRP levels greater than 2&#46;7mg&#47;dl and low haemoglobin levels &#40;Table 4&#41;&#46; A survival analysis was performed for the endpoint event with Kaplan-Meier curves in order to evaluate their associated with albuminuria levels &#40;Figure 1&#41;&#46; We found no significant differences between patients with and without progression of their CKD &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;566&#41;&#46;</p><p class="elsevierStylePara">Male sex&#44; diabetes mellitus&#44; cardiovascular history and reduced GFR maintained their independent predictive value on multivariate analysis by logical regression&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Classic cardiovascular risk factors such as being male&#44; diabetic&#44; having a higher stage of kidney disease or having a cardiovascular history are independent predictors of cardiovascular events and mortality in patients with CKD&#46;</p><p class="elsevierStylePara">The incidence of events in our population is around 5&#37; annually&#44; findings that are slightly lower than previously published series&#46;<span class="elsevierStyleSup">19&#44;20</span> This is probably due to a different distribution of patients by stages in our series &#40;with a greater number in stage 3&#41;&#44; the younger age of our patients and the lesser history of cardiovascular risk factors&#46; In addition&#44; the distribution of cardiovascular events increases with kidney disease stage&#46; However&#44; this progression disappears when mortality is combined in the endpoint event&#46; The reason is probably the same since an event in stages 1 and 2 leads to a significant increase in the total percentage&#46;</p><p class="elsevierStylePara">As in our case&#44; male sex has been shown to be an independent factor for cardiovascular events and mortality in populations with and without kidney disease&#46;<span class="elsevierStyleSup">21&#44;22</span> However&#44; age does not achieve a significant value between both groups&#46; This is probably because of the very narrow age range in our patients&#46; Conversely&#44; tobacco use&#44; which is associated with having an event&#44; loses its predictive value&#46; This is because the majority of smokers have a cardiovascular history&#46; In addition&#44; the percentage of smokers in our outpatient clinic is low compared to the general population&#46;<span class="elsevierStyleSup">23</span></p><p class="elsevierStylePara">The association between kidney disease and cardiovascular events is known and has been studied broadly&#46;<span class="elsevierStyleSup">4&#44;5</span> The element that contributes most to an increase in these events is probably endothelial dysfunction given that this is considered to be the first step in the development of atheromas&#46; This endothelial damage is not only explained by classic cardiovascular risk factors but also by the microinflammation environment in patients with CKD&#44; uraemia&#44; malnutrition&#44; volume overload or calcium-phosphorus metabolism alterations&#46;<span class="elsevierStyleSup">24-26</span> These data support the assertion that kidney disease itself is a cardiovascular risk factor and leads to the determination that&#44; despite carrying out exhaustive monitoring of these factors&#44; the population with CKD continues to be at an increased risk for an event&#46;<span class="elsevierStyleSup">27</span> The classic RENAAL and LIFE studies on cardiovascular risk&#44; which include diabetic and&#47;or hypertensive patients&#44; demonstrate that baseline creatinine is the most significant independent predictor for the development of cardiovascular events&#46;<span class="elsevierStyleSup">28-30</span></p><p class="elsevierStylePara">The association between elevated cardiac markers and cardiovascular events indicates the presence of these subclinical asymptomatic lesions in patients with CKD&#46;<span class="elsevierStyleSup">6</span> Several studies have demonstrated that both troponin and natriuretic peptide levels are elevated in patients with CKD&#59; however&#44; this situation does not seem to be related to the deterioration in GFR but instead is due to silent myocardial damage or volume overload&#46;<span class="elsevierStyleSup">7&#44;31&#44;32</span> Therefore&#44; it is not surprising that after adjusting the multivariate model for cardiovascular risk factors&#44; these variables lose their independent predictive ability&#46; This is because they are not effectors but simply cardiovascular risk markers and their baseline value should therefore be obtained in the nephrology department&#46;<span class="elsevierStyleSup">33</span></p><p class="elsevierStylePara">Diabetes mellitus is a cardiovascular risk factor on its own&#46; It causes an increase in cardiovascular events&#44; as is seen in our data&#46;<span class="elsevierStyleSup">34&#44;35</span> However&#44; although proteinuria shows an association with cardiovascular events&#44; we have not been able to demonstrate that it is an independent predictive factor&#46; This is probably due to the fact that diabetics make up the highest percentage of patients with a urine albumin&#47;creatinine ratio greater than 1000mg&#47;g&#44; which causes it to lose its significance in multivariate analysis that includes diabetic patients&#46; Conversely&#44; the presence of hypertension was not associated with the presence of events&#44; though low diastolic blood pressure was associated with having an event&#46; Both high and low systolic and diastolic blood pressure has been associated with the presence of cardiovascular events and mortality&#44; meaning that excessive control of hypertensive patients carries an increased risk that is similar to that seen in patients with high levels &#40;J-curve effect&#41;&#46;<span class="elsevierStyleSup">37&#44;38</span> As can be seen in the distribution of CKD aetiology in Table 1&#44; more than 40&#37; of patients have vascular disease or diabetes&#46; This confirms the high prevalence of these pathologies in patients with deteriorated kidney function&#46; This distribution coincides with the data in the Spanish Nephrology Society registry&#46;</p><p class="elsevierStylePara">We were not able to demonstrate an association between increased cardiovascular risk and the emerging factors mentioned previously&#46; In our cohort&#44; neither the presence of increased uric acid nor inflammation markers demonstrated an association with the combined endpoint event&#46; This is probably due to low baseline levels of these variables&#46; Therefore&#44; it would seem that monitoring these variables is less relevant in the prognosis of these patients when compared to the classic factors&#46; These data lead us to think that indiscriminate measurement of these variables in nephrology department is&#44; for the moment&#44; not justified when compared to the classic cardiovascular risk parameters&#46;</p><p class="elsevierStylePara">Our study has some limitations such as being a single-site study and it lacks the echocardiographic parameters necessary to perform a more exhaustive study of heart disease&#46; As these are consecutive patients&#44; the distribution of patients by stage is not homogeneous and above all the results are valid for the population studied &#40;patients in an outpatient nephrology clinic&#41;&#46; In addition&#44; the number of patients and the follow-up time are also limitations of the study&#46;</p><p class="elsevierStylePara">In conclusion&#44; male sex&#44; diabetes mellitus&#44; having a reduced GFR &#40;CKD-EPI&#41; and a history of cardiovascular risk are independent predictors of cardiovascular risk factors and mortality in patients with CKD &#40;stages 1-4&#41;&#46; In addition&#44; the presence of an albumin&#47;creatinine ratio greater than 1000mg&#47;g is associated with a greater number of events&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49223&#95;en&#95;t111895&#95;03&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49223_en_t111895_03.jpg" alt="Baseline characteristics of the study population"></img></a></p><p class="elsevierStylePara">Table 1&#46; Baseline characteristics of the study population</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49224&#95;en&#95;t211895&#95;03&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49224_en_t211895_03.jpg" alt="Variables measured at baseline in the study population"></img></a></p><p class="elsevierStylePara">Table 2&#46; Variables measured at baseline in the study population</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49225&#95;en&#95;t311895&#95;03&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49225_en_t311895_03.jpg" alt="Cardiovascular events and mortality distributed by stages&#46;"></img></a></p><p class="elsevierStylePara">Table 3&#46; Cardiovascular events and mortality distributed by stages&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49226&#95;en&#95;t411895&#95;03&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49226_en_t411895_03.jpg" alt="Univariate and multivariate analysis for combined event"></img></a></p><p class="elsevierStylePara">Table 4&#46; Univariate and multivariate analysis for combined event</p><p class="elsevierStylePara"><a href="grande&#47;11895&#95;16025&#95;49227&#95;en&#95;f111895&#95;035&#46;jpg" class="elsevierStyleCrossRefs"><img src="11895_16025_49227_en_f111895_035.jpg" alt="Kaplan-Meier survival analysis between patients with a urine albumin&#47;creatinine ratio above or below 1 g&#47;g &#40;log-rank 5&#46;99&#44; p &#38;"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Kaplan-Meier survival analysis between patients with a urine albumin&#47;creatinine ratio above or below 1 g&#47;g &#40;log-rank 5&#46;99&#44; p &#38;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introducci&#243;n&#58; </span>Los eventos cardiovasculares &#40;CV&#41; son la primera causa de mortalidad en pacientes con enfermedad renal cr&#243;nica &#40;ERC&#41;&#46; El objetivo de nuestro estudio fue determinar los factores predictores de eventos CV y mortalidad en pacientes con ERC &#40;estadios 1-4&#41;&#46; <span class="elsevierStyleBold">Material y m&#233;todos&#58; </span>Realizamos un estudio prospectivo con 218 pacientes &#40;62&#160;&#37; varones&#41;&#44; con una mediana de edad de 69 a&#241;os &#40;rango intercuart&#237;lico 56-78&#41;&#46; Basalmente se recogieron variables demogr&#225;ficas&#44; antecedentes CV y par&#225;metros anal&#237;ticos&#46; Se recogieron los eventos CV y la mortalidad &#40;variable final&#41;&#46; <span class="elsevierStyleBold">Resultados&#58; </span>Durante el seguimiento &#40;38 &#91;37-39&#93; meses&#41;&#44; 50 pacientes tuvieron un evento&#58; 37 pacientes &#40;17&#160;&#37;&#41; tuvieron un evento CV y 13 &#40;6&#160;&#37;&#41; fallecieron de causa no CV&#46; Se asoci&#243; con la variable final ser var&#243;n&#44; ser fumador activo&#44; diabetes mellitus&#44; antecedentes CV&#44; presi&#243;n arterial diast&#243;lica baja&#44; menor filtrado glomerular&#44; un &#237;ndice alb&#250;mina&#47;creatinina en orina superior a 1000 mg&#47;g&#44; niveles de troponina T elevados&#44; niveles de p&#233;ptido natriur&#233;tico cerebral elevados&#44; niveles de prote&#237;na C reactiva elevados y niveles de hemoglobina bajos&#46; En el an&#225;lisis multivariante&#44; mantuvieron su poder predictivo independiente para el evento final ser var&#243;n&#44; diabetes mellitus&#44; antecedentes CV y menor filtrado glomerular&#46; <span class="elsevierStyleBold">Conclusi&#243;n&#58; </span>El sexo var&#243;n&#44; la diabetes mellitus&#44; tener menor filtrado glomerular y tener antecedentes de evento CV son predictores independientes de tener evento CV y de mortalidad en pacientes con ERC&#46; No hemos podido demostrar la superioridad de los marcadores emergentes de riesgo CV frente a los cl&#225;sicos&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold"><span class="elsevierStyleItalic">Introduction&#58;</span></span><span class="elsevierStyleItalic"> Cardiovascular events &#40;CV&#41; are the major cause of mortality in chronic kidney disease patients &#40;CKD&#41;&#46; The aim of the present study was to determine the independent predictors of CV and mortality in CKD patients &#40;stages 1-4&#41;&#46; <span class="elsevierStyleBold">Methods&#58; </span>A prospective study was conducted with 218 patients &#40;62&#37; male&#41;&#44; with a median age of 69 years &#40;interquartile range 56-78&#41;&#46; Basally&#44; demographic variables&#44; CV risk factors and biochemical values were collected&#46; During follow-up&#44; new CV events and deaths were collected &#40;final variable&#41;&#46; <span class="elsevierStyleBold">Results&#58;</span> During follow-up &#40;38 &#91;37-39&#93; months&#41;&#44; 50 patients suffered a final event&#58; 37 patients &#40;17&#37;&#41; had a CV and 13 &#40;6&#37;&#41; died due to a non-CV death&#46; Having a final event was associated to male sex&#44; smoker&#44; diabetes mellitus&#44; history of CV event&#44; low diastolic blood pressure values&#44; low glomerular filtration&#44; urine albumin&#47;creatinine higher than 1000 mg&#47;g&#44; higher troponin T levels&#44; higher BNP levels&#44; higher CRP levels and lower haemoglobin levels&#46; Multivariate analysis&#44; showed that only male sex&#44; diabetes mellitus&#44; previous CV event and lower glomerular filtration independently predicted having the final event&#46;<span class="elsevierStyleBold"> Conclusion&#58; </span>Male sex&#44; diabetes mellitus&#44; previous CV event and lower glomerular filtration independently predicted having a CV event or death in CKD patients&#46; We could not demonstrate the superiority of emerging CV risk markers compared to the classic ones&#46;</span></p>"
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Article information
ISSN: 20132514
Original language: English
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Idiomas
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