Aldosterone and Mortality in Hemodialysis Patients: Role of Volume Overload

Abstract

BackgroundElevated 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.MethodsWe 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).ResultsOverall, 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.ConclusionsThe 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.

Aldosterone, mortality, cardiovascular events and reverse epidemiology in end stage renal disease

“…In this trial, high aldosterone was directly associated with a high incident risk of sudden death [12], which is an established sequel of LVH [30]. On the other hand, a small study in Japan which gathered just 30 death events over a 7-year follow-up reported an inverse association between aldosterone and mortality [13,14] pointing to aldosterone as an additional biomarker influenced by the reverse epidemiology of ESRD [19]. This inverse association was confirmed in a subsequent study which identified volume expansion as measured bioimpedance as a major driver of low aldosterone in this population [14].…”

“…On the other hand, a small study in Japan which gathered just 30 death events over a 7-year follow-up reported an inverse association between aldosterone and mortality [13,14] pointing to aldosterone as an additional biomarker influenced by the reverse epidemiology of ESRD [19]. This inverse association was confirmed in a subsequent study which identified volume expansion as measured bioimpedance as a major driver of low aldosterone in this population [14]. The present study is the largest observational study performed so far in HD patients and the sole considering also renin levels, that is a major determinant of plasma aldosterone, as well as LAV and combined biomarker of volume expansion and LV dysfunction such as ANP.…”

“…Accordingly, high aldosterone predicted an excessive risk for sudden death in type 2 diabetics on chronic dialysis [12]. On the other hand, other studies in ESRD show that low rather than high aldosterone predicts death in this population [13,14]. ESRD is a very highrisk condition which is characterised by reverse causality [15], that is by the fact some classical risk factors such as hypertension [16], obesity [17] and hypercholesterolaemia [18] which are directly associated with adverse clinical outcomes in the general population are instead inversely associated with the same outcomes in ESRD.…”

Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease: Efficacy and Safety

“…ESRD patients typically have LVH, and LVMI correlates with aldosterone levels in non-diabetic patients on hemodialysis [33,34] . In a recent study of 328 hemodialysis patients, the median serum aldosterone level was 18.4 ng/dl, and the highest tertile (level >28 ng/dl, as compared with level <14 ng/dl) was associated with a doubling of mortality and cardiovascular events in euvolemic patients [24] .…”

“…The inverse relationship between ECV and serum aldosterone concentration suggests that in the setting of low dietary sodium intake, levels of renin, angiotensin II, and aldosterone increase but do not cause inflammation and end-organ damage [21] . However, CKD [22,23] and ESRD [24] are notable states of relative hyperaldosteronism despite ECV expansion -that is, aldosterone levels are not sufficiently suppressed for the degree of ECV expansion ( fig. 2 ) -leading to proinflammatory MR activation [22,23,25,26] .…”