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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The main factor causing the anaemia associated with chronic kidney disease &#40;CKD&#41; is a decrease &#40;both absolute and relative&#41; in the synthesis of erythropoietin &#40;EPO&#41;&#46; Inadequate response to treatment with exogenous EPO is described in 10&#37; of patients with CKD&#46;<span class="elsevierStyleSup">1</span> Anaemia is also common in patients with heart disease in general and heart failure &#40;HF&#41; in particular<span class="elsevierStyleSup">2</span>&#59; the most common form is anaemia associated with chronic disorders&#46;<span class="elsevierStyleSup">3</span> In this case&#44; we observe a relative EPO deficit &#8212; resistance to endogenous EPO &#8212; in conjunction with inhibition of iron uptake&#44; and both conditions are largely provoked by an increase in cytokines&#46;<span class="elsevierStyleSup">4</span> Inflammatory processes are usually accompanied by an increase in hepcidin which impedes the release of iron by intestinal cells and those in the mononuclear phagocyte system&#46; Inflammation is an important factor in HF and CKD&#46; In the latter process&#44; the increase in hepcidin is favoured by the reduction in the amount excreted renally&#46;<span class="elsevierStyleSup">5</span> In both conditions &#40;CKD and HF&#41;&#44; decreased availability of Fe is a factor that exacerbates anaemia&#46;</p><p class="elsevierStylePara">In patients who suffer from both conditions simultaneously &#40;chronic cardiorenal syndrome types IV and V&#44; according to the Ronco classification<span class="elsevierStyleSup">6</span>&#41;&#44; EPO resistance is logically more common&#46; These patients need to take larger doses of EPO in order to maintain similar haemoglobin &#40;Hb&#41; levels&#44; as seen in prior studies conducted in patients on haemodialysis with a history of HF&#46;<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara">This study has a dual purpose&#58; a&#41; to examine the prevalence of heart diseases in general and HF episodes in particular&#44; and determine their influence on the EPO doses administered in a representative sample of our stage 4-5 CKD patients&#59; b&#41; use this CKD population to prospectively study the influence of pre-existing heart disease and EPO requirements on patients&#8217; 3 year survival rates&#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">The study was both cross-sectional &#40;for the prevalence analysis&#41; and longitudinal &#40;for the survival analysis&#41;&#44; and included all patients attended in sequential order in our Advanced Chronic Kidney Disease &#40;ACKD&#41; Unit from the beginning of January to the end of February 2008&#46; The follow-up period ended on 28 February 2011 and included the patient&#8217;s status at the end of that period &#40;outpatient monitoring&#44; on dialysis&#44; transplant recipient or deceased&#41;&#46; No patients were excluded from the overall study of heart disease prevalence and survival&#46; We recruited 134 patients&#44; representing 16&#37; of the 824 patients attended in our Unit throughout 2008&#46; One patient was positive for the hepatitis B virus and another for hepatitis C&#46; We excluded 2 patients from the baseline analysis of the subgroup of patients on EPO treatment &#40;n&#61;91&#41; due to severe associated conditions &#40;cirrhosis of the liver with advanced portal hypertension in 1 case&#59; chronic infectious process associated with an enterocutaneous fistula following radiotherapy in the other&#41; and who required EPO doses higher than 20&#160;000IU&#47;week&#46; The baseline study therefore contained the remaining 89 patients&#46; In addition&#44; 6 patients who were not being treated with EPO at the time of recruitment either began or returned to treatment throughout the 3-year follow up period&#46; The study of survival according to EPO dose therefore contained 97 patients&#46; In summary&#44; 89 patients participated in the baseline study and 97 participated in the study of survival according to EPO dose&#46;</p><p class="elsevierStylePara">Using patients&#8217; medical histories&#44; we recorded demographic and anthropometric data&#44; mean blood pressure&#44; CKD aetiology&#44; history of heart disease including ischaemic heart disease &#40;acute myocardial infarction or angina diagnosed and monitored by the Cardiology department&#41;&#44; severe valvular heart disease or arrhythmia &#40;atrial fibrillation in all cases&#41; and history of heart failure episodes&#44; defined as left ventricular failure manifesting as dyspnoea of cardiac origin which required hospital treatment&#44; and was considered or diagnosed as such in the patient&#39;s medical history&#46; We also gathered data regarding treatment with angiotensin converter enzyme inhibitors &#40;ACE inhibitors&#41; or angiotensin II receptor blockers &#40;ARB&#41;&#44; date of death and cause of death when known&#46; During follow-up&#44; 39 patients died &#40;33 in the outpatient monitoring programme and 6 after beginning dialysis&#41;&#46;</p><p class="elsevierStylePara">All patients undergoing treatment received subcutaneous EPO beta &#40;erythropoietin beta&#41; EPO requirements were measured using the erythropoietin resistance index &#40;ERI&#41;&#58; weekly units of EPO&#47;weight in kg&#47;Hb in g per 100ml&#46; The baseline ERI recorded at the beginning of the study was used to analyse survival in patients who started dialysis or died during the first year of follow-up&#46; For patients who began dialysis or died after the first year&#44; we used mean ERI&#44; referring to the arithmetic mean of the baseline ERI and final ERI&#46; The latter refers to indices calculated with data gathered during the 6 months prior to death&#44; initiation of dialysis or the end of the follow-up period&#46; As a result&#44; mean ERI corresponds in some cases to baseline ERI and in others to the mean of baseline ERI and final ERI in the survival study&#46;</p><p class="elsevierStylePara">We analysed the following parameters&#58; C-reactive protein &#40;CRP&#41;&#44; homocysteine&#44; haemogram&#44; Fe deposits&#44; renal function as measured by creatine clearance in urine over 24 hours and the estimate given by the Cockcroft-Gault equation normalised according to body surface area &#40;calculated using the Mosteller formula&#41;&#44; uric acid&#44; Ca-P metabolism&#44; parathyroid hormone and proteinuria&#46; The Charlson comorbidity index was used to indicate comorbidity&#46;</p><p class="elsevierStylePara">Statistical analysis was performed using IBM SPSS software version 18&#46; The descriptive population study used absolute and relative frequencies for categorical variables&#59; quantitative variables were represented by the median and typical deviation for the total population&#44; while median&#44; 25th percentile and 75th percentile were used in study subgroups since they did not follow a normal distribution&#46; When comparing groups according to ERI being above or below the median&#44; we used the Mann-Whitney U-test for quantitative variables and chi-squared for qualitative variables&#46; Spearman&#39;s rank correlation coefficient was used to study correlations between EPO dose and different variables&#46;&#160; Variables with an effect on ERI were analysed using forward stepwise linear regression&#44; with ERI as a dependent variable&#46; The survival study was carried out using Kaplan-Meier curves &#40;log-rank test&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Causes of CKD among the 134 patients in the study &#40;51&#37; men&#44; 49&#37; women&#41; were as follows&#58; 36&#37; vascular nephropathy&#59; 27&#37; diabetic nephropathy&#59; 10&#37; tubulo-interstitial nephritis of different aetiologies&#59; 10&#37; unknown causes&#59; 8&#37; chronic glomerular disease diagnosed by renal biopsy&#59; 4&#37; polycystic renal disease&#59; 5&#37; systemic conditions &#40;systemic lupus erythematosus&#44; rheumatoid arthritis&#44; Sj&#246;gren&#8217;s syndrome&#44; atypical haemolytic-uraemic syndrome&#41;&#46; At the beginning of the follow-up period&#44; 91 patients were being treated with EPO &#40;68&#37;&#41;&#59; 97 received treatment at some point during that period &#40;72&#46;3&#37;&#41;&#46; High blood pressure was present in 96&#37; of patients&#44; and 75&#46;7&#37; of these patients were treated with ACE inhibitors&#47;ARB&#46; A history of heart disease was present in 39 patients &#40;29&#46;1&#37;&#41; and 22 patients &#40;16&#46;4&#37;&#41; had a history of HF episodes&#46; According to echocardiographic data&#44; 61 patients &#40;45&#46;5&#37;&#41; had left ventricular hypertrophy&#44; 49 &#40;42&#46;6&#37;&#41; had diastolic dysfunction and 11 &#40;9&#46;2&#37;&#41; had systolic dysfunction&#46; Table 1 lists this data and other data of interest for the entire group&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Subgroup of patients with erythropoietin </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Baseline data for the subgroup of 89 patients &#40;56&#37; women&#44; 43&#37; men&#41; treated with EPO at the outset of the study&#44; after exclusion of the 2 patients mentioned previously&#44; are shown in Table 2&#46;</p><p class="elsevierStylePara">When comparing these patients according to whether baseline ERI was above or below the median &#40;2&#46;6IU&#47;kg&#47;g in 100ml&#41; &#40;Table 3&#41; we find significant differences in their cholesterol levels &#40;<span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41;&#44; renal function estimated using the Cockcroft-Gault equation normalised for a body surface area of 1&#46;73 m<span class="elsevierStyleSup">2 </span>&#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;04&#41; and Hb &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;007&#41;&#46; TSAT and the Charlson comorbidity index almost reached the statistical significance level &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;06 in both cases&#41;&#46;</p><p class="elsevierStylePara">Comparison of different qualitative variables revealed that the percentage of patients with a history of HF was higher in the group whose ERI was above the median &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;04&#41;&#46; There were no significant differences with regard to sex&#44; percentage of diabetes mellitus&#44; history of heart disease in general&#44; echocardiographic abnormalities&#44; or in the percentage of patients treated with ACE inhibitors&#47;ARB&#46; However&#44; patients treated with ACE inhibitors&#47;ARB had a higher baseline ERI than the untreated group&#58; median 2&#46;3 &#40;p25-75&#58; 1&#46;1-4&#46;9&#41; vs 3&#46;6 &#40;p25-75&#58; 2&#46;5-7&#41; IU&#47;kg&#47;g Hb &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;01&#41;&#46;</p><p class="elsevierStylePara">We found a significant correlation for baseline ERI which was positive for P levels &#40;r&#61;0&#46;246&#59; <span class="elsevierStyleItalic">P</span>&#61;&#46;02&#41; and negative for CrCl &#40;r&#61;&#8211;0&#46;373&#59; <span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41;&#44; Hb &#40;r&#61;&#8211;0&#46;323&#59; <span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41;&#44; haematocrit &#40;r&#61;&#8211;0&#46;216&#59; P&#61;&#46;04&#41;&#44; cholesterol &#40;r&#61;&#8211;0&#46;442&#59; P&#60;&#46;001&#41; and triglycerides &#40;r&#61;&#8211;0&#46;200&#59; <span class="elsevierStyleItalic">P</span>&#60;&#46;03&#41;&#46;</p><p class="elsevierStylePara">Multivariate analysis was conducted using forward stepwise linear regression and the range of variables traditionally related to each dose of EPO &#40;measured by the baseline ERI&#41;&#58; Charlson comorbidity index&#44; Hb&#44; ferritin&#44; transferrin saturation index&#44; renal function estimated using the Cockcroft-Gault equation normalised for body surface area&#44; history of HF &#40;analysed as absence of HF history&#41; and history of heart problems in general&#44; diabetes mellitus and sex&#46; Of the variables listed above&#44; ferritin&#44; Hb&#44; renal function and lack of history of HF were the variables used in the final model &#40;Table 4&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Evolution at 36 months </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">During the 36 month period in which 134 patients were monitored&#44; 31 &#40;23&#37;&#41; began dialysis&#44; 4 received pre-emptive transplants &#40;3&#37;&#41; and 66 &#40;49&#37;&#41; remained in the ACKD Unit&#46; There were 39 deaths &#40;29&#37;&#41;&#58; 33 in an ACKD unit outpatient monitoring programme and 6 after beginning renal replacement therapy&#46; None of the patients receiving transplants died&#46; Causes of death among all 39 patients were as follows&#58; cardiovascular&#44; 18 &#40;46&#37;&#41;&#59; infection&#44; 7 &#40;18&#37;&#41;&#59; neoplasia&#44; 6 &#40;15&#37;&#41;&#59; other&#44; 2 &#40;5&#37;&#41; &#40;1 patient due to cirrhosis and the other due to digestive tract haemorrhage&#41;&#59; cause unknown in 6 &#40;15&#37;&#41; &#40;occurred at home or another hospital&#44; or we were unable to contact the family&#44; or the family did not know cause of death&#41;&#46;</p><p class="elsevierStylePara">As mentioned in the &#8220;Material and Method&#8221; section&#44; when analysing 3 year survival according to EPO dose&#44; measured as mean ERI &#40;97 patients&#44; mean&#58; 3&#46;3&#177;2&#46;5IU&#47;kg&#47;g Hb&#59; range&#58; 0&#46;5-13&#46;1IU&#47;kg&#47;g Hb&#59; median&#58; 2&#46;5IU&#47;kg&#47;g Hb&#41; we considered all patients receiving EPO treatment at the time of recruitment plus the other 6 who began EPO treatment at a later date&#44; for a total of 97 patients&#46;</p><p class="elsevierStylePara">The Kaplan-Meier survival study showed that patients whose mean ERI was higher than the median &#40;2&#46;6IU&#47;kg&#47;g Hb&#41; had lower survival rates &#40;log-rank <span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41; &#40;Figure 1&#41;&#46; Likewise&#44; patients with a history of HF also had lower survival rates&#58; log-rank <span class="elsevierStyleItalic">P</span>&#61;&#46;001 &#40;Figure 2&#41;&#44; as did patients with a history of general heart disease&#44; with log-rank <span class="elsevierStyleItalic">P&#61;</span>&#60;&#46;001 &#40;Figure 3&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Patients not treated with erythropoietin </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Different quantitative and qualitative variables were compared between the groups of patients treated with EPO &#40;97 patients&#41; and those who never received EPO &#40;37 patients&#41; during the 3 year follow-up or prior to that follow-up period&#46; Statistically significant differences were found for levels of Hb&#44; Hct &#40;both higher in patients without EPO&#41;&#44; ferritin &#40;lower in patients without EPO&#41; and renal function &#40;higher in patients without EPO&#41;&#46; There were also lower percentages of diabetes mellitus &#40;DM&#41; and history of HF among patients without EPO treatment&#46; Results are shown in Table 5&#46;</p><p class="elsevierStylePara">There were no statistically significant differences between survival of patients treated with EPO and survival of untreated patients according to the Kaplan-Meier survival study &#40;log-rank test <span class="elsevierStyleItalic">P</span>&#61;&#46;1&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">This study shows that a representative sample of non-dialysis CKD patients in stages 4-5 undergoing regular monitoring by our ACKD Unit had high comorbidity - 6 on the Charlson index - and a high prevalence rate for heart disease&#46; The sample is representative because it consists of patients seen at the clinic in sequential order&#44; without any type of selection process&#46; Atherosclerosis increases with age&#59; CKD may be just another sign of that process&#44; as is true for atherosclerosis in other locations &#40;heart&#44; brain&#44; peripheral arteries&#41;&#46; Ageing of the population as life expectancy increases is also extending exposure time to CKD risk factors&#44; and this causes the alarming increase in CKD worldwide&#46;<span class="elsevierStyleSup">8&#44;9</span></p><p class="elsevierStylePara">Response to EPO was evaluated by using ERI&#44; as has been done in prior studies&#46;<span class="elsevierStyleSup">10&#44;11</span> This index relates the dose administered per kg body weight with the Hb level achieved&#59; high values indicate the presence of mechanisms that slow erythrocyte response&#46; It also serves a prognostic purpose&#44; since increased EPO resistance is associated with increased risk of death among patients on haemodialysis&#46;<span class="elsevierStyleSup">7&#44;12</span> Our study also confirms its usefulness in ACKD outpatients not on dialysis&#44; since the percentage of patients with an ERI above the median &#40;2&#46;6IU&#47;kg&#47;g Hb&#41; was higher among patients who died&#46; This tendency is confirmed by the survival analysis&#46; A recent article&#44;<span class="elsevierStyleSup">13</span> drawing on data from the TREAT study<span class="elsevierStyleSup">14</span> conducted in diabetic patients with stage 3-4 CKD&#44; evaluates response to darbepoetin by means of the percentage of change in Hb after the first 2 doses&#46; The article observed increased mortality and increased incidence of cardiovascular events among patients in the lowest quartile for Hb response to darbepoetin&#46;</p><p class="elsevierStylePara">Our study clearly shows that patients with a history of HF need larger doses of EPO&#46; This fact was confirmed by the multivariate analysis in a model containing history of HF&#44; renal function parameters and Hb and Fe deposits&#46; We believe that this supports the existence of a relationship between ERI and HF in our group of patients&#46; Resistance to EPO in patients with HF has already been observed in patients on haemodialysis&#46;<span class="elsevierStyleSup">7</span> This would explain why the simultaneous presence of both diseases gives rise to a low-grade state of inflammation&#44; with increased production of inflammatory cytokines &#40;IL-1&#44; IL-6&#44; TNF&#44; interferon&#44; etc&#46;&#41; which induce apoptosis in erythroid progenitor cells and decrease Fe availability by stimulating hepcidin production&#46;<span class="elsevierStyleSup">4</span></p><p class="elsevierStylePara">When we analyse and compare different characteristics between patients with and without EPO treatment&#44; we observe that patients with EPO have lower incidence rates of HF and DM&#44; as well as higher Hb levels&#46; However&#44; having this patient profile&#44; which is theoretically healthier&#44; does not result in differences in survival&#44; or at least this is true in our group&#46; We cannot rule out the possibility that in a larger sample&#44; patients who do not need EPO could show better survival rates than those treated with EPO&#46;</p><p class="elsevierStylePara">Although CRP level&#44; which is considered an inflammation parameter&#44; was higher among patients with a more elevated baseline ERI&#44; the difference was not significant&#46; This fact could be explained by a considerable dispersion among the values that were recorded&#59; the median CRP value in patients with a higher ERI was clearly superior to that in the lower ERI group&#46; The study mentioned above<span class="elsevierStyleSup">13</span> which made use of TREAT study data from diabetic patients with stage 3-4 CKD also observed higher CRP levels in patients with the most moderate response to the first doses of darbepoetin&#46; Likewise&#44; this relationship between EPO response and inflammation has also been observed with levels of endogenous EPO&#46; A recent study analysed endogenous EPO levels in patients with DM and CKD &#40;mean CrCl 50cc&#47;min&#41;&#44; examining different parameters and their effect on mortality after a 7 year follow-up period&#46; That study showed higher endogenous EPO levels in patients with higher CRP levels and a history of cardiovascular disease&#44; as well as increased mortality in that patient group&#46;<span class="elsevierStyleSup">15</span></p><p class="elsevierStylePara">Homocysteine levels tend to be high during renal failure because of the decrease in urinary elimination&#46;<span class="elsevierStyleSup">16&#44;17</span> Although increase in homocysteine levels is associated with higher vascular risk&#44; we found no significant differences in patients with a higher ERI&#46; This could be because the factor with the greatest effect on homocysteine serum levels is renal function&#44; and this was similar in both groups&#46;</p><p class="elsevierStylePara">Baseline ERI was negatively correlated with renal function &#40;also true in the linear regression model&#41;&#44; as might be expected&#44; since synthesis of endogenous EPO is primarily renal and depends on critical functioning renal mass&#46;<span class="elsevierStyleSup">1</span> However&#44; a study carried out in patients with stage 3-4 CKD in which response to EPO was evaluated at doses of less than 100IU&#47;kg&#47;week did not find this inverse relation between EPO dose and renal function&#46;<span class="elsevierStyleSup">18</span> This could be explained by the fact that these patients had higher glomerular filtration rates &#40;25-60ml&#47;minute&#41; than our own patients&#46; Given these levels of renal function&#44; other factors &#40;age&#44; prior Hb level&#44; Fe deposits&#44; ACE inhibitor treatment&#44; body mass index&#44; proteinuria&#41; could have a greater influence on response to EPO&#46;</p><p class="elsevierStylePara">In our study&#44; treatment with renin-angiotensin system blockers was shown to have an effect on ERI&#44; which is higher in patients receiving such treatments&#46; This effect was previously described both in patients on EPO&#44; who needed higher doses&#44; and in patients who developed anaemia after beginning ACE inhibitor or ARB treatment&#46;<span class="elsevierStyleSup">19</span> Although the underlying mechanism is not completely understood&#44; we know that angiotensin II regulates circulating EPO levels in both normal individuals and CKD patients&#44; and that activation of the RAS increases EPO levels&#46; Therefore&#44; using renin-angiotensin system blockers will decrease endogenous EPO levels&#44; exacerbate anaemia and increase the need for exogenous EPO&#46;<span class="elsevierStyleSup">20</span></p><p class="elsevierStylePara">The serum cholesterol level was inversely correlated with baseline ERI&#46; This relationship has been described in patients on haemodialysis&#44;<span class="elsevierStyleSup">21</span> and the reason is that low cholesterol levels are a marker for the presence of malnutrition and inflammation&#46; This in turn would explain lower survival in these patients&#44; which is contrary to what occurs in the population without CKD&#46; The same trend occurs with obesity among haemodialysis patients &#40;this has not been found consistently among patients on peritoneal dialysis&#41;&#46; In this group&#44; obesity does not increase cardiovascular risk&#44; unlike what happens in the general population&#59; this is part of the so-called &#8220;reverse epidemiology&#8221; described by the DOPPS study&#46;<span class="elsevierStyleSup">22</span></p><p class="elsevierStylePara">When evaluating the relationship between EPO dose&#44; ERI and Hb level in patients with CKD and HF&#44; it is important to keep in mind the complexity of administering EPO treatment in this situation&#44; which is becoming increasingly common&#46; The Hb level may fall and rise in an &#8220;unreal&#8221; way depending on the intensity of diuretic treatment and the simultaneous presence of oedemas &#40;haemoconcentration and haemodilution&#41;&#46; Due to these reasons&#44; the EPO dose may change without variation in the real mass of red blood cells&#44; and therefore the nephrologist must adjust the EPO dose for these patients&#44; while considering the effect which changes in plasma volume will have on the Hb concentration&#46;<span class="elsevierStyleSup">23-25</span></p><p class="elsevierStylePara">One of this study&#8217;s limitations is that it contains a small number of patients&#46; It does&#44; however&#44; have the advantage of being homogenous&#44; since it was conducted in one centre with a single observer and a consecutive array of patients who had the same therapeutic criteria&#44; and these characteristics reduce population and observer biases&#46; To compensate for the bias occurring from correlating baseline ERI with a patient&#8217;s evolution over 3 years of follow-up&#44; we took a second ERI measurement &#40;in the 6 months prior to exitus&#44; beginning dialysis or the end of follow-up for patients still treated on an outpatient basis&#41; and used the mean ERI for studying survival&#46; With this approach&#44; we are able to reconcile ERI with the evolution we observed&#46; All things considered&#44; this study and its conclusions have the same limitations as any survival analysis&#44; including the low rate of events in some groups which does not permit us to calculate median survival&#44; risk over time&#44; etc&#46;</p><p class="elsevierStylePara">One aspect that makes this study a useful contribution to the literature is that few studies analyse the progression of patients with advanced CKD &#40;non-dialysis stage 3-4 CKD&#41; with regard to cardiac morbidity&#44; which is very prevalent and likely to increase given the population profile and its current tendencies&#46;</p><p class="elsevierStylePara">Although some of the findings from studies of patients on dialysis mirror those in earlier stages of CKD&#44; important differences are present&#46; ERI and EPO dose per kg in non-dialysis CKD stage 4-5 are much lower to those recorded for patients on haemodialysis&#46; In the article by L&#243;pez G&#243;mez<span class="elsevierStyleSup">7</span> describing a multi-centre Spanish study of patients during the first year of inclusion in a haemodialysis programme&#44; mean ERI was 10&#46;2&#177;7&#46;3IU&#47;kg&#47;g Hb&#44; while ERI in our study was 3&#46;7&#177; 3IU&#47;kg&#47;g Hb&#44; just over a third of the other index&#46; It is likely that better renal function among our patients and absence of the negative effects of haemodialysis are the main factors accounting for this difference&#44; since comorbidity &#40;the Charlson comorbidity index&#41;&#44; the percentage of heart disease and age are quite similar&#46;</p><p class="elsevierStylePara">As a group&#44; patients with CKD and a high ERI have the following profile&#58; history of heart disease in general or&#44; more specifically&#44; episodes of HF&#59; higher Charlson comorbidity index and ferritin levels&#59; lower renal function&#44; Hb and cholesterol levels&#46;</p><p class="elsevierStylePara">In summary&#44; this study shows a high prevalence of heart disease among patients attended by the ACKD outpatient unit&#46; Simultaneous presence of CKD and HF increases the need for EPO&#44; both in terms of absolute value and with regard to Hb levels&#44; expressed as the resistance index&#46; Likewise&#44; both a history of heart disease&#47;HF episodes and high ERI seem to be associated to poorer survival&#44; and both may be considered markers of increased risk of mortality over the short to medium term&#46; High ERI may be a marker for patients requiring increased diagnostic and therapeutic intensity&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest </span></p><p class="elsevierStylePara">The authors affirm that they have no conflicts of interest related to the content of this article&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28819&#95;en&#95;t1&#95;11111&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28819_en_t1_11111.jpg" alt="Patient characteristics &#40;full group&#41;"></img></a></p><p class="elsevierStylePara">Table 1&#46; Patient characteristics &#40;full group&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28820&#95;en&#95;t2&#95;11111&#95;copy1&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28820_en_t2_11111_copy1.jpg" alt="Patient characteristics &#40;subgroup on erythropoietin&#41;"></img></a></p><p class="elsevierStylePara">Table 2&#46; Patient characteristics &#40;subgroup on erythropoietin&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28821&#95;en&#95;t3111112&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28821_en_t3111112.jpg" alt="Erythropoietin resistance index &#40;ERI&#41;&#62; or &#38;"></img></a></p><p class="elsevierStylePara">Table 3&#46; Erythropoietin resistance index &#40;ERI&#41;&#62; or &#38;</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28822&#95;en&#95;t4&#95;11111&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28822_en_t4_11111.jpg" alt="Forward stepwise linear regression analysis"></img></a></p><p class="elsevierStylePara">Table 4&#46; Forward stepwise linear regression analysis</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28823&#95;en&#95;t5&#95;11111&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28823_en_t5_11111.jpg" alt="Patients with or without erythropoietin treatment"></img></a></p><p class="elsevierStylePara">Table 5&#46; Patients with or without erythropoietin treatment</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28824&#95;en&#95;f1&#95;11111&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28824_en_f1_11111.jpg" alt="Survival analysis"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Survival analysis</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Antecedentes&#58; </span>Los pacientes con enfermedad renal cr&#243;nica &#40;ERC&#41; tienen con frecuencia patolog&#237;a card&#237;aca asociada&#46; La coincidencia de ambos procesos puede potenciar la inflamaci&#243;n&#44; aumentando los requerimientos de eritropoyetina &#40;EPO&#41; y empeorando la supervivencia&#46; <span class="elsevierStyleBold">Objetivos&#58; </span>Conocer la prevalencia de patolog&#237;a card&#237;aca&#44; su influencia en la dosis de EPO y la de ambos factores sobre la mortalidad en pacientes con ERC 4-5 no-D &#40;no di&#225;lisis&#41;&#46; <span class="elsevierStyleBold">M&#233;todos&#58; </span>134 pacientes &#40;68&#37; con EPO al inicio y el 72&#44;3&#37; a lo largo del seguimiento&#41; seguidos durante 36 meses&#46; Para evaluar la respuesta a la EPO se utiliz&#243; su &#237;ndice de resistencia a la eritropoyetina &#40;IRE&#41;&#58; dosis de EPO semanal&#47;peso&#47;hemoglobina &#40;Hb&#41;&#59; el IRE se estim&#243; basalmente y durante el per&#237;odo de los seis meses precedentes a la finalizaci&#243;n del estudio&#46; <span class="elsevierStyleBold">Resultados&#58; </span>39 pacientes &#40;29&#44;1&#37;&#41;&#44; antecedentes de cardiopat&#237;a&#59; 22 &#40;16&#44;4&#37;&#41;&#44; episodios de insuficiencia card&#237;aca &#40;IC&#41;&#46; El IRE fue superior en los pacientes con antecedentes de cardiopat&#237;a&#44; con IC y en los tratados con inhibidores de la enzima convertidora de angiotensina&#47;antagonistas de los receptores de angiotensina II&#59; en el an&#225;lisis multivariante &#40;IRE como variable dependiente&#41; compusieron el modelo final&#58; ferritina&#44; Hb&#44; funci&#243;n renal y episodios de IC&#46; Durante el per&#237;odo de seguimiento&#44; 39 pacientes fallecieron&#46; La supervivencia &#40;Kaplan-Meier&#41; a los 36 meses fue inferior en los pacientes con un IRE superior a la mediana &#40;2&#44;6 UI semana&#47;kg&#47;g de Hb en 100 ml&#41; &#40;p &#61; 0&#44;002&#41;&#44; los que hab&#237;an sufrido episodios de IC &#40;p &#61; 0&#44;001&#41; y los que ten&#237;an antecedentes de cardiopat&#237;a &#40;p &#60; 0&#44;001&#41;<span class="elsevierStyleBold">&#46; Conclusiones&#58; </span>Los pacientes con antecedentes cardiol&#243;gicos en general y de IC en particular tienen un IRE aumentado&#46; Tanto la presencia de estos antecedentes como un mayor IRE se asocian a la disminuci&#243;n de la supervivencia&#44; pudiendo considerarse el IRE como marcador de riesgo de muerte a corto-medio plazo&#46; </p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction&#58;</span><span class="elsevierStyleBold"> </span>Patients with chronic kidney disease &#40;CKD&#41; frequently suffer from heart disease as well&#46; The combination of the two processes can exacerbate inflammation&#44; resulting in increases in both resistance to erythropoietin &#40;EPO&#41; and mortality&#46; <span class="elsevierStyleBold">Objectives&#58; </span>The aim of this study was to determine the prevalence of heart disease in a representative group of non-dialysis patients with stage 4-5 CKD&#44; and the influence of that entity on EPO requirements and on mortality during a period of 36 months&#46;<span class="elsevierStyleBold"> Methods&#58; </span>134 patients &#40;68&#37; on EPO at the beginning&#44; increasing to 72&#46;3&#37; during follow-up&#41; were monitored for 36 months&#46; To evaluate the dose-response effect of EPO therapy&#44; we used the erythropoietin resistance index &#40;ERI&#41; calculated as the weekly weight-adjusted dose of EPO divided by the haemoglobin level&#46; The ERI was determined both initially and during the last six months before the end of the study&#46; <span class="elsevierStyleBold">Results&#58;</span> 39 patients &#40;29&#46;1&#37;&#41; had history of heart disease&#59; 22 &#40;16&#46;4&#37;&#41; had suffered from heart failure &#40;HF&#41;&#46; The ERI was higher in patients with a history of heart disease or HF and those treated with drugs acting on the renin-angiotensin system &#40;ACE inhibitors or ARBs&#41;&#46; Using ERI as the dependent variable in the multivariate analysis&#44; the variables that composed the final model were ferritin&#44; haemoglobin&#44; glomerular filtration rate and history of HF&#46; The 36 month mortality rate &#40;n&#61;39 patients&#41; was higher in the group having ERI above the median &#40;2&#46;6IU&#47;week&#47;kg&#47;gram of haemoglobin in 100ml&#41; &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41;&#44; and in the groups with heart disease &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;001&#41; or HF &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;001&#41; according to the Kaplan-Meier survival analysis&#46; <span class="elsevierStyleBold">Conclusions&#58;</span> Patients with history of heart disease or HF have a higher ERI&#44; and all of these characteristics are associated with lower survival&#46; ERI can be considered a marker for risk of death in the short to-medium term&#46;</p>"
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Erythropoietin resistance and survival in non-dialysis patients with stage 4-5 chronic kidney disease and heart disease
Resistencia a eritropoyetina y supervivencia en pacientes con enfermedad renal crónica 4-5 no-D y enfermedad cardíaca
Maria Ángeles Guerrero Riscosa, M. Ángeles Guerrero-Riscosb, Rafael Montes Delgadoa, Rafael Montes-Delgadob, Maria Seda Guzmána, María Seda-Guzmánb, Juan Manuel Praena-Fernándezc, Juan M. Praena-Fernándezd
a Nefrología, Hospital Virgen del Rocio, Sevilla, Spain,
b Servicio de Nefrología, Hospital Universitario Virgen del Rocío, Sevilla,
c Unidad de Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI), IBIS, Hospital Virgen del Rocio, Sevilla, Spain,
d Unidad de Metodología y Evaluación de Investigación, Fundación Pública Andaluza para la Gestión de la Investigación en Salud de Sevilla (FISEVI). Inst, Hospital Universitario Virgen del Rocío, Sevilla,
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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The main factor causing the anaemia associated with chronic kidney disease &#40;CKD&#41; is a decrease &#40;both absolute and relative&#41; in the synthesis of erythropoietin &#40;EPO&#41;&#46; Inadequate response to treatment with exogenous EPO is described in 10&#37; of patients with CKD&#46;<span class="elsevierStyleSup">1</span> Anaemia is also common in patients with heart disease in general and heart failure &#40;HF&#41; in particular<span class="elsevierStyleSup">2</span>&#59; the most common form is anaemia associated with chronic disorders&#46;<span class="elsevierStyleSup">3</span> In this case&#44; we observe a relative EPO deficit &#8212; resistance to endogenous EPO &#8212; in conjunction with inhibition of iron uptake&#44; and both conditions are largely provoked by an increase in cytokines&#46;<span class="elsevierStyleSup">4</span> Inflammatory processes are usually accompanied by an increase in hepcidin which impedes the release of iron by intestinal cells and those in the mononuclear phagocyte system&#46; Inflammation is an important factor in HF and CKD&#46; In the latter process&#44; the increase in hepcidin is favoured by the reduction in the amount excreted renally&#46;<span class="elsevierStyleSup">5</span> In both conditions &#40;CKD and HF&#41;&#44; decreased availability of Fe is a factor that exacerbates anaemia&#46;</p><p class="elsevierStylePara">In patients who suffer from both conditions simultaneously &#40;chronic cardiorenal syndrome types IV and V&#44; according to the Ronco classification<span class="elsevierStyleSup">6</span>&#41;&#44; EPO resistance is logically more common&#46; These patients need to take larger doses of EPO in order to maintain similar haemoglobin &#40;Hb&#41; levels&#44; as seen in prior studies conducted in patients on haemodialysis with a history of HF&#46;<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara">This study has a dual purpose&#58; a&#41; to examine the prevalence of heart diseases in general and HF episodes in particular&#44; and determine their influence on the EPO doses administered in a representative sample of our stage 4-5 CKD patients&#59; b&#41; use this CKD population to prospectively study the influence of pre-existing heart disease and EPO requirements on patients&#8217; 3 year survival rates&#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">The study was both cross-sectional &#40;for the prevalence analysis&#41; and longitudinal &#40;for the survival analysis&#41;&#44; and included all patients attended in sequential order in our Advanced Chronic Kidney Disease &#40;ACKD&#41; Unit from the beginning of January to the end of February 2008&#46; The follow-up period ended on 28 February 2011 and included the patient&#8217;s status at the end of that period &#40;outpatient monitoring&#44; on dialysis&#44; transplant recipient or deceased&#41;&#46; No patients were excluded from the overall study of heart disease prevalence and survival&#46; We recruited 134 patients&#44; representing 16&#37; of the 824 patients attended in our Unit throughout 2008&#46; One patient was positive for the hepatitis B virus and another for hepatitis C&#46; We excluded 2 patients from the baseline analysis of the subgroup of patients on EPO treatment &#40;n&#61;91&#41; due to severe associated conditions &#40;cirrhosis of the liver with advanced portal hypertension in 1 case&#59; chronic infectious process associated with an enterocutaneous fistula following radiotherapy in the other&#41; and who required EPO doses higher than 20&#160;000IU&#47;week&#46; The baseline study therefore contained the remaining 89 patients&#46; In addition&#44; 6 patients who were not being treated with EPO at the time of recruitment either began or returned to treatment throughout the 3-year follow up period&#46; The study of survival according to EPO dose therefore contained 97 patients&#46; In summary&#44; 89 patients participated in the baseline study and 97 participated in the study of survival according to EPO dose&#46;</p><p class="elsevierStylePara">Using patients&#8217; medical histories&#44; we recorded demographic and anthropometric data&#44; mean blood pressure&#44; CKD aetiology&#44; history of heart disease including ischaemic heart disease &#40;acute myocardial infarction or angina diagnosed and monitored by the Cardiology department&#41;&#44; severe valvular heart disease or arrhythmia &#40;atrial fibrillation in all cases&#41; and history of heart failure episodes&#44; defined as left ventricular failure manifesting as dyspnoea of cardiac origin which required hospital treatment&#44; and was considered or diagnosed as such in the patient&#39;s medical history&#46; We also gathered data regarding treatment with angiotensin converter enzyme inhibitors &#40;ACE inhibitors&#41; or angiotensin II receptor blockers &#40;ARB&#41;&#44; date of death and cause of death when known&#46; During follow-up&#44; 39 patients died &#40;33 in the outpatient monitoring programme and 6 after beginning dialysis&#41;&#46;</p><p class="elsevierStylePara">All patients undergoing treatment received subcutaneous EPO beta &#40;erythropoietin beta&#41; EPO requirements were measured using the erythropoietin resistance index &#40;ERI&#41;&#58; weekly units of EPO&#47;weight in kg&#47;Hb in g per 100ml&#46; The baseline ERI recorded at the beginning of the study was used to analyse survival in patients who started dialysis or died during the first year of follow-up&#46; For patients who began dialysis or died after the first year&#44; we used mean ERI&#44; referring to the arithmetic mean of the baseline ERI and final ERI&#46; The latter refers to indices calculated with data gathered during the 6 months prior to death&#44; initiation of dialysis or the end of the follow-up period&#46; As a result&#44; mean ERI corresponds in some cases to baseline ERI and in others to the mean of baseline ERI and final ERI in the survival study&#46;</p><p class="elsevierStylePara">We analysed the following parameters&#58; C-reactive protein &#40;CRP&#41;&#44; homocysteine&#44; haemogram&#44; Fe deposits&#44; renal function as measured by creatine clearance in urine over 24 hours and the estimate given by the Cockcroft-Gault equation normalised according to body surface area &#40;calculated using the Mosteller formula&#41;&#44; uric acid&#44; Ca-P metabolism&#44; parathyroid hormone and proteinuria&#46; The Charlson comorbidity index was used to indicate comorbidity&#46;</p><p class="elsevierStylePara">Statistical analysis was performed using IBM SPSS software version 18&#46; The descriptive population study used absolute and relative frequencies for categorical variables&#59; quantitative variables were represented by the median and typical deviation for the total population&#44; while median&#44; 25th percentile and 75th percentile were used in study subgroups since they did not follow a normal distribution&#46; When comparing groups according to ERI being above or below the median&#44; we used the Mann-Whitney U-test for quantitative variables and chi-squared for qualitative variables&#46; Spearman&#39;s rank correlation coefficient was used to study correlations between EPO dose and different variables&#46;&#160; Variables with an effect on ERI were analysed using forward stepwise linear regression&#44; with ERI as a dependent variable&#46; The survival study was carried out using Kaplan-Meier curves &#40;log-rank test&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Causes of CKD among the 134 patients in the study &#40;51&#37; men&#44; 49&#37; women&#41; were as follows&#58; 36&#37; vascular nephropathy&#59; 27&#37; diabetic nephropathy&#59; 10&#37; tubulo-interstitial nephritis of different aetiologies&#59; 10&#37; unknown causes&#59; 8&#37; chronic glomerular disease diagnosed by renal biopsy&#59; 4&#37; polycystic renal disease&#59; 5&#37; systemic conditions &#40;systemic lupus erythematosus&#44; rheumatoid arthritis&#44; Sj&#246;gren&#8217;s syndrome&#44; atypical haemolytic-uraemic syndrome&#41;&#46; At the beginning of the follow-up period&#44; 91 patients were being treated with EPO &#40;68&#37;&#41;&#59; 97 received treatment at some point during that period &#40;72&#46;3&#37;&#41;&#46; High blood pressure was present in 96&#37; of patients&#44; and 75&#46;7&#37; of these patients were treated with ACE inhibitors&#47;ARB&#46; A history of heart disease was present in 39 patients &#40;29&#46;1&#37;&#41; and 22 patients &#40;16&#46;4&#37;&#41; had a history of HF episodes&#46; According to echocardiographic data&#44; 61 patients &#40;45&#46;5&#37;&#41; had left ventricular hypertrophy&#44; 49 &#40;42&#46;6&#37;&#41; had diastolic dysfunction and 11 &#40;9&#46;2&#37;&#41; had systolic dysfunction&#46; Table 1 lists this data and other data of interest for the entire group&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Subgroup of patients with erythropoietin </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Baseline data for the subgroup of 89 patients &#40;56&#37; women&#44; 43&#37; men&#41; treated with EPO at the outset of the study&#44; after exclusion of the 2 patients mentioned previously&#44; are shown in Table 2&#46;</p><p class="elsevierStylePara">When comparing these patients according to whether baseline ERI was above or below the median &#40;2&#46;6IU&#47;kg&#47;g in 100ml&#41; &#40;Table 3&#41; we find significant differences in their cholesterol levels &#40;<span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41;&#44; renal function estimated using the Cockcroft-Gault equation normalised for a body surface area of 1&#46;73 m<span class="elsevierStyleSup">2 </span>&#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;04&#41; and Hb &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;007&#41;&#46; TSAT and the Charlson comorbidity index almost reached the statistical significance level &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;06 in both cases&#41;&#46;</p><p class="elsevierStylePara">Comparison of different qualitative variables revealed that the percentage of patients with a history of HF was higher in the group whose ERI was above the median &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;04&#41;&#46; There were no significant differences with regard to sex&#44; percentage of diabetes mellitus&#44; history of heart disease in general&#44; echocardiographic abnormalities&#44; or in the percentage of patients treated with ACE inhibitors&#47;ARB&#46; However&#44; patients treated with ACE inhibitors&#47;ARB had a higher baseline ERI than the untreated group&#58; median 2&#46;3 &#40;p25-75&#58; 1&#46;1-4&#46;9&#41; vs 3&#46;6 &#40;p25-75&#58; 2&#46;5-7&#41; IU&#47;kg&#47;g Hb &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;01&#41;&#46;</p><p class="elsevierStylePara">We found a significant correlation for baseline ERI which was positive for P levels &#40;r&#61;0&#46;246&#59; <span class="elsevierStyleItalic">P</span>&#61;&#46;02&#41; and negative for CrCl &#40;r&#61;&#8211;0&#46;373&#59; <span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41;&#44; Hb &#40;r&#61;&#8211;0&#46;323&#59; <span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41;&#44; haematocrit &#40;r&#61;&#8211;0&#46;216&#59; P&#61;&#46;04&#41;&#44; cholesterol &#40;r&#61;&#8211;0&#46;442&#59; P&#60;&#46;001&#41; and triglycerides &#40;r&#61;&#8211;0&#46;200&#59; <span class="elsevierStyleItalic">P</span>&#60;&#46;03&#41;&#46;</p><p class="elsevierStylePara">Multivariate analysis was conducted using forward stepwise linear regression and the range of variables traditionally related to each dose of EPO &#40;measured by the baseline ERI&#41;&#58; Charlson comorbidity index&#44; Hb&#44; ferritin&#44; transferrin saturation index&#44; renal function estimated using the Cockcroft-Gault equation normalised for body surface area&#44; history of HF &#40;analysed as absence of HF history&#41; and history of heart problems in general&#44; diabetes mellitus and sex&#46; Of the variables listed above&#44; ferritin&#44; Hb&#44; renal function and lack of history of HF were the variables used in the final model &#40;Table 4&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Evolution at 36 months </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">During the 36 month period in which 134 patients were monitored&#44; 31 &#40;23&#37;&#41; began dialysis&#44; 4 received pre-emptive transplants &#40;3&#37;&#41; and 66 &#40;49&#37;&#41; remained in the ACKD Unit&#46; There were 39 deaths &#40;29&#37;&#41;&#58; 33 in an ACKD unit outpatient monitoring programme and 6 after beginning renal replacement therapy&#46; None of the patients receiving transplants died&#46; Causes of death among all 39 patients were as follows&#58; cardiovascular&#44; 18 &#40;46&#37;&#41;&#59; infection&#44; 7 &#40;18&#37;&#41;&#59; neoplasia&#44; 6 &#40;15&#37;&#41;&#59; other&#44; 2 &#40;5&#37;&#41; &#40;1 patient due to cirrhosis and the other due to digestive tract haemorrhage&#41;&#59; cause unknown in 6 &#40;15&#37;&#41; &#40;occurred at home or another hospital&#44; or we were unable to contact the family&#44; or the family did not know cause of death&#41;&#46;</p><p class="elsevierStylePara">As mentioned in the &#8220;Material and Method&#8221; section&#44; when analysing 3 year survival according to EPO dose&#44; measured as mean ERI &#40;97 patients&#44; mean&#58; 3&#46;3&#177;2&#46;5IU&#47;kg&#47;g Hb&#59; range&#58; 0&#46;5-13&#46;1IU&#47;kg&#47;g Hb&#59; median&#58; 2&#46;5IU&#47;kg&#47;g Hb&#41; we considered all patients receiving EPO treatment at the time of recruitment plus the other 6 who began EPO treatment at a later date&#44; for a total of 97 patients&#46;</p><p class="elsevierStylePara">The Kaplan-Meier survival study showed that patients whose mean ERI was higher than the median &#40;2&#46;6IU&#47;kg&#47;g Hb&#41; had lower survival rates &#40;log-rank <span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41; &#40;Figure 1&#41;&#46; Likewise&#44; patients with a history of HF also had lower survival rates&#58; log-rank <span class="elsevierStyleItalic">P</span>&#61;&#46;001 &#40;Figure 2&#41;&#44; as did patients with a history of general heart disease&#44; with log-rank <span class="elsevierStyleItalic">P&#61;</span>&#60;&#46;001 &#40;Figure 3&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Patients not treated with erythropoietin </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Different quantitative and qualitative variables were compared between the groups of patients treated with EPO &#40;97 patients&#41; and those who never received EPO &#40;37 patients&#41; during the 3 year follow-up or prior to that follow-up period&#46; Statistically significant differences were found for levels of Hb&#44; Hct &#40;both higher in patients without EPO&#41;&#44; ferritin &#40;lower in patients without EPO&#41; and renal function &#40;higher in patients without EPO&#41;&#46; There were also lower percentages of diabetes mellitus &#40;DM&#41; and history of HF among patients without EPO treatment&#46; Results are shown in Table 5&#46;</p><p class="elsevierStylePara">There were no statistically significant differences between survival of patients treated with EPO and survival of untreated patients according to the Kaplan-Meier survival study &#40;log-rank test <span class="elsevierStyleItalic">P</span>&#61;&#46;1&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">This study shows that a representative sample of non-dialysis CKD patients in stages 4-5 undergoing regular monitoring by our ACKD Unit had high comorbidity - 6 on the Charlson index - and a high prevalence rate for heart disease&#46; The sample is representative because it consists of patients seen at the clinic in sequential order&#44; without any type of selection process&#46; Atherosclerosis increases with age&#59; CKD may be just another sign of that process&#44; as is true for atherosclerosis in other locations &#40;heart&#44; brain&#44; peripheral arteries&#41;&#46; Ageing of the population as life expectancy increases is also extending exposure time to CKD risk factors&#44; and this causes the alarming increase in CKD worldwide&#46;<span class="elsevierStyleSup">8&#44;9</span></p><p class="elsevierStylePara">Response to EPO was evaluated by using ERI&#44; as has been done in prior studies&#46;<span class="elsevierStyleSup">10&#44;11</span> This index relates the dose administered per kg body weight with the Hb level achieved&#59; high values indicate the presence of mechanisms that slow erythrocyte response&#46; It also serves a prognostic purpose&#44; since increased EPO resistance is associated with increased risk of death among patients on haemodialysis&#46;<span class="elsevierStyleSup">7&#44;12</span> Our study also confirms its usefulness in ACKD outpatients not on dialysis&#44; since the percentage of patients with an ERI above the median &#40;2&#46;6IU&#47;kg&#47;g Hb&#41; was higher among patients who died&#46; This tendency is confirmed by the survival analysis&#46; A recent article&#44;<span class="elsevierStyleSup">13</span> drawing on data from the TREAT study<span class="elsevierStyleSup">14</span> conducted in diabetic patients with stage 3-4 CKD&#44; evaluates response to darbepoetin by means of the percentage of change in Hb after the first 2 doses&#46; The article observed increased mortality and increased incidence of cardiovascular events among patients in the lowest quartile for Hb response to darbepoetin&#46;</p><p class="elsevierStylePara">Our study clearly shows that patients with a history of HF need larger doses of EPO&#46; This fact was confirmed by the multivariate analysis in a model containing history of HF&#44; renal function parameters and Hb and Fe deposits&#46; We believe that this supports the existence of a relationship between ERI and HF in our group of patients&#46; Resistance to EPO in patients with HF has already been observed in patients on haemodialysis&#46;<span class="elsevierStyleSup">7</span> This would explain why the simultaneous presence of both diseases gives rise to a low-grade state of inflammation&#44; with increased production of inflammatory cytokines &#40;IL-1&#44; IL-6&#44; TNF&#44; interferon&#44; etc&#46;&#41; which induce apoptosis in erythroid progenitor cells and decrease Fe availability by stimulating hepcidin production&#46;<span class="elsevierStyleSup">4</span></p><p class="elsevierStylePara">When we analyse and compare different characteristics between patients with and without EPO treatment&#44; we observe that patients with EPO have lower incidence rates of HF and DM&#44; as well as higher Hb levels&#46; However&#44; having this patient profile&#44; which is theoretically healthier&#44; does not result in differences in survival&#44; or at least this is true in our group&#46; We cannot rule out the possibility that in a larger sample&#44; patients who do not need EPO could show better survival rates than those treated with EPO&#46;</p><p class="elsevierStylePara">Although CRP level&#44; which is considered an inflammation parameter&#44; was higher among patients with a more elevated baseline ERI&#44; the difference was not significant&#46; This fact could be explained by a considerable dispersion among the values that were recorded&#59; the median CRP value in patients with a higher ERI was clearly superior to that in the lower ERI group&#46; The study mentioned above<span class="elsevierStyleSup">13</span> which made use of TREAT study data from diabetic patients with stage 3-4 CKD also observed higher CRP levels in patients with the most moderate response to the first doses of darbepoetin&#46; Likewise&#44; this relationship between EPO response and inflammation has also been observed with levels of endogenous EPO&#46; A recent study analysed endogenous EPO levels in patients with DM and CKD &#40;mean CrCl 50cc&#47;min&#41;&#44; examining different parameters and their effect on mortality after a 7 year follow-up period&#46; That study showed higher endogenous EPO levels in patients with higher CRP levels and a history of cardiovascular disease&#44; as well as increased mortality in that patient group&#46;<span class="elsevierStyleSup">15</span></p><p class="elsevierStylePara">Homocysteine levels tend to be high during renal failure because of the decrease in urinary elimination&#46;<span class="elsevierStyleSup">16&#44;17</span> Although increase in homocysteine levels is associated with higher vascular risk&#44; we found no significant differences in patients with a higher ERI&#46; This could be because the factor with the greatest effect on homocysteine serum levels is renal function&#44; and this was similar in both groups&#46;</p><p class="elsevierStylePara">Baseline ERI was negatively correlated with renal function &#40;also true in the linear regression model&#41;&#44; as might be expected&#44; since synthesis of endogenous EPO is primarily renal and depends on critical functioning renal mass&#46;<span class="elsevierStyleSup">1</span> However&#44; a study carried out in patients with stage 3-4 CKD in which response to EPO was evaluated at doses of less than 100IU&#47;kg&#47;week did not find this inverse relation between EPO dose and renal function&#46;<span class="elsevierStyleSup">18</span> This could be explained by the fact that these patients had higher glomerular filtration rates &#40;25-60ml&#47;minute&#41; than our own patients&#46; Given these levels of renal function&#44; other factors &#40;age&#44; prior Hb level&#44; Fe deposits&#44; ACE inhibitor treatment&#44; body mass index&#44; proteinuria&#41; could have a greater influence on response to EPO&#46;</p><p class="elsevierStylePara">In our study&#44; treatment with renin-angiotensin system blockers was shown to have an effect on ERI&#44; which is higher in patients receiving such treatments&#46; This effect was previously described both in patients on EPO&#44; who needed higher doses&#44; and in patients who developed anaemia after beginning ACE inhibitor or ARB treatment&#46;<span class="elsevierStyleSup">19</span> Although the underlying mechanism is not completely understood&#44; we know that angiotensin II regulates circulating EPO levels in both normal individuals and CKD patients&#44; and that activation of the RAS increases EPO levels&#46; Therefore&#44; using renin-angiotensin system blockers will decrease endogenous EPO levels&#44; exacerbate anaemia and increase the need for exogenous EPO&#46;<span class="elsevierStyleSup">20</span></p><p class="elsevierStylePara">The serum cholesterol level was inversely correlated with baseline ERI&#46; This relationship has been described in patients on haemodialysis&#44;<span class="elsevierStyleSup">21</span> and the reason is that low cholesterol levels are a marker for the presence of malnutrition and inflammation&#46; This in turn would explain lower survival in these patients&#44; which is contrary to what occurs in the population without CKD&#46; The same trend occurs with obesity among haemodialysis patients &#40;this has not been found consistently among patients on peritoneal dialysis&#41;&#46; In this group&#44; obesity does not increase cardiovascular risk&#44; unlike what happens in the general population&#59; this is part of the so-called &#8220;reverse epidemiology&#8221; described by the DOPPS study&#46;<span class="elsevierStyleSup">22</span></p><p class="elsevierStylePara">When evaluating the relationship between EPO dose&#44; ERI and Hb level in patients with CKD and HF&#44; it is important to keep in mind the complexity of administering EPO treatment in this situation&#44; which is becoming increasingly common&#46; The Hb level may fall and rise in an &#8220;unreal&#8221; way depending on the intensity of diuretic treatment and the simultaneous presence of oedemas &#40;haemoconcentration and haemodilution&#41;&#46; Due to these reasons&#44; the EPO dose may change without variation in the real mass of red blood cells&#44; and therefore the nephrologist must adjust the EPO dose for these patients&#44; while considering the effect which changes in plasma volume will have on the Hb concentration&#46;<span class="elsevierStyleSup">23-25</span></p><p class="elsevierStylePara">One of this study&#8217;s limitations is that it contains a small number of patients&#46; It does&#44; however&#44; have the advantage of being homogenous&#44; since it was conducted in one centre with a single observer and a consecutive array of patients who had the same therapeutic criteria&#44; and these characteristics reduce population and observer biases&#46; To compensate for the bias occurring from correlating baseline ERI with a patient&#8217;s evolution over 3 years of follow-up&#44; we took a second ERI measurement &#40;in the 6 months prior to exitus&#44; beginning dialysis or the end of follow-up for patients still treated on an outpatient basis&#41; and used the mean ERI for studying survival&#46; With this approach&#44; we are able to reconcile ERI with the evolution we observed&#46; All things considered&#44; this study and its conclusions have the same limitations as any survival analysis&#44; including the low rate of events in some groups which does not permit us to calculate median survival&#44; risk over time&#44; etc&#46;</p><p class="elsevierStylePara">One aspect that makes this study a useful contribution to the literature is that few studies analyse the progression of patients with advanced CKD &#40;non-dialysis stage 3-4 CKD&#41; with regard to cardiac morbidity&#44; which is very prevalent and likely to increase given the population profile and its current tendencies&#46;</p><p class="elsevierStylePara">Although some of the findings from studies of patients on dialysis mirror those in earlier stages of CKD&#44; important differences are present&#46; ERI and EPO dose per kg in non-dialysis CKD stage 4-5 are much lower to those recorded for patients on haemodialysis&#46; In the article by L&#243;pez G&#243;mez<span class="elsevierStyleSup">7</span> describing a multi-centre Spanish study of patients during the first year of inclusion in a haemodialysis programme&#44; mean ERI was 10&#46;2&#177;7&#46;3IU&#47;kg&#47;g Hb&#44; while ERI in our study was 3&#46;7&#177; 3IU&#47;kg&#47;g Hb&#44; just over a third of the other index&#46; It is likely that better renal function among our patients and absence of the negative effects of haemodialysis are the main factors accounting for this difference&#44; since comorbidity &#40;the Charlson comorbidity index&#41;&#44; the percentage of heart disease and age are quite similar&#46;</p><p class="elsevierStylePara">As a group&#44; patients with CKD and a high ERI have the following profile&#58; history of heart disease in general or&#44; more specifically&#44; episodes of HF&#59; higher Charlson comorbidity index and ferritin levels&#59; lower renal function&#44; Hb and cholesterol levels&#46;</p><p class="elsevierStylePara">In summary&#44; this study shows a high prevalence of heart disease among patients attended by the ACKD outpatient unit&#46; Simultaneous presence of CKD and HF increases the need for EPO&#44; both in terms of absolute value and with regard to Hb levels&#44; expressed as the resistance index&#46; Likewise&#44; both a history of heart disease&#47;HF episodes and high ERI seem to be associated to poorer survival&#44; and both may be considered markers of increased risk of mortality over the short to medium term&#46; High ERI may be a marker for patients requiring increased diagnostic and therapeutic intensity&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest </span></p><p class="elsevierStylePara">The authors affirm that they have no conflicts of interest related to the content of this article&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28819&#95;en&#95;t1&#95;11111&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28819_en_t1_11111.jpg" alt="Patient characteristics &#40;full group&#41;"></img></a></p><p class="elsevierStylePara">Table 1&#46; Patient characteristics &#40;full group&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28820&#95;en&#95;t2&#95;11111&#95;copy1&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28820_en_t2_11111_copy1.jpg" alt="Patient characteristics &#40;subgroup on erythropoietin&#41;"></img></a></p><p class="elsevierStylePara">Table 2&#46; Patient characteristics &#40;subgroup on erythropoietin&#41;</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28821&#95;en&#95;t3111112&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28821_en_t3111112.jpg" alt="Erythropoietin resistance index &#40;ERI&#41;&#62; or &#38;"></img></a></p><p class="elsevierStylePara">Table 3&#46; Erythropoietin resistance index &#40;ERI&#41;&#62; or &#38;</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28822&#95;en&#95;t4&#95;11111&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28822_en_t4_11111.jpg" alt="Forward stepwise linear regression analysis"></img></a></p><p class="elsevierStylePara">Table 4&#46; Forward stepwise linear regression analysis</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28823&#95;en&#95;t5&#95;11111&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28823_en_t5_11111.jpg" alt="Patients with or without erythropoietin treatment"></img></a></p><p class="elsevierStylePara">Table 5&#46; Patients with or without erythropoietin treatment</p><p class="elsevierStylePara"><a href="grande&#47;11111&#95;16025&#95;28824&#95;en&#95;f1&#95;11111&#46;jpg" class="elsevierStyleCrossRefs"><img src="11111_16025_28824_en_f1_11111.jpg" alt="Survival analysis"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Survival analysis</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Antecedentes&#58; </span>Los pacientes con enfermedad renal cr&#243;nica &#40;ERC&#41; tienen con frecuencia patolog&#237;a card&#237;aca asociada&#46; La coincidencia de ambos procesos puede potenciar la inflamaci&#243;n&#44; aumentando los requerimientos de eritropoyetina &#40;EPO&#41; y empeorando la supervivencia&#46; <span class="elsevierStyleBold">Objetivos&#58; </span>Conocer la prevalencia de patolog&#237;a card&#237;aca&#44; su influencia en la dosis de EPO y la de ambos factores sobre la mortalidad en pacientes con ERC 4-5 no-D &#40;no di&#225;lisis&#41;&#46; <span class="elsevierStyleBold">M&#233;todos&#58; </span>134 pacientes &#40;68&#37; con EPO al inicio y el 72&#44;3&#37; a lo largo del seguimiento&#41; seguidos durante 36 meses&#46; Para evaluar la respuesta a la EPO se utiliz&#243; su &#237;ndice de resistencia a la eritropoyetina &#40;IRE&#41;&#58; dosis de EPO semanal&#47;peso&#47;hemoglobina &#40;Hb&#41;&#59; el IRE se estim&#243; basalmente y durante el per&#237;odo de los seis meses precedentes a la finalizaci&#243;n del estudio&#46; <span class="elsevierStyleBold">Resultados&#58; </span>39 pacientes &#40;29&#44;1&#37;&#41;&#44; antecedentes de cardiopat&#237;a&#59; 22 &#40;16&#44;4&#37;&#41;&#44; episodios de insuficiencia card&#237;aca &#40;IC&#41;&#46; El IRE fue superior en los pacientes con antecedentes de cardiopat&#237;a&#44; con IC y en los tratados con inhibidores de la enzima convertidora de angiotensina&#47;antagonistas de los receptores de angiotensina II&#59; en el an&#225;lisis multivariante &#40;IRE como variable dependiente&#41; compusieron el modelo final&#58; ferritina&#44; Hb&#44; funci&#243;n renal y episodios de IC&#46; Durante el per&#237;odo de seguimiento&#44; 39 pacientes fallecieron&#46; La supervivencia &#40;Kaplan-Meier&#41; a los 36 meses fue inferior en los pacientes con un IRE superior a la mediana &#40;2&#44;6 UI semana&#47;kg&#47;g de Hb en 100 ml&#41; &#40;p &#61; 0&#44;002&#41;&#44; los que hab&#237;an sufrido episodios de IC &#40;p &#61; 0&#44;001&#41; y los que ten&#237;an antecedentes de cardiopat&#237;a &#40;p &#60; 0&#44;001&#41;<span class="elsevierStyleBold">&#46; Conclusiones&#58; </span>Los pacientes con antecedentes cardiol&#243;gicos en general y de IC en particular tienen un IRE aumentado&#46; Tanto la presencia de estos antecedentes como un mayor IRE se asocian a la disminuci&#243;n de la supervivencia&#44; pudiendo considerarse el IRE como marcador de riesgo de muerte a corto-medio plazo&#46; </p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introduction&#58;</span><span class="elsevierStyleBold"> </span>Patients with chronic kidney disease &#40;CKD&#41; frequently suffer from heart disease as well&#46; The combination of the two processes can exacerbate inflammation&#44; resulting in increases in both resistance to erythropoietin &#40;EPO&#41; and mortality&#46; <span class="elsevierStyleBold">Objectives&#58; </span>The aim of this study was to determine the prevalence of heart disease in a representative group of non-dialysis patients with stage 4-5 CKD&#44; and the influence of that entity on EPO requirements and on mortality during a period of 36 months&#46;<span class="elsevierStyleBold"> Methods&#58; </span>134 patients &#40;68&#37; on EPO at the beginning&#44; increasing to 72&#46;3&#37; during follow-up&#41; were monitored for 36 months&#46; To evaluate the dose-response effect of EPO therapy&#44; we used the erythropoietin resistance index &#40;ERI&#41; calculated as the weekly weight-adjusted dose of EPO divided by the haemoglobin level&#46; The ERI was determined both initially and during the last six months before the end of the study&#46; <span class="elsevierStyleBold">Results&#58;</span> 39 patients &#40;29&#46;1&#37;&#41; had history of heart disease&#59; 22 &#40;16&#46;4&#37;&#41; had suffered from heart failure &#40;HF&#41;&#46; The ERI was higher in patients with a history of heart disease or HF and those treated with drugs acting on the renin-angiotensin system &#40;ACE inhibitors or ARBs&#41;&#46; Using ERI as the dependent variable in the multivariate analysis&#44; the variables that composed the final model were ferritin&#44; haemoglobin&#44; glomerular filtration rate and history of HF&#46; The 36 month mortality rate &#40;n&#61;39 patients&#41; was higher in the group having ERI above the median &#40;2&#46;6IU&#47;week&#47;kg&#47;gram of haemoglobin in 100ml&#41; &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41;&#44; and in the groups with heart disease &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;001&#41; or HF &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;001&#41; according to the Kaplan-Meier survival analysis&#46; <span class="elsevierStyleBold">Conclusions&#58;</span> Patients with history of heart disease or HF have a higher ERI&#44; and all of these characteristics are associated with lower survival&#46; ERI can be considered a marker for risk of death in the short to-medium term&#46;</p>"
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Nefrología (English Edition)