Aldosterone and mortality in hemodialysis patients: role of volume overload.

BACKGROUND: Elevated aldosterone is associated with increased mortality in the general population. In patients on dialysis, however, the association is reversed. This paradox may be explained by volume overload, which is associated with lower aldosterone and higher mortality. METHODS: We evaluated the relationship between aldosterone and outcomes in a prospective cohort of 328 hemodialysis patients stratified by the presence or absence of volume overload (defined as extracellular water/total body water >48%, as measured with bioimpedance). Baseline plasma aldosterone was measured before dialysis and categorized as low (<140 pg/mL), middle (140 to 280 pg/mL) and high (>280 pg/mL). RESULTS: Overall, 36% (n = 119) of the hemodialysis patients had evidence of volume overload. Baseline aldosterone was significantly lower in the presence of volume overload than in its absence. During a median follow-up of 54 months, 83 deaths and 70 cardiovascular events occurred. Cox multivariate analysis showed that by using the low aldosterone as the reference, high aldosterone was inversely associated with decreased hazard ratios for mortality (0.49; 95% confidence interval, 0.25-0.76) and first cardiovascular event (0.70; 95% confidence interval, 0.33-0.78) in the presence of volume overload. In contrast, high aldosterone was associated with an increased risk for mortality (1.97; 95% confidence interval, 1.69-3.75) and first cardiovascular event (2.01; 95% confidence interval, 1.28-4.15) in the absence of volume overload. CONCLUSIONS: The inverse association of aldosterone with adverse outcomes in hemodialysis patients is due to the confounding effect of volume overload. These findings support treatment of hyperaldosteronemia in hemodialysis patients who have achieved strict volume control

Baseline characteristics of the study participants by categories of ECW/TBW and plasma aldosterone.

<p>For abbreviations see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057511#pone-0057511-t001" target="_blank">Table 1</a>.</p>a<p>Comparisons among three groups in patients with ECW/TBW ≤48% and >48%, respectively. Statistical analysis by one-way ANOVA test, Pearson <i>x</i>² test, and Kruskal-Wallis test as appropriate.</p>b<p>P<0.05 versus patients with plasma aldosterone of <140 pg/mL.</p>c<p>P<0.05 versus patients with plasma aldosterone of 140–280 pg/mL.</p><p>Prior CVD category consisted of congestive heart failure, coronary artery disease, cerebrovascular disease, and peripheral arterial disease.</p

Volume status for predicting mortality.

<p>The receiver operating characteristic (ROC) curve for prediction of all-cause mortality constructed using the ratio of extracellular water to total body water (ECW/TBW) at baseline (A). The optimal cutoff point for ECW/TBW is listed in the attached table, along with the sensitivity, specificity and accuracy for predicting mortality at the end of the follow-up period. The area under ROC curve is significantly larger than 0.5. Kaplan-Meier analysis curve for all-cause mortality in relation to the ECW/TBW at baseline, stratified by the cutoff point among hemodialysis patients (B).</p

Kaplan-Meier mortality curves according to aldosterone tertile.

<p>All-cause mortality in relation to plasma aldosterone levels at baseline among hemodialysis patients.</p

Baseline characteristics of the study participants by categories of ECW/TBW.

<p>Abbreviations: BMI denotes body mass index; BP, blood pressure; CVD, cardiovascular disease; ECW, extracellular water; ECW/TBW, ratio of extracellular water to total body water; EPO, erythropoietin; HD, hemodialysis; hs-CRP, high-sensitivity C-reactive protein; IL-6, inerleukin-6; RAAS, renin-angiotensin-aldosterone system; TBW, total body water; UF, ultrafiltration.</p>a<p>Comparison between two groups of patients with ECW/TBW ≤48% and >48%.</p><p>Statistical analysis by ^bStudent <i>t</i>-test, ^cPearson <i>x</i>² test, and ^dMann-Whitney U test.</p><p>Prior CVD category consisted of congestive heart failure, coronary artery disease, cerebrovascular disease, and peripheral arterial disease.</p

Hazard ratios for mortality and first cardiovascular event by categorical or continuous measure of plasma aldosterone modified by ECW/TBW.

<p>Abbreviations: CI denotes confidence interval; CV, cardiovascular; CVD, cardiovascular disease; ECW/TBW, ratio of extracellular water to total body water; HR, hazard ratio; IL-6, inerleukin-6.</p>a<p>The interaction P values assessed the modifying effect of volume overload (ECW/TBW >48%) on the risk relationship between plasma aldosterone and overall mortality and CV events.</p

Kaplan-Meier mortality curves according to aldosterone tertile, modified by volume status.

<p>All-cause mortality in relation to plasma aldosterone levels at baseline modified by the ratio of extracellular water to total body water (ECW/TBW) >48% (A) and ≤48% (B) among hemodialysis patients.</p