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which has been increasing in prevalence particularly among elderly individuals&#44; the studies suggest that the incidence of hyperuricaemia has also increased during this time&#46;<span class="elsevierStyleSup">4</span></p><p class="elsevierStylePara">In addition to the role of UA in the onset of rheumatism and gout&#44; it has been postulated for some time that it is a possible determinant of the onset of hypertension &#40;AHT&#41;&#44; diabetes mellitus and chronic kidney disease &#40;CKD&#41;&#46;<span class="elsevierStyleSup">2&#44;5</span></p><p class="elsevierStylePara">In recent years&#44; there has been growing evidence of a relationship between high levels of UA in blood and renal and cardiovascular disease&#44; endothelial lesions being the proposed pathogenic mechanism&#46;<span class="elsevierStyleSup">2&#44;6</span></p><p class="elsevierStylePara">Prospective epidemiological studies have shown the association between baseline levels of UA and the incidence of CKD &#40;with increasing risk as UA levels increase&#41;&#46;<span class="elsevierStyleSup">7&#44;8</span></p><p class="elsevierStylePara">Regarding cardiovascular comorbidity&#44; some studies found an association between UA and increased risk of heart attacks and coronary ischaemic strokes&#46; However&#44; other studies have not confirmed these results in multivariate analyses&#46;<span class="elsevierStyleSup">2</span></p><p class="elsevierStylePara">On the other hand&#44; some studies have shown that UA levels behave as a risk factor for both cardiovascular and overall mortality&#46;<span class="elsevierStyleSup">9</span>&#160;</p><p class="elsevierStylePara">In this study&#44; we analysed the role of UA as an overall mortality marker in a cohort of elderly patients monitored for a period of 5 years&#46; We also examined the association between baseline UA levels and cardiovascular history&#44; the use of diuretics and renal function &#40;RF&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">PATIENTS AND METHODS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Patients</span></p><p class="elsevierStylePara">This study was performed by analysing 5-year outcomes for a cohort of patients included in a study of elderly patients with CKD<span class="elsevierStyleSup">10&#44;11&#44;12</span> at the General Hospital of Segovia&#46; Patients were recruited randomly while they visited the Geriatrics and General Nephrology departments during the period January-April 2006&#46; Patients were in a period of clinical stability when they were selected and were monitored prospectively for 5 years &#40;re-evaluation between January-April 2011&#41;&#46; These patients had a mean age of 82&#46;4&#177;6 years &#40;range 69-97 years&#41; at baseline recruitment&#46; Of these&#44; 68&#46;8&#37; were women&#44; 82&#46;5&#37; had histories of AHT&#44; 35&#37; were diabetic&#44; 19&#46;5&#37; had histories of heart failure &#40;HF&#41;&#44; 15&#37; had histories of ischaemic heart disease &#40;IHD&#41; and 68&#46;4&#37; were receiving diuretic therapy&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Laboratory analysis</span></p><p class="elsevierStylePara">A baseline analysis was performed one week before patients attended scheduled visits at the Geriatrics and Nephrology departments&#46; According to the standard procedures of our hospital&#39;s laboratory&#44; we measured creatinine&#44; UA&#44; albumin&#44; cholesterol and triglycerides in venous blood&#46; We also analysed creatinine and proteinuria in 24-hour urine &#40;Nephrology visits&#41; or in first morning urine &#40;Geriatrics visits&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Methods</span></p><p class="elsevierStylePara">This was a prospective observational study&#46; Glomerular filtration rate &#40;GFR&#41; was calculated with the abbreviated MDRD formula&#46;<span class="elsevierStyleSup">13</span> Based on the median baseline UA&#44; we established two study groups&#58; Group 1 consisting of 40 patients with UA &#60;5&#46;85mg&#47;dl&#44; and group 2 consisting of 40 patients with UA &#62;5&#46;85mg&#47;dl&#46; We also examined the possible association between high levels of UA &#40;P75&#41; and demographic characteristics&#44; RF and mortality&#46;</p><p class="elsevierStylePara">After five years&#44; we analysed mortality according to study group&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Statistics</span></p><p class="elsevierStylePara">Statistical analysis was performed using the SPSS 15&#46;0 program&#46; Data are expressed as mean and standard deviation&#44; or median and percentiles&#46; Comparison of means was made with the Student&#39;s t-test and comparison of proportions with the chi-squared test&#46; To analyse the simultaneous effect of several variables on mortality&#44; we used a Cox analysis&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara">UA showed a normal distribution&#46; Mean baseline levels of UA were 6&#46;11&#177;1&#46;7mg&#47;dl &#40;range 2&#46;8-11&#41; and their median was 5&#46;85mg&#47;dl &#40;P25&#61;4&#46;90mg&#47;dl&#44; P75&#61;7&#46;07mg&#47;dl&#41;&#46; Regarding the use of diuretics&#44; 42&#46;6&#37; used loop diuretics and 29&#46;5&#37; used thiazides&#46; Potassium-sparing diuretics were the least prescribed&#44; at a rate of 11&#46;5&#37;&#46; Table 1 shows the association between uric acid levels and gender&#44; cardiovascular history and use of diuretics&#46; Patients with histories of HF had significantly higher levels of UA &#40;7&#46;00&#177;1&#46;74mg&#47;dl vs 5&#46;90&#177;1&#46;71mg&#47;dl&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;031&#41;&#46;</p><p class="elsevierStylePara">Table 2 shows the comparison between demographic characteristics&#44; RF parameters&#44; comorbidity and mortality at 5 years&#44; according to median UA&#46; Patients with UA higher than the median had significantly lower GFR and higher mortality at 5 years&#46;</p><p class="elsevierStylePara">Twenty patients had UA greater than P75 &#40;7&#46;07mg&#47;dl&#41;&#46; Table 3 compares the variables according to this percentile&#46;</p><p class="elsevierStylePara">There were no patients lost to follow-up that were not due to death&#46;</p><p class="elsevierStylePara">Overall&#44; 41 patients died during the 5-year follow-up&#58; 15 due to general deterioration&#44; 8 due to infections&#44; 4 due to stroke&#44; 4 due to tumours&#44; 3 due to cardiovascular problems&#44; 2 due to fracture complications and 5 due to unknown reasons&#46; In the multivariate Cox analysis&#44; the only predictor of overall mortality after adjusting for age&#44; gender&#44; Charlson score&#44; history of HF&#44; use of diuretic and creatinine&#44; presence of proteinuria and GFR-MDRD was UA level &#40;mg&#47;dl&#41; &#40;relative risk 1&#46;35&#59; 1&#46;17-1&#46;56&#59; <span class="elsevierStyleItalic">P</span>&#61;&#46;000&#41;&#46; Figures 1A and 1B show the Kaplan-Meier mortality curves according to the median uric acid and P75&#46; Both figures show significantly higher mortality in patients with UA greater than P50 and P75&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara">Overall mortality in the patient group with UA levels higher than the median was significantly higher&#46; Moreover&#44; if we analyse patients with UA levels &#62;P75 &#40;7&#46;07mg&#47;dl&#41;&#44; their mortality increases even further&#44; reaching 80&#37;&#44; results that are consistent with other recent studies&#46;<span class="elsevierStyleSup">9</span></p><p class="elsevierStylePara">In this cohort of longer-lived patients&#44; the most frequent cause of mortality was progressive deterioration rather than cardiovascular disease&#44; and baseline UA levels were found to be the only predictors of mortality in the Cox analysis&#46;</p><p class="elsevierStylePara">Hyperuricaemia has been linked to various diseases in humans&#46;<span class="elsevierStyleSup">4</span> Gout is a disease that predominantly affects men&#44; with an increase in prevalence in both genders as age increases&#46; In our study&#44; men also had higher levels of UA&#44; although these differences were not significant&#44; which may be due to the fact that we treated postmenopausal women in whom estrogenic activity had ceased&#46;<span class="elsevierStyleSup">14</span></p><p class="elsevierStylePara">CKD has been associated with hyperuricaemia&#46;<span class="elsevierStyleSup">2</span> In experimental studies in rats with hyperuricaemia&#44; renal lesions included afferent arteriolopathy&#44; mild interstitial fibrosis&#44; glomerular hypertrophy and&#47;or glomerulosclerosis&#46;<span class="elsevierStyleSup">15</span> We also found in our study that elderly patients with greater levels of UA had significantly worse RF&#46; This association may be valid in both directions&#44; that is&#44; the high levels of UA may be explained by renal ischaemia and reduced RF&#44; and&#47;or reduced GFR in patients with higher levels of UA may be due to the direct toxic effects of UA&#46;</p><p class="elsevierStylePara">Diuretics&#44; widely used to treat AHT with the additional benefit of preventing HF episodes&#44;<span class="elsevierStyleSup">16</span> increase UA by stimulating the reabsorption of sodium and urate in the proximal tubule&#46;<span class="elsevierStyleSup">3</span> Moreover&#44; the increase in UA has also been observed in conditions that are accompanied by hypoxia &#40;obstructive pulmonary disease&#44; congestive HF&#41;&#46;<span class="elsevierStyleSup">17&#44;18</span> Leyva et al first studied UA concentrations in patients with chronic HF and found an inverse relationship between UA levels and oxygenation&#44; suggesting that damage from oxidative metabolism may play a role in the pathogenesis of HF&#46;<span class="elsevierStyleSup">19</span> In the SHEP study&#44; diuretics were demonstrated to reduce cardiovascular mortality in the elderly&#46; However&#44; a recent subanalysis found that cardioprotection was lower in those patients who had high levels of UA&#46;<span class="elsevierStyleSup">20</span></p><p class="elsevierStylePara">In our study&#44; we found that UA levels were similar among those who received diuretics and those who did not&#46; Moreover&#44; elderly patients with histories of HF&#44; who generally require higher doses of diuretics&#44; had significantly greater levels of UA&#46; It is therefore conceivable that the increase in UA levels in elderly patients with histories of HF is showing the effect of a local ischaemia rather than the increase associated with diuretics&#46; Similarly&#44; patients with history of IHD have higher levels of UA&#44; although in this case it was not statistically significant&#44; possibly due to the low number of patients who had this disease&#46;</p><p class="elsevierStylePara">Lastly&#44; ischaemia determines an increase in xanthine oxidase&#44; which leads to an increase in UA levels&#46;<span class="elsevierStyleSup">3</span> Treatment with xanthine oxidase inhibitors&#44; such as allopurinol&#44; has shown to reduce cardiovascular complications after coronary bypass and in patients with dilated cardiomyopathy&#46;<span class="elsevierStyleSup">21</span> Recently&#44; Goicoechea et al found that treatment with allopurinol in patients with chronic renal failure reduced the decline in RF&#46;<span class="elsevierStyleSup">22</span>&#160;</p><p class="elsevierStylePara">With the data from our study&#44; we cannot confirm that there is a causal relationship between high levels of UA and mortality&#46; A step forward in our study would have been to confirm whether the reduction in UA levels with allopurinol&#44; or more recently with febuxostat &#40;a new inhibitor of the xanthine oxidase&#41;&#44;<span class="elsevierStyleSup">23</span> contributes to reduced mortality in these patients&#46;</p><p class="elsevierStylePara">An important prognostic factor of morbidity and mortality is the presence of proteinuria&#46;<span class="elsevierStyleSup">24&#44;25</span> In our follow-up study of RF in the elderly&#44; the presence of proteinuria at 36 months was an independent factor of mortality&#46;<span class="elsevierStyleSup">12</span> This did not occur in our analysis at five years&#44; either proteinuria is included in the model as a qualitative variable &#40;yes&#47;no&#41; or if its numerical value is used&#46; This may be explained by the lack of proteinuria in the baseline sample and by the fact that the patients with higher proteinuria died in the first years of follow-up&#46;</p><p class="elsevierStylePara">In conclusion&#44; our data show that UA is an independent risk factor for overall mortality&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">The authors have no potential conflicts of interest to declare&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25343&#95;en&#95;t1&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25343_en_t1_11021i.jpg" alt="Baseline levels of uric acid &#40;mg&#47;dl&#41; according to gender&#44; cardiovascular history and use of diuretics"></img></a></p><p class="elsevierStylePara">Table 1&#46; Baseline levels of uric acid &#40;mg&#47;dl&#41; according to gender&#44; cardiovascular history and use of diuretics</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25344&#95;en&#95;t2&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25344_en_t2_11021i.jpg" alt="Comparison of variables according to the median uric acid &#40;5&#46;85mg&#47;dl&#41;"></img></a></p><p class="elsevierStylePara">Table 2&#46; Comparison of variables according to the median uric acid &#40;5&#46;85mg&#47;dl&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25345&#95;en&#95;t3&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25345_en_t3_11021i.jpg" alt="Comparison of variables according to P75 of uric acid &#40;7&#46;07mg&#47;dl&#41;"></img></a></p><p class="elsevierStylePara">Table 3&#46; Comparison of variables according to P75 of uric acid &#40;7&#46;07mg&#47;dl&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25346&#95;en&#95;f1&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25346_en_f1_11021i.jpg" alt="Kaplan-Meier mortality curve according to the median uric acid &#40;P50&#41;"></img></a></p><p class="elsevierStylePara">Figure 1A&#46; Kaplan-Meier mortality curve according to the median uric acid &#40;P50&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25347&#95;en&#95;f2&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25347_en_f2_11021i.jpg" alt="Kaplan-Meier mortality curve according to P75 of uric acid &#40;P50&#41;"></img></a></p><p class="elsevierStylePara">Figure 1B&#46; Kaplan-Meier mortality curve according to P75 of uric acid &#40;P50&#41;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introducci&#243;n</span><span class="elsevierStyleBold">&#58;</span> Existe evidencia creciente del papel del &#225;cido &#250;rico &#40;AU&#41; como factor de riesgo cardiovascular y renal&#46; En este trabajo analizamos la asociaci&#243;n entre niveles basales de AU y mortalidad global en una cohorte de ancianos seguidos prospectivamente durante 5 a&#241;os&#46; <span class="elsevierStyleBold">Pacientes y m&#233;todos</span><span class="elsevierStyleBold">&#58;</span> 80 pacientes cl&#237;nicamente estables&#59; mediana de edad&#44; 83 a&#241;os &#40;rango 69-97&#41;&#59; 31&#44;3&#37; varones&#59; 35&#37; diab&#233;ticos&#59; 83&#37; hipertensos&#59; reclutados aleatoriamente en consultas de Geriatr&#237;a y Nefrolog&#237;a entre enero y abril de 2006 y seguidos durante 5 a&#241;os&#46; Medimos basalmente AU y creatinina en plasma y estimamos filtrado glomerular &#40;FG&#41; con f&#243;rmula MDRD abreviada&#46; Asimismo&#44; en los pacientes de Nefrolog&#237;a se midi&#243; la proteinuria mediante la recogida de orina de 24 horas&#44; y en los vistos en Geriatr&#237;a se estim&#243; a partir del cociente prote&#237;nas &#40;mg&#47;dl&#41;&#47;creatinina &#40;mg&#47;dl&#41; en primera orina de la ma&#241;ana&#46; Registramos edad&#44; g&#233;nero&#44; comorbilidad basal &#40;&#205;ndice de Charlson&#41;&#44; patolog&#237;as cardiovasculares individualizadas&#44; tratamientos y mortalidad&#46; Estad&#237;stica&#58; SPSS15&#46;0&#46; <span class="elsevierStyleBold">Resultados</span><span class="elsevierStyleBold">&#58;</span> El AU basal presentaba una distribuci&#243;n normal y su mediana era de 5&#44;85 mg&#47;dl&#46; No encontramos diferencias significativas en los niveles de AU seg&#250;n g&#233;nero&#44; antecedentes de diabetes m&#233;llitus&#44; hipertensi&#243;n arterial&#44; uso de diur&#233;ticos&#44; cardiopat&#237;a isqu&#233;mica&#44; arteriopat&#237;a perif&#233;rica o ictus&#46; Los pacientes con antecedentes de insuficiencia card&#237;aca ten&#237;an AU significativamente mayor &#40;7&#44;00 &#177; 1&#44;74 vs&#46; 5&#44;90 &#177; 1&#44;71&#59; p &#61; 0&#44;031&#41;&#46; 41 pacientes &#40;15 varones y 26 mujeres&#41; fallecieron&#58; 15 por deterioro en el estado general&#59; 8 por infecciones&#59; 4 por ictus&#59; 4 por tumores&#59; 3 por causas cardiovasculares&#59; 2 por complicaciones de fracturas y 5 por causas desconocidas&#46; Los pacientes con AU superior a la mediana ten&#237;an un FG significativamente menor y una mortalidad a los 5 a&#241;os m&#225;s elevada&#46; En el an&#225;lisis de Cox para mortalidad global &#40;variables independientes&#58; edad&#44; g&#233;nero&#44; Charlson&#44; antecedentes de insuficiencia card&#237;aca&#44; AU&#44; creatinina&#44; proteinuria y filtrado glomerular-MDRD&#41; s&#243;lo los niveles de AU &#40;riesgo relativo&#58; 1&#44;35&#59; 1&#44;17-1&#44;56&#44;&#160;p &#61; 0&#44;000&#41; se asociaban de forma independiente a la mortalidad&#46; <span class="elsevierStyleBold">Conclusiones</span><span class="elsevierStyleBold">&#58;</span> en nuestro estudio&#44; los niveles de AU se muestran como factor de riesgo independiente de mortalidad en ancianos&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction&#58;</span> There is growing evidence of the role of serum uric acid &#40;SUA&#41; as a risk factor for cardiovascular and renal disease&#46; We analysed the association between baseline SUA and overall mortality in a cohort of elderly patients followed prospectively for 5 years&#46; <span class="elsevierStyleBold">Patients and Methods&#58;</span> Eighty clinically stable patients&#44; median age 83 years &#40;range 69-97&#41;&#44; 31&#46;3&#37; men&#44; 35&#37; diabetics&#44; 83&#37; hypertensives were randomly recruited at Geriatrics and Nephrology visits between January and April 2006 and followed for 5 years&#46; We measured baseline SUA and serum creatinine and estimated glomerular filtration rate &#40;GFR&#41; with MDRD abbreviated&#46; In Nephrology Department patients&#44; we measured proteinuria in 24-hour urine and in Geriatrics department patients we measured proteinuria &#40;mg&#47;dl&#41;&#47;creatinine &#40;mg&#47;dl&#41; in urine &#40;first morning urine&#41;&#46; Predictive variables were&#58; baseline SUA and plasma creatinine&#59; estimated GFR &#40;abbreviated MDRD formula&#41;&#59; and we recorded age&#44; gender&#44; baseline comorbidity &#40;Charlson index&#41;&#44; individualised cardiovascular treatment and mortality&#46; Statistical analysis&#58; SPSS15&#46;0&#46; <span class="elsevierStyleBold">Results&#58;</span> baseline SUA was normally distributed and its median was 5&#46;85mg&#47;dl&#46; We found no significant differences in levels of SUA by gender&#44; history of diabetes mellitus&#44; hypertension&#44; diuretic drug use&#44; heart disease&#44; peripheral arterial disease or stroke&#46; Patients with a history of heart failure had significantly higher SUA &#40;7&#46;00&#177;1&#46;74 vs 5&#46;90&#177;1&#46;71&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;031&#41;&#46; Some 41 deaths occurred during follow-up &#40;15 men and 26 women&#41;&#58; 15 due to general deterioration&#44; 8 due to infections&#44; 4 due to stroke&#44; 4 due to tumours&#44; 3 due to cardiovascular disease&#44; 2 due to complications of fractures and 5 due to unknown causes&#46; Patients with SUA higher than the median had significantly lower GFR and higher mortality at 5 years&#46; In the Cox analysis for overall mortality &#91;independent variables&#58; age&#44; gender&#44; Charlson Index&#44; history of heart failure&#44; SUA&#44; creatinine&#44; proteinuria and GFR &#40;MDRD&#41;&#93; only SUA levels &#40;HR&#58; 1&#46;35&#59; 1&#46;17-1&#46;56 <span class="elsevierStyleItalic">P</span>&#61;&#46;000&#41; were independently associated with mortality&#46; <span class="elsevierStyleBold">Conclusions&#58;</span> In our study&#44; levels of SUA are an independent risk factor for mortality in elderly patients&#46;</p>"
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Serum uric acid as a marker of all-cause mortality in an elderly patient cohort
Utilidad del ácido úrico como marcador de mortalidad global en una cohorte de ancianos
MANUEL HERASa, Manuel Herasb, MARIA JOSE FERNANDEZ-REYESa, María J. Fernández-Reyesb, ROSA SANCHEZa, Rosa Sánchezb, ALVARO MOLINAa, Álvaro Molinab, ASTRID RODRIGUEZa, Astrid Rodríguezb, FERNANDO ALVAREZ-UDEa, Fernando Álvarez-Udeb
a Servicio de Nefrología, Hospital General de Segovia, Spain,
b Servicio de Nefrología, Hospital General de Segovia,
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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara">Uric acid &#40;UA&#41;&#44; a waste product of purine metabolism&#44; is degraded by urate oxidase &#40;uricase&#41; to allantoin&#44; which is freely eliminated in urine&#46; One of the consequences of the absence of uricase in humans is the appearance of higher levels of UA in humans than in other species&#46; It may even reach plasma UA concentrations fifty times higher than in other mammals&#46; This condition&#44; far from being a drawback&#44; has been postulated to be an evolutionary advance related to the protective ability of UA against oxidative damage of free radicals&#46;<span class="elsevierStyleSup">1&#44;2</span></p><p class="elsevierStylePara">Hyperuricaemia is generally defined by UA levels &#62;6&#46;5mg&#47;dl or 7mg&#47;dl in men and &#62;6mg&#47;dl in women&#46;<span class="elsevierStyleSup">3</span></p><p class="elsevierStylePara">Although recent epidemiological studies have focused on gout&#44; which has been increasing in prevalence particularly among elderly individuals&#44; the studies suggest that the incidence of hyperuricaemia has also increased during this time&#46;<span class="elsevierStyleSup">4</span></p><p class="elsevierStylePara">In addition to the role of UA in the onset of rheumatism and gout&#44; it has been postulated for some time that it is a possible determinant of the onset of hypertension &#40;AHT&#41;&#44; diabetes mellitus and chronic kidney disease &#40;CKD&#41;&#46;<span class="elsevierStyleSup">2&#44;5</span></p><p class="elsevierStylePara">In recent years&#44; there has been growing evidence of a relationship between high levels of UA in blood and renal and cardiovascular disease&#44; endothelial lesions being the proposed pathogenic mechanism&#46;<span class="elsevierStyleSup">2&#44;6</span></p><p class="elsevierStylePara">Prospective epidemiological studies have shown the association between baseline levels of UA and the incidence of CKD &#40;with increasing risk as UA levels increase&#41;&#46;<span class="elsevierStyleSup">7&#44;8</span></p><p class="elsevierStylePara">Regarding cardiovascular comorbidity&#44; some studies found an association between UA and increased risk of heart attacks and coronary ischaemic strokes&#46; However&#44; other studies have not confirmed these results in multivariate analyses&#46;<span class="elsevierStyleSup">2</span></p><p class="elsevierStylePara">On the other hand&#44; some studies have shown that UA levels behave as a risk factor for both cardiovascular and overall mortality&#46;<span class="elsevierStyleSup">9</span>&#160;</p><p class="elsevierStylePara">In this study&#44; we analysed the role of UA as an overall mortality marker in a cohort of elderly patients monitored for a period of 5 years&#46; We also examined the association between baseline UA levels and cardiovascular history&#44; the use of diuretics and renal function &#40;RF&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">PATIENTS AND METHODS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Patients</span></p><p class="elsevierStylePara">This study was performed by analysing 5-year outcomes for a cohort of patients included in a study of elderly patients with CKD<span class="elsevierStyleSup">10&#44;11&#44;12</span> at the General Hospital of Segovia&#46; Patients were recruited randomly while they visited the Geriatrics and General Nephrology departments during the period January-April 2006&#46; Patients were in a period of clinical stability when they were selected and were monitored prospectively for 5 years &#40;re-evaluation between January-April 2011&#41;&#46; These patients had a mean age of 82&#46;4&#177;6 years &#40;range 69-97 years&#41; at baseline recruitment&#46; Of these&#44; 68&#46;8&#37; were women&#44; 82&#46;5&#37; had histories of AHT&#44; 35&#37; were diabetic&#44; 19&#46;5&#37; had histories of heart failure &#40;HF&#41;&#44; 15&#37; had histories of ischaemic heart disease &#40;IHD&#41; and 68&#46;4&#37; were receiving diuretic therapy&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Laboratory analysis</span></p><p class="elsevierStylePara">A baseline analysis was performed one week before patients attended scheduled visits at the Geriatrics and Nephrology departments&#46; According to the standard procedures of our hospital&#39;s laboratory&#44; we measured creatinine&#44; UA&#44; albumin&#44; cholesterol and triglycerides in venous blood&#46; We also analysed creatinine and proteinuria in 24-hour urine &#40;Nephrology visits&#41; or in first morning urine &#40;Geriatrics visits&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Methods</span></p><p class="elsevierStylePara">This was a prospective observational study&#46; Glomerular filtration rate &#40;GFR&#41; was calculated with the abbreviated MDRD formula&#46;<span class="elsevierStyleSup">13</span> Based on the median baseline UA&#44; we established two study groups&#58; Group 1 consisting of 40 patients with UA &#60;5&#46;85mg&#47;dl&#44; and group 2 consisting of 40 patients with UA &#62;5&#46;85mg&#47;dl&#46; We also examined the possible association between high levels of UA &#40;P75&#41; and demographic characteristics&#44; RF and mortality&#46;</p><p class="elsevierStylePara">After five years&#44; we analysed mortality according to study group&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Statistics</span></p><p class="elsevierStylePara">Statistical analysis was performed using the SPSS 15&#46;0 program&#46; Data are expressed as mean and standard deviation&#44; or median and percentiles&#46; Comparison of means was made with the Student&#39;s t-test and comparison of proportions with the chi-squared test&#46; To analyse the simultaneous effect of several variables on mortality&#44; we used a Cox analysis&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara">UA showed a normal distribution&#46; Mean baseline levels of UA were 6&#46;11&#177;1&#46;7mg&#47;dl &#40;range 2&#46;8-11&#41; and their median was 5&#46;85mg&#47;dl &#40;P25&#61;4&#46;90mg&#47;dl&#44; P75&#61;7&#46;07mg&#47;dl&#41;&#46; Regarding the use of diuretics&#44; 42&#46;6&#37; used loop diuretics and 29&#46;5&#37; used thiazides&#46; Potassium-sparing diuretics were the least prescribed&#44; at a rate of 11&#46;5&#37;&#46; Table 1 shows the association between uric acid levels and gender&#44; cardiovascular history and use of diuretics&#46; Patients with histories of HF had significantly higher levels of UA &#40;7&#46;00&#177;1&#46;74mg&#47;dl vs 5&#46;90&#177;1&#46;71mg&#47;dl&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;031&#41;&#46;</p><p class="elsevierStylePara">Table 2 shows the comparison between demographic characteristics&#44; RF parameters&#44; comorbidity and mortality at 5 years&#44; according to median UA&#46; Patients with UA higher than the median had significantly lower GFR and higher mortality at 5 years&#46;</p><p class="elsevierStylePara">Twenty patients had UA greater than P75 &#40;7&#46;07mg&#47;dl&#41;&#46; Table 3 compares the variables according to this percentile&#46;</p><p class="elsevierStylePara">There were no patients lost to follow-up that were not due to death&#46;</p><p class="elsevierStylePara">Overall&#44; 41 patients died during the 5-year follow-up&#58; 15 due to general deterioration&#44; 8 due to infections&#44; 4 due to stroke&#44; 4 due to tumours&#44; 3 due to cardiovascular problems&#44; 2 due to fracture complications and 5 due to unknown reasons&#46; In the multivariate Cox analysis&#44; the only predictor of overall mortality after adjusting for age&#44; gender&#44; Charlson score&#44; history of HF&#44; use of diuretic and creatinine&#44; presence of proteinuria and GFR-MDRD was UA level &#40;mg&#47;dl&#41; &#40;relative risk 1&#46;35&#59; 1&#46;17-1&#46;56&#59; <span class="elsevierStyleItalic">P</span>&#61;&#46;000&#41;&#46; Figures 1A and 1B show the Kaplan-Meier mortality curves according to the median uric acid and P75&#46; Both figures show significantly higher mortality in patients with UA greater than P50 and P75&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara">Overall mortality in the patient group with UA levels higher than the median was significantly higher&#46; Moreover&#44; if we analyse patients with UA levels &#62;P75 &#40;7&#46;07mg&#47;dl&#41;&#44; their mortality increases even further&#44; reaching 80&#37;&#44; results that are consistent with other recent studies&#46;<span class="elsevierStyleSup">9</span></p><p class="elsevierStylePara">In this cohort of longer-lived patients&#44; the most frequent cause of mortality was progressive deterioration rather than cardiovascular disease&#44; and baseline UA levels were found to be the only predictors of mortality in the Cox analysis&#46;</p><p class="elsevierStylePara">Hyperuricaemia has been linked to various diseases in humans&#46;<span class="elsevierStyleSup">4</span> Gout is a disease that predominantly affects men&#44; with an increase in prevalence in both genders as age increases&#46; In our study&#44; men also had higher levels of UA&#44; although these differences were not significant&#44; which may be due to the fact that we treated postmenopausal women in whom estrogenic activity had ceased&#46;<span class="elsevierStyleSup">14</span></p><p class="elsevierStylePara">CKD has been associated with hyperuricaemia&#46;<span class="elsevierStyleSup">2</span> In experimental studies in rats with hyperuricaemia&#44; renal lesions included afferent arteriolopathy&#44; mild interstitial fibrosis&#44; glomerular hypertrophy and&#47;or glomerulosclerosis&#46;<span class="elsevierStyleSup">15</span> We also found in our study that elderly patients with greater levels of UA had significantly worse RF&#46; This association may be valid in both directions&#44; that is&#44; the high levels of UA may be explained by renal ischaemia and reduced RF&#44; and&#47;or reduced GFR in patients with higher levels of UA may be due to the direct toxic effects of UA&#46;</p><p class="elsevierStylePara">Diuretics&#44; widely used to treat AHT with the additional benefit of preventing HF episodes&#44;<span class="elsevierStyleSup">16</span> increase UA by stimulating the reabsorption of sodium and urate in the proximal tubule&#46;<span class="elsevierStyleSup">3</span> Moreover&#44; the increase in UA has also been observed in conditions that are accompanied by hypoxia &#40;obstructive pulmonary disease&#44; congestive HF&#41;&#46;<span class="elsevierStyleSup">17&#44;18</span> Leyva et al first studied UA concentrations in patients with chronic HF and found an inverse relationship between UA levels and oxygenation&#44; suggesting that damage from oxidative metabolism may play a role in the pathogenesis of HF&#46;<span class="elsevierStyleSup">19</span> In the SHEP study&#44; diuretics were demonstrated to reduce cardiovascular mortality in the elderly&#46; However&#44; a recent subanalysis found that cardioprotection was lower in those patients who had high levels of UA&#46;<span class="elsevierStyleSup">20</span></p><p class="elsevierStylePara">In our study&#44; we found that UA levels were similar among those who received diuretics and those who did not&#46; Moreover&#44; elderly patients with histories of HF&#44; who generally require higher doses of diuretics&#44; had significantly greater levels of UA&#46; It is therefore conceivable that the increase in UA levels in elderly patients with histories of HF is showing the effect of a local ischaemia rather than the increase associated with diuretics&#46; Similarly&#44; patients with history of IHD have higher levels of UA&#44; although in this case it was not statistically significant&#44; possibly due to the low number of patients who had this disease&#46;</p><p class="elsevierStylePara">Lastly&#44; ischaemia determines an increase in xanthine oxidase&#44; which leads to an increase in UA levels&#46;<span class="elsevierStyleSup">3</span> Treatment with xanthine oxidase inhibitors&#44; such as allopurinol&#44; has shown to reduce cardiovascular complications after coronary bypass and in patients with dilated cardiomyopathy&#46;<span class="elsevierStyleSup">21</span> Recently&#44; Goicoechea et al found that treatment with allopurinol in patients with chronic renal failure reduced the decline in RF&#46;<span class="elsevierStyleSup">22</span>&#160;</p><p class="elsevierStylePara">With the data from our study&#44; we cannot confirm that there is a causal relationship between high levels of UA and mortality&#46; A step forward in our study would have been to confirm whether the reduction in UA levels with allopurinol&#44; or more recently with febuxostat &#40;a new inhibitor of the xanthine oxidase&#41;&#44;<span class="elsevierStyleSup">23</span> contributes to reduced mortality in these patients&#46;</p><p class="elsevierStylePara">An important prognostic factor of morbidity and mortality is the presence of proteinuria&#46;<span class="elsevierStyleSup">24&#44;25</span> In our follow-up study of RF in the elderly&#44; the presence of proteinuria at 36 months was an independent factor of mortality&#46;<span class="elsevierStyleSup">12</span> This did not occur in our analysis at five years&#44; either proteinuria is included in the model as a qualitative variable &#40;yes&#47;no&#41; or if its numerical value is used&#46; This may be explained by the lack of proteinuria in the baseline sample and by the fact that the patients with higher proteinuria died in the first years of follow-up&#46;</p><p class="elsevierStylePara">In conclusion&#44; our data show that UA is an independent risk factor for overall mortality&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">The authors have no potential conflicts of interest to declare&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25343&#95;en&#95;t1&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25343_en_t1_11021i.jpg" alt="Baseline levels of uric acid &#40;mg&#47;dl&#41; according to gender&#44; cardiovascular history and use of diuretics"></img></a></p><p class="elsevierStylePara">Table 1&#46; Baseline levels of uric acid &#40;mg&#47;dl&#41; according to gender&#44; cardiovascular history and use of diuretics</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25344&#95;en&#95;t2&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25344_en_t2_11021i.jpg" alt="Comparison of variables according to the median uric acid &#40;5&#46;85mg&#47;dl&#41;"></img></a></p><p class="elsevierStylePara">Table 2&#46; Comparison of variables according to the median uric acid &#40;5&#46;85mg&#47;dl&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25345&#95;en&#95;t3&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25345_en_t3_11021i.jpg" alt="Comparison of variables according to P75 of uric acid &#40;7&#46;07mg&#47;dl&#41;"></img></a></p><p class="elsevierStylePara">Table 3&#46; Comparison of variables according to P75 of uric acid &#40;7&#46;07mg&#47;dl&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25346&#95;en&#95;f1&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25346_en_f1_11021i.jpg" alt="Kaplan-Meier mortality curve according to the median uric acid &#40;P50&#41;"></img></a></p><p class="elsevierStylePara">Figure 1A&#46; Kaplan-Meier mortality curve according to the median uric acid &#40;P50&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11021&#95;108&#95;25347&#95;en&#95;f2&#95;11021i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11021_108_25347_en_f2_11021i.jpg" alt="Kaplan-Meier mortality curve according to P75 of uric acid &#40;P50&#41;"></img></a></p><p class="elsevierStylePara">Figure 1B&#46; Kaplan-Meier mortality curve according to P75 of uric acid &#40;P50&#41;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introducci&#243;n</span><span class="elsevierStyleBold">&#58;</span> Existe evidencia creciente del papel del &#225;cido &#250;rico &#40;AU&#41; como factor de riesgo cardiovascular y renal&#46; En este trabajo analizamos la asociaci&#243;n entre niveles basales de AU y mortalidad global en una cohorte de ancianos seguidos prospectivamente durante 5 a&#241;os&#46; <span class="elsevierStyleBold">Pacientes y m&#233;todos</span><span class="elsevierStyleBold">&#58;</span> 80 pacientes cl&#237;nicamente estables&#59; mediana de edad&#44; 83 a&#241;os &#40;rango 69-97&#41;&#59; 31&#44;3&#37; varones&#59; 35&#37; diab&#233;ticos&#59; 83&#37; hipertensos&#59; reclutados aleatoriamente en consultas de Geriatr&#237;a y Nefrolog&#237;a entre enero y abril de 2006 y seguidos durante 5 a&#241;os&#46; Medimos basalmente AU y creatinina en plasma y estimamos filtrado glomerular &#40;FG&#41; con f&#243;rmula MDRD abreviada&#46; Asimismo&#44; en los pacientes de Nefrolog&#237;a se midi&#243; la proteinuria mediante la recogida de orina de 24 horas&#44; y en los vistos en Geriatr&#237;a se estim&#243; a partir del cociente prote&#237;nas &#40;mg&#47;dl&#41;&#47;creatinina &#40;mg&#47;dl&#41; en primera orina de la ma&#241;ana&#46; Registramos edad&#44; g&#233;nero&#44; comorbilidad basal &#40;&#205;ndice de Charlson&#41;&#44; patolog&#237;as cardiovasculares individualizadas&#44; tratamientos y mortalidad&#46; Estad&#237;stica&#58; SPSS15&#46;0&#46; <span class="elsevierStyleBold">Resultados</span><span class="elsevierStyleBold">&#58;</span> El AU basal presentaba una distribuci&#243;n normal y su mediana era de 5&#44;85 mg&#47;dl&#46; No encontramos diferencias significativas en los niveles de AU seg&#250;n g&#233;nero&#44; antecedentes de diabetes m&#233;llitus&#44; hipertensi&#243;n arterial&#44; uso de diur&#233;ticos&#44; cardiopat&#237;a isqu&#233;mica&#44; arteriopat&#237;a perif&#233;rica o ictus&#46; Los pacientes con antecedentes de insuficiencia card&#237;aca ten&#237;an AU significativamente mayor &#40;7&#44;00 &#177; 1&#44;74 vs&#46; 5&#44;90 &#177; 1&#44;71&#59; p &#61; 0&#44;031&#41;&#46; 41 pacientes &#40;15 varones y 26 mujeres&#41; fallecieron&#58; 15 por deterioro en el estado general&#59; 8 por infecciones&#59; 4 por ictus&#59; 4 por tumores&#59; 3 por causas cardiovasculares&#59; 2 por complicaciones de fracturas y 5 por causas desconocidas&#46; Los pacientes con AU superior a la mediana ten&#237;an un FG significativamente menor y una mortalidad a los 5 a&#241;os m&#225;s elevada&#46; En el an&#225;lisis de Cox para mortalidad global &#40;variables independientes&#58; edad&#44; g&#233;nero&#44; Charlson&#44; antecedentes de insuficiencia card&#237;aca&#44; AU&#44; creatinina&#44; proteinuria y filtrado glomerular-MDRD&#41; s&#243;lo los niveles de AU &#40;riesgo relativo&#58; 1&#44;35&#59; 1&#44;17-1&#44;56&#44;&#160;p &#61; 0&#44;000&#41; se asociaban de forma independiente a la mortalidad&#46; <span class="elsevierStyleBold">Conclusiones</span><span class="elsevierStyleBold">&#58;</span> en nuestro estudio&#44; los niveles de AU se muestran como factor de riesgo independiente de mortalidad en ancianos&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction&#58;</span> There is growing evidence of the role of serum uric acid &#40;SUA&#41; as a risk factor for cardiovascular and renal disease&#46; We analysed the association between baseline SUA and overall mortality in a cohort of elderly patients followed prospectively for 5 years&#46; <span class="elsevierStyleBold">Patients and Methods&#58;</span> Eighty clinically stable patients&#44; median age 83 years &#40;range 69-97&#41;&#44; 31&#46;3&#37; men&#44; 35&#37; diabetics&#44; 83&#37; hypertensives were randomly recruited at Geriatrics and Nephrology visits between January and April 2006 and followed for 5 years&#46; We measured baseline SUA and serum creatinine and estimated glomerular filtration rate &#40;GFR&#41; with MDRD abbreviated&#46; In Nephrology Department patients&#44; we measured proteinuria in 24-hour urine and in Geriatrics department patients we measured proteinuria &#40;mg&#47;dl&#41;&#47;creatinine &#40;mg&#47;dl&#41; in urine &#40;first morning urine&#41;&#46; Predictive variables were&#58; baseline SUA and plasma creatinine&#59; estimated GFR &#40;abbreviated MDRD formula&#41;&#59; and we recorded age&#44; gender&#44; baseline comorbidity &#40;Charlson index&#41;&#44; individualised cardiovascular treatment and mortality&#46; Statistical analysis&#58; SPSS15&#46;0&#46; <span class="elsevierStyleBold">Results&#58;</span> baseline SUA was normally distributed and its median was 5&#46;85mg&#47;dl&#46; We found no significant differences in levels of SUA by gender&#44; history of diabetes mellitus&#44; hypertension&#44; diuretic drug use&#44; heart disease&#44; peripheral arterial disease or stroke&#46; Patients with a history of heart failure had significantly higher SUA &#40;7&#46;00&#177;1&#46;74 vs 5&#46;90&#177;1&#46;71&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;031&#41;&#46; Some 41 deaths occurred during follow-up &#40;15 men and 26 women&#41;&#58; 15 due to general deterioration&#44; 8 due to infections&#44; 4 due to stroke&#44; 4 due to tumours&#44; 3 due to cardiovascular disease&#44; 2 due to complications of fractures and 5 due to unknown causes&#46; Patients with SUA higher than the median had significantly lower GFR and higher mortality at 5 years&#46; In the Cox analysis for overall mortality &#91;independent variables&#58; age&#44; gender&#44; Charlson Index&#44; history of heart failure&#44; SUA&#44; creatinine&#44; proteinuria and GFR &#40;MDRD&#41;&#93; only SUA levels &#40;HR&#58; 1&#46;35&#59; 1&#46;17-1&#46;56 <span class="elsevierStyleItalic">P</span>&#61;&#46;000&#41; were independently associated with mortality&#46; <span class="elsevierStyleBold">Conclusions&#58;</span> In our study&#44; levels of SUA are an independent risk factor for mortality in elderly patients&#46;</p>"
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Article information
ISSN: 20132514
Original language: English
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