Effect of aldosterone breakthrough on albuminuria during treatment with a direct renin inhibitor and combined effect with a mineralocorticoid receptor antagonist

Abstract

We have reported observing aldosterone breakthrough in the course of relatively long-term treatment with renin-angiotensin (RA) system inhibitors, where the plasma aldosterone concentration (PAC) increased following an initial decrease. Aldosterone breakthrough has the potential to eliminate the organ-protective effects of RA system inhibitors. We therefore conducted a study in essential hypertensive patients to determine whether aldosterone breakthrough occurred during treatment with the direct renin inhibitor (DRI) aliskiren and to ascertain its clinical significance. The study included 40 essential hypertensive patients (18 men and 22 women) who had been treated for 12 months with aliskiren. Aliskiren significantly decreased blood pressure and plasma renin activity (PRA). The PAC was also decreased significantly at 3 and 6 months; however, the significant difference disappeared after 12 months. Aldosterone breakthrough was observed in 22 of the subjects (55%). Urinary albumin excretion differed depending on whether breakthrough occurred. For the subjects in whom aldosterone breakthrough was observed, eplerenone was added. A significant decrease in urinary albumin excretion was observed after 1 month, independent of changes in blood pressure. In conclusion, this study demonstrated that aldosterone breakthrough occurs in some patients undergoing DRI therapy. Aldosterone breakthrough affects the drug's ability to improve urinary albumin excretion, and combining a mineralocorticoid receptor antagonist with the DRI may be useful for decreasing urinary albumin excretion. When the objective is organ protection in hypertensive patients, a two-pronged approach using combination therapy to inhibit both the RA system and aldosterone may be highly effective.

The renin‐angiotensin‐aldosterone system and its suppression

“…Redundancies that bypass our therapeutic blockade or inadvertent suppression of beneficial components of this system might reduce the efficacy of our RAAS suppressive therapies. For example, Angiotensin II and aldosterone levels occasionally rise despite pharmacologic RAAS suppression, and the underlying mechanisms are still not well understood . Furthermore, Some drugs and strategies used to treat cardiovascular disease, including furosemide, amlodipine, hydralazine and dietary sodium restriction, stimulate the RAAS (Supporting Information Figure S1).…”

Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders

“…Moreover, multiple studies have shown that add-on therapy with an MR antagonist reduces albuminuria in humans with type 2 diabetes on an ACEI, ARB, or renin inhibitor [59][60][61]. Further, low-dose spironolactone was recently shown to exert significant lowering of blood pressure and urinary albumin creatinine ratio in high-risk patients with resistant hypertension and type 2 diabetes [62].…”

The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy

“…Aldosterone breakthrough usually does not influence the antihypertensive effects of RAS inhibitors, but breakthroughed aldosterone attenuates the organ-protective effects of RAS inhibitors through the actions of mineralocorticoid receptors (MRs). [18][19][20][21][22][23] With relatively long-term treatment with RAS inhibitors, regardless of dose or combination of drugs, aldosterone breakthrough may be impossible to prevent. Inadequate blockade of aldosterone may be one of the reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with DM nephropathy.…”