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Any therapeutic measure that reduces proteinuria will have a positive renoprotective effect on the long-term outcome of renal function&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">8&#44;9</span></a> The most effective antiproteinuric measures among these therapies are a renin&#8211;angiotensin&#8211;aldosterone system &#40;RAAS&#41; blockade in its various modalities&#44; angiotensin-converting enzyme inhibitors &#40;ACEIs&#41;&#44; angiotensin-receptor antagonists &#40;ARAs&#41; and&#44; more recently&#44; aldosterone antagonists &#40;AAs&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">10&#44;11</span></a> Considering the above&#44; as well as the role of obesity in the progression of kidney diseases and the epidemic proportions that obesity has reached in developed societies&#44; the response of patients with obesity and proteinuric nephropathy to the various strategies that block RAAS is a topic of extraordinary clinical importance&#44; considering that RAAS activity is greater in obesity&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">12&#44;13</span></a> Although the initials data on the antiproteinuric response of ACEIs or ARAs in obese patients were contradictory&#44; recently the post hoc analysis of the Ramipril Efficacy in Nephropathy &#40;REIN&#41; trial indicated that the risk reduction for renal disease progression to end-stage-renal-diseases &#40;ESRD&#41; and the antiproteinuric effect by ramipril was more pronounced in obese population&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">14</span></a> Current studies suggest that patients with obesity have increased aldosterone synthesis&#44; which could play an important role in the various complications associated with obesity&#44; including renal damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">15&#44;16</span></a> Experimental studies conducted with obese animals have shown that the use of AAs drastically reduces renal lesion progression&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">17&#44;18</span></a> This research suggests that patients with obesity and proteinuric nephropathy could have a more favorable antiproteinuric response to AAs than to traditional RAAS blockage with ACEIs or ARAs&#46; However&#44; there is little information in the literature on the role of AAs in the proteinuria of patients with obesity&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">There is little information regarding the antiproteinuric effect of AA alone or combined with RAAS blockade long term obese patients with proteinuric nephropathies&#46; In the scientific community there is growing concern about the new epidemic of the XXI century&#44; the obesity&#46; The aim of this study was analyze how obese patients responded to treatment with AA compared with non-obese patients&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In 2004&#44; a clinical protocol was started based on the addition of spironolactone to patients with proteinuric nephropathy who maintained proteinuria levels &#62;1<span class="elsevierStyleHsp" style=""></span>g&#47;day&#44; despite treatment with ACEIs or ARAs&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">21</span></a> This study is a substudy that analyzes &#40;a&#41; the antiproteinuric effect over time of AAs on patients with obesity and &#40;b&#41; whether treatment with spironolactone slows the progression of renal failure in this patient group&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients</span><p id="par0020" class="elsevierStylePara elsevierViewall">In January 2004&#44; we began a prospective cohort study based on the addition of spironolactone to patients who had persistent proteinuria levels &#62;1<span class="elsevierStyleHsp" style=""></span>g&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; despite the maximum tolerated dosages of ACEIs&#44; ARAs or their combination for more than 6 months regardless of the etiology of renal disease&#46; There were no restrictions based on age or renal function&#46; We excluded patients with the same criteria as in the previous study&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">21</span></a> This substudy excluded those patients with follow-up less than 12 months for various reasons&#46; In the obese group were excluded 6 patients&#44; 2 for follow-up less than 3 months&#44; 2 patients had developed a deterioration of renal function in the first month after AA treatment and 2 patients for hyperkalemia uncontrolled in the first month after AA treatment&#46; In the control group 10 patients were excluded&#44; 5 for follow-up less than 3 months&#44; 1 patient had developed an acute deterioration of renal function and 4 patients developed hyperkalemia after AA treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Seventy-one patients were included in this protocol&#46; We established 2 patient groups according to body mass index &#40;BMI&#41;&#58; an obesity group for patients with a BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> and a control group for patients with a BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#46; The study was approved by the Hospital&#39;s Ethics Committee&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Therapeutic intervention</span><p id="par0030" class="elsevierStylePara elsevierViewall">Spironolactone was added at a dosage of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;day to the baseline therapy of all patients&#46; During the follow-up&#44; the spironolactone dosage was adjusted according to measurements of blood pressure &#40;BP&#41; or serum potassium levels&#46; For a number of the patients who had an insufficient antiproteinuric response &#40;&#60;30&#37; of baseline values&#41; but had good tolerance&#44; the dosage was increased to 50<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; For the patients who experienced adverse effects other than hyperpotassemia &#40;mainly gynecomastia&#41;&#44; spironolactone was replaced with eplerenone at a dosage of 25<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#46; The baseline dosages of ACEIs&#44; ARAs or both were not modified at the start of the study&#46; The dosages were subsequently modified for a number of patients based on measurements of BP and serum potassium levels&#46; For a number of the patients with antiproteinuric responses &#62;30&#37; of baseline values and a difficult management of serum potassium levels&#44; the ACEI and&#47;or ARA-2 dosages were progressively lowered or&#44; in a number of cases&#44; had to be discontinued&#46; For proper control of serum potassium levels&#44; we recommended the same measures as in the previous study&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">21</span></a> The BP objective was established at levels below 130&#47;80<span class="elsevierStyleHsp" style=""></span>mm Hg&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Follow-up and data collection</span><p id="par0035" class="elsevierStylePara elsevierViewall">All patients were treated in outpatient clinics after 1 month of treatment with spironolactone&#46; These data were collected as in the previous study&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">21</span></a> The mean follow-up was 28&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14 &#40;14&#8211;84&#41; months&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Study objectives</span><p id="par0040" class="elsevierStylePara elsevierViewall">The primary study objective was to compare the reduction in proteinuria in the obesity group at the end of the follow-up compared with the control group&#46; We analyzed the number of patients who achieved a &#62;50&#37; reduction in proteinuria from baseline values during their follow-up&#46; The secondary objectives included comparing the change in the glomerular filtration rate &#40;GFR&#41; during the 12-month period prior to spironolactone treatment compared with the period between baseline and the end of the follow-up and the period between the first month following treatment and the end of follow-up&#46; The change in GFR was measured in mL&#47;min&#47;year&#46; The response to AA treatment was analyzed separately for the obesity and control groups&#46; We also analyzed the tolerance to spironolactone and its adverse effects&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Definitions</span><p id="par0045" class="elsevierStylePara elsevierViewall">The follow-up period was calculated with the same criteria as in the previous study&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">21</span></a> Renal function was measured by GFR using the simplified 4-variable Modification of Diet in Renal Disease formula &#40;MDRD-4&#41;&#46; BMI was measured as weight in kilograms divided by the height squared in meters&#46; Mean arterial pressure &#40;MAP&#41; was calculated as the sum of the diastolic blood pressure and one third of the pulse pressure&#46; To calculate the improvement in the loss of GFR&#44; we established a cutoff for the mean value of the GFR slope in the first 12 months prior to treatment &#40;&#8722;3<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;year&#41;&#44; considering that the patients who managed to reduce this loss of GFR from the start of treatment to the end of follow-up were categorized as patients who achieved an improvement in renal function&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">The data are expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation &#40;SD&#41; or median and interquartile range for continuous normal and non-normal variables&#44; respectively&#46; The continuous variables with normal distribution are expressed as mean and SD&#44; while the noncontinuous variables are expressed as medians&#44; 25 and 75 percentiles and interquartile range&#46; Categorical variables are expressed as frequencies and percentages&#46; The Spearman correlation test&#44; paired t tests and Wilcoxon test were employed for the analysis of continuous variables when indicated&#46; Differences between the qualitative variables were compared using the chi-squared test&#46; For all tests&#44; values of <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05 were considered statistically significant&#46; The data were assessed with the SPSS program&#44; version 15&#46;0 for Windows &#40;SPSS&#44; Chicago&#44; IL&#44; USA&#41;&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Patient characteristics</span><p id="par0055" class="elsevierStylePara elsevierViewall">Seventy-one patients were included in the protocol with spironolactone&#46; Their demographic&#44; clinical and laboratory test characteristics at the start of the study are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The number of patients who were treated with antihypertensive drugs other than RAAS blockers at the start and end of the follow-up was as follows&#58; calcium-antagonists&#44; 8 &#40;11&#37;&#41; and 6 &#40;8&#37;&#41;&#44; respectively&#59; beta-blockers&#44; 6 &#40;8&#37;&#41; and 6 &#40;8&#37;&#41;&#59; and alpha blockers&#44; 5 &#40;7&#37;&#41; and 4 &#40;6&#37;&#41;&#46; Before starting treatment with an AA&#44; 15 &#40;21&#37;&#41; patients were treated with an ACEI&#44; 37 &#40;52&#37;&#41; were treated with an ARA and 19 &#40;27&#37;&#41; were treated with a combination of an ACEI and ARA&#46; Forty-five patients were treated with ARA&#43;AA&#44; 20 patients were treated with ACEI&#43;AA and 4 were treated with ACEI&#43;ARA&#43;AA at the end of the follow-up&#44; while 2 patients were treated with an AA alone&#46; In <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; we can observe the main differences between the 2 study groups&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Proteinuria</span><p id="par0060" class="elsevierStylePara elsevierViewall">In the obesity group&#44; we observed a significant reduction in proteinuria from the first month of treatment with spironolactone &#40;2&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;1 to 1&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;8<span class="elsevierStyleHsp" style=""></span>g&#47;day&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#44; which represents a 46&#46;3&#37; reduction &#91;range 26&#46;9&#8211;58&#46;4&#93; from baseline values&#41;&#46; The mean reduction in proteinuria was maintained in 65&#37; of the patients &#40;range 48&#46;7&#8211;82&#46;8&#41; at 12 months&#44; with no tendency toward reduction during the follow-up &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a> and <a class="elsevierStyleCrossRefs" href="#fig0010">Figs&#46; 2 and 3</a>&#41;&#46; At the end of the follow-up&#44; the proteinuria levels were 1&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;6<span class="elsevierStyleHsp" style=""></span>g&#47;day &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001 compared with baseline proteinuria&#41;&#44; which represents a 59&#37; reduction &#40;range 43&#8211;73&#37;&#41; when compared with baseline values&#46; A shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#44; most patients of obesity group achieved reductions of more than 50&#37; in proteinuria from baseline values&#44; and this reduction was maintained over the course of the follow-up &#40;72&#37; of patients at month 12&#44; 65&#46;5&#37; at month 24&#44; 63&#46;2&#37; at month 36&#44; 57&#46;1&#37; at month 48 and 68&#46;8&#37; of at the end of follow-up&#41;&#46; There was no correlation between the changes in GFR and the changes in proteinuria &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;27&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;12&#41; or between the changes in blood pressure and the reduction in proteinuria &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;24&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;19&#41;&#46; In the control group&#44; the mean reduction in proteinuria was maintained in 63&#37; of the patients &#40;range 25&#46;1&#8211;78&#46;9&#41; at 12 months&#44; similar to the obesity group&#46; This reduction was maintained throughout the follow-up and was even higher than the obesity group 69&#37; &#40;range 57&#8211;83&#41; vs 59&#37; &#40;range 43&#8211;73&#37;&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 at the end follow-up &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Changes in renal function</span><p id="par0065" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a> and <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#44; renal function deteriorated significantly during the previous period 12 months before the start of treatment with spironolactone &#40;&#8722;0&#46;27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;6<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#47;month&#41;&#46; After the first month of treatment with spironolactone&#44; renal function showed a significant drop &#40;&#8722;3&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;8<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> with respect to baseline values&#41;&#46; The estimated glomerular filtration rate &#40;eGFR&#41; showed an acute fall in the first month of treatment&#44; but it remained stable thereafter &#40;&#43;0&#46;01<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;35<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m&#40;2&#41;&#47;month&#41;&#44; with a tendency toward no significant difference with respect to the eGFR slope during the 12-month pre-treatment period&#46; There was a non significant improvement in the slope of the GFR drop between the period prior to treatment with spironolactone &#40;&#8722;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;1<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;year&#41; and from the start of treatment to the end of the follow-up &#40;&#8722;1&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;9<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;year&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;37&#41;&#46; Twenty patients &#40;62&#46;5&#37;&#41; showed improvement in renal function during the follow-up&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In the non-obesity group&#44; there was non significant improvement between the slope of GFR drop between the period prior to treatment with spironolactone &#40;&#8722;4&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&#46;7<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;year&#41; and from the start of treatment to the end of the follow-up &#40;&#8722;2&#46;3 observed<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;3<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;year&#44; <span class="elsevierStyleItalic">p</span> &#46;54&#41;&#46; Twenty-three patients &#40;59&#37;&#41; showed improvement in renal function during the follow-up&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Changes in blood pressure and serum potassium levels</span><p id="par0075" class="elsevierStylePara elsevierViewall">Blood pressure levels was significantly reduced in both groups during the first month of treatment with spironolactone &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; and remained stable during the follow-up&#46; Serum potassium levels increased significantly after the first month of treatment but remained stable during the follow in both groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; There was no significant influence between the changes in BP and GFR &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;27&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;13&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Safety and tolerance of spironolactone</span><p id="par0080" class="elsevierStylePara elsevierViewall">During the study&#44; there were no deaths and no onset of advanced chronic renal failure or duplication of baseline serum creatinine levels&#46; Nine patients &#40;28&#37;&#41; developed gynecomastia shortly after starting treatment with spironolactone and were therefore switched to eplerenone &#40;25<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#46; It is important to note that the incidence of gynecomastia in the control group was clearly lower &#40;5&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; There were no differences in terms of renal function and proteinuria results between the patients who switched to eplerenone and those who remained with spironolactone&#46; During the study&#44; 2 patients &#40;6&#37;&#41; discontinued the treatment with AA due to persistent hyperpotassemia &#40;&#62;5&#46;5&#8211;6<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#41;&#44; despite the adopted therapeutic measures&#46; The number of patients who discontinued the treatment in the control group was similar &#40;2 patients&#44; 5&#37;&#41;&#46; Of the 2 patients with obesity who had to discontinue the treatment&#44; both had diabetes and 1 had a GFR<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> at the start of the study&#46; The discontinuation of AA occurred 14 and 19 months after the start of the treatment&#46; The 2 cases that had to discontinue spironolactone were treated with ARA at the start of the study&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">At the end of the follow-up&#44; 22 patients were undergoing concomitant treatment for hyperpotassemia &#40;12 patients with cation exchange resins and 10 patients with low doses of thiazide&#41;&#46; The mean dosage of spironolactone and eplerenone at the end of the study was 27&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;6<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h &#40;12&#46;5&#8211;100&#41; and 37&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;8<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h &#40;12&#46;5&#8211;75&#41;&#44; respectively&#46;</p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Our study provides clinical information on the long-term outcome of reducing proteinuria and the changes in renal function in a cohort of patients with obesity and with various types of kidney diseases who were treated with spironolactone due to persistent proteinuria &#62;1<span class="elsevierStyleHsp" style=""></span>g&#47;d&#44; despite treatment with ACEIs&#44; ARAs or their combination&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; renal function showed a progressive reduction in the 12-month period prior to treatment with spironolactone&#46; Although we observed an abrupt drop in GFR &#40;&#8722;3&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;8<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41; after the first month of treatment&#44; which could lead us to reconsider discontinuing the use of the drug&#44; renal function improved after the first month of treatment until the end of the follow-up&#46; The comparison of GFR slopes during the pretreatment period &#40;12 months prior&#41; and from the first month of treatment to the end of the follow-up showed a tendency that did not achieve statistical significance&#46; An important aspect of our study is the extended follow-up time&#44; which enables us to confidently assert the beneficial effect spironolactone has on the reduction of proteinuria and the improvement and&#47;or stabilization of renal function&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Experimental and clinical studies have shown that RAAS activity is increased in obesity and that adipose tissue&#44; especially visceral&#44; synthesizes all RAAS components&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">13&#44;22</span></a> Moreover&#44; patients with obesity have high plasma aldosterone levels&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">17&#44;23</span></a> and recent studies have shown that visceral adipocytes can secrete various factors that increase aldosterone production by adrenal glands&#44; through pathways other than the classical renin-angiotensin pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">24</span></a> Oxidized fatty acids&#44; typically found in high levels in patients with obesity&#44; can also increase aldosterone synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">25</span></a> This collection of data could suggest a more favorable effect of AAs in patients with obesity&#44; due to the hyperaldosteronism associated with obesity&#46; However&#44; our study did not find any difference in the proteinuric effect&#44; control of the blood pressure or slowing of the decline in GFR between obese and non-obese patients&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Our study shows that the antiproteinuric effect in patients with obesity persists without change during the follow-up&#44; a fairly important fact given that it could only be evaluated over short periods of time&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">19&#44;20</span></a> The antiproteinuric effect was notably homogeneous&#59; most of the patients showed sustained proteinuria reductions greater than 50&#37;&#44; even 48 months after the introduction of AA&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">It is very interesting the behavior of the 25 diabetic patients in this substudy&#46; In both groups showed a significant reduction in proteinuria &#40;68&#46;2&#37;&#41; during the follow-up &#40;3&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;3 to 1&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;6<span class="elsevierStyleHsp" style=""></span>g&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; with a clear slowing of decline in GFR &#40;6&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;7<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;year to 2&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;year&#44; <span class="elsevierStyleItalic">p</span> &#46;36&#41; since the introduction of aldosterone&#46; These findings show us that the early introduction of these drugs in patients with diabetic nephropathy could find a beneficial renoprotective effect&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Although serum potassium levels showed a significant increase after the introduction of spironolactone&#44; they were easily controlled with a low-potassium diet&#44; cation exchange resins or low-dose thiazide diuretics&#46; During the study&#44; only 2 patients &#40;6&#37;&#41; discontinued the treatment with AA due to persistent hyperpotassemia &#40;&#62;5&#46;5&#8211;6<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#41;&#44; despite the adopted therapeutic measures&#46; Gynecomastia is a relatively common secondary effect in patients with obesity treated with spironolactone and was observed in 28&#46;1&#37; of the patients&#44; which was higher than in the control group &#40;5&#46;1&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;007&#41;&#46; The condition was completely resolved by changing to eplerenone&#44; another AA that does not share this complication&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Although our results show a low incidence of hyperpotassemia and other severe complications&#44; it is important to emphasize that careful monitoring of our patients is necessary and that this policy should be recommended for all patients treated with AAs&#44; particularly those cases with mild levels of renal failure&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Recent studies have alerted us to the risk of severe complications &#40;renal function impairment&#44; hyperpotassemia and hypotension&#41; in patients treated with dual ACEI&#43;ARA blockers&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">26&#44;27</span></a> We observed no more adverse effects in our patients after the introduction of the AA in patients who were treated with ACEI&#43;ARA when compared with the patients treated with ACEI or ARA alone&#46; All patients treated with dual blockers at the start of the study &#40;9 of 32&#41; progressively withdrew the ACEI or ARA during the follow-up due to better blood pressure control and satisfactory proteinuria reduction after the introduction of the AA&#46; In this respect&#44; our data suggest that ACEI&#43;AA or ARA&#43;AA combinations could be an interesting alternative to dual ACEI&#43;ARA blockers&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Another fundamental issue is the beneficial effect of AA on cardiometabolic syndrome and resistant arterial hypertension in patients with obesity&#46; There is increasing scientific evidence that relates an excess of circulating aldosterone to metabolic effects and endothelial function&#44; which contribute to the genesis of hypertension&#44; cardiovascular disease and nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">28</span></a> Therefore&#44; the use of AAs has clear utility in cardiovascular prevention and blood pressure control&#46; In our study&#44; we were able to observe a clear reduction in BP &#40;8&#46;5&#37;&#41;&#44; which&#44; coupled with the renoprotective effects&#44; may be considered an excellent therapeutic option for this patient group&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Our study has significant limitations&#44; such as a small number of patients&#44; the fact that it is not a randomized and controlled study and a lack of biochemical measurements for renin-aldosterone and ions in urine&#44; which could have verified the beneficial effects of these drugs&#46; An important limitation of this study is that the formula used to calculate the GFR-MDRD-4 is not validated in the obese population&#46; However&#44; this study reproduces the standard clinical practice with significant fidelity&#46; For this reason&#44; more comparative studies are warranted to determine whether these antiproteinuric and renoprotective effects of AA are shared by other types of diuretics in the population with obesity&#44; given that a number of studies have shown that thiazides can induce significant reductions in proteinuria when added to ACEIs and&#47;or ARAs&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">29</span></a> Similarly&#44; sodium restriction boosts the antiproteinuric response to ACEIs and ARAs&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">30</span></a> and the combination of hydrochlorothiazide with a low-sodium diet increases the response even further&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">31</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">In summary&#44; the antiproteinuric effect and trend to slowing progression of renal failure with AA treatment in proteinuric nephropathies not changed by the condition of obesity&#46; The renoprotective effect of aldosterone antagonists should be confirmed in larger prospective trials&#46; The rational use of these drugs in adequate doses with close monitoring of side effects can combine their antiproteinuric effect and an adequate safety profile&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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              "titulo" => "Patient characteristics"
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              "titulo" => "Changes in renal function"
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              "titulo" => "Changes in blood pressure and serum potassium levels"
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              "titulo" => "Safety and tolerance of spironolactone"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Over the past decade&#44; obesity has become a risk factor for developing chronic kidney disease&#46; Proteinuria is known to be an independent determinant of the progression of chronic kidney disease&#44; and adipose tissue is a recognized source of components of the renin&#8211;angiotensin&#8211;aldosterone system &#40;RAAS&#41;&#46; Recent studies have shown that plasma aldosterone levels are disproportionately higher in patients with obesity&#46; Drugs that block the RAAS are unable to inhibit aldosterone in the long term&#46; The aim of our study was to analyze the renoprotective effect of an aldosterone antagonist in combination with RAAS blockers in patients with obesity and proteinuric nephropathy&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This study is a substudy of previously published study on the renoprotective effect of mineralocorticoid receptor blockers in patients with proteinuric nephropathies&#46; Patients with proteinuria levels &#62;1<span class="elsevierStyleHsp" style=""></span>g&#47;24<span class="elsevierStyleHsp" style=""></span>h who were taking spironolactone and were being treated with other RAAS blockers were divided according to body mass index &#40;BMI&#41; into an obesity group &#40;BMI &#8805;30<span class="elsevierStyleHsp" style=""></span>kg&#47;m2&#41; and a control group&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Seventy-one patients were included in the study&#44; with a mean age of 56&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;1 years&#46; More than 50&#37; of the patients in both groups had diabetes&#46; Thirty-two patients were included in the obesity group and 39 were included in the control group&#46; There were no significant differences in renal function&#44; proteinuria&#44; blood pressure&#44; serum potassium levels and the percentage of RAAS blockers in both groups&#46; After a follow-up of 28&#46;9 &#40;14&#8211;84&#41; months&#44; there was a 59&#46;4&#37; reduction in proteinuria in the obesity group &#40;2&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;1 vs&#46; 1&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;6<span class="elsevierStyleHsp" style=""></span>g&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#46; The reduction in proteinuria was greater than 50&#37; in 22 &#40;68&#46;8&#37;&#41; cases&#44; and the mean blood pressure showed a significant decrease &#40;from 100&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9 to 92&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;4<span class="elsevierStyleHsp" style=""></span>mm Hg&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&#46; The control group showed a 69&#46;6&#37; reduction in proteinuria &#40;1&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;4 to 0&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; The reduction of proteinuria was higher than 50&#37; in 22 &#40;68&#46;8&#37;&#41; cases in obese patients and in 33 &#40;84&#46;6&#37;&#41; cases in non-obese group&#46; Renal function remained stable in both groups during the follow-up&#46; Nine patients &#40;28&#46;1&#37;&#41; in the obesity group experienced gynecomastia&#46; The incidence of hyperkalemia was similar for the 2 groups &#40;6&#46;3&#37;&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Aldosterone antagonist treatment in obese patients with proteinuric nephropathies induces a drastic and sustained reduction in proteinuria but not more than the non-obese group&#46; There was a trend toward slowing progression of renal failure with few adverse events&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Durante la &#250;ltima d&#233;cada&#44; la obesidad se ha convertido en un factor de riesgo para el desarrollo de la enfermedad renal cr&#243;nica&#46; La proteinuria est&#225; considerada un factor independiente de la progresi&#243;n de la enfermedad renal cr&#243;nica y el tejido adiposo se reconoce como una fuente de los componentes del sistema renina-angiotensina-aldosterona &#40;SRAA&#41;&#46; Estudios recientes han demostrado que los niveles de aldosterona plasm&#225;tica son desproporcionadamente mayores en pacientes con obesidad&#46; Los f&#225;rmacos que bloquean el SRAA son incapaces de inhibir la aldosterona a largo plazo&#46; El objetivo de nuestro estudio fue analizar el efecto protector a nivel renal de un antagonista de la aldosterona en combinaci&#243;n con bloqueadores del SRAA en pacientes con obesidad y nefropat&#237;a con proteinuria&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Este estudio es un subestudio del estudio publicado previamente sobre el efecto protector a nivel renal de los bloqueadores del receptor de mineralocorticoides en pacientes con nefropat&#237;as con proteinuria&#46; Se dividi&#243; a los pacientes con niveles de proteinuria &#62;1 g&#47;24 h que estaban tomando espironolactona y se los trataba con otros bloqueadores del SRAA seg&#250;n el &#237;ndice de masa corporal &#40;IMC&#41; en un grupo de obesidad &#40;IMC &#8805;30 kg&#47;m<span class="elsevierStyleSup">2</span>&#41; y un grupo de control&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se incluy&#243; a 71&#160;pacientes en el estudio&#44; con una media de edad de 56&#44;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#44;1&#160;a&#241;os&#46; M&#225;s del 50&#37; de los pacientes en ambos grupos ten&#237;a diabetes&#46; Se incluy&#243; a 32&#160;pacientes en el grupo de obesidad y a 39 en el grupo de control&#46; No hubo diferencias significativas en la funci&#243;n renal&#44; proteinuria&#44; presi&#243;n arterial&#44; niveles de potasio s&#233;rico y el porcentaje de bloqueadores del SRAA en ambos grupos&#46; Tras un seguimiento de 28&#44;9&#160;meses &#40;14-84&#41;&#44; hubo una reducci&#243;n del 59&#44;4&#37; de la proteinuria en el grupo de obesidad &#40;2&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#44;1 frente a 1&#44;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;6 g&#47;24&#160;h&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; La reducci&#243;n de la proteinuria fue superior al 50&#37; en 22&#160;casos &#40;68&#44;8&#37;&#41; y la presi&#243;n arterial media experiment&#243; una disminuci&#243;n significativa &#40;de 100&#44;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9 a 92&#44;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#44;4&#160;mm Hg&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; El grupo de control experiment&#243; una reducci&#243;n del 69&#44;6&#37; de la proteinuria &#40;de 1&#44;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;4 a 0&#44;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;5&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; La reducci&#243;n de la proteinuria fue superior al 50&#37; en 22&#160;casos &#40;68&#44;8&#37;&#41; en pacientes obesos y en 33&#160;casos &#40;84&#44;6&#37;&#41; en el grupo de no obesos&#46; La funci&#243;n renal de ambos grupos permaneci&#243; estable durante el seguimiento&#46; En 9&#160;pacientes &#40;28&#44;1&#37;&#41; del grupo de obesidad se observ&#243; ginecomastia&#46; La incidencia de hiperpotasemia fue similar en los 2 grupos &#40;6&#44;3&#37;&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El tratamiento con un antagonista de la aldosterona en pacientes obesos con nefropat&#237;as con proteinuria induce una reducci&#243;n dr&#225;stica y sostenida de la proteinuria&#44; pero no superior a la del grupo de no obesos&#46; La tendencia fue frenar la progresi&#243;n de la insuficiencia renal con pocos eventos adversos&#46;</p></span>"
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