RENIN ANGIOTENSIN SYSTEM BLOCKADE AT BEDTIME VERSUS ON AWAKENING TO PREVENT ALDOSTERONE BREAKTHROUGH

Abstract

Objective: Aldosterone breakthrough (AB) is defined by an increase of serum aldosterone levels over baseline values before starting blockers of renine angiotensine system (RAS) treatment by angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). AB may limit the efficacy of these drugs. We hypothesized that short-acting blockers taken on awakening may not inhibit the aldosterone peak occuring at the awakening. To address this hypothesis, we compared the incidence of AB in patients randomized to take their medications either on awakening or at bedtime. Design and method: participants had chronic kidney disease stage 3 or 4 and a urinary protein over creatinine ratio above than 0.5 g/g. Blood pressure, renal function, urinary sodium excretion, levels of aldosterone and renin were measured at baseline and after 1 year exposure to RAS blockers. Incidence of AB was tested with Chi-square test and the variables associated with AB were searched with Mann-Whitney-Wilcoxon tests. Results: among 105 participants, 97 were randomized and 77 completed the study. The incidence of AB was not significantly different between subjects having their treatment on awakening or at bedtime (43% versus 41%, p = 0.83). AB was associated with the decrease of systolic blood pressure (-1 ± 14 vs 5 ± 19 mm Hg, p = 0.05), the decrease of urinary sodium excretion (-31 ± 52 vs 1 ± 59 meq/d, p = 0.007), or the increase of serum creatinine levels (-0.2 ± 0.36 vs -0.10 ± 0.30 mg/dl, p = 0.018). As expected, AB was also associated with the increase of plasma levels of renin (42 ± 125 vs -1 ± 65 ng/L, p = 0.04) and the increase of urinary aldosterone excretion (4 ± 13 vs -1 ± 3, p = 0.0003). The independent factors associated with AB were systolic blood pressure (p = 0.03) and urinary aldosterone excretion (0.03). Conclusions: the intake of a short half-life RAS blockers at bedtime does not prevent AB in CKD patients with macroproteinuria. Mineralocorticoid receptor antagonists may be required to prevent the deleterious consequences of AB.