SP 01-1 ALDOSTERONE ANTAGONISTS FOR THE TREATMENT OF HYPERTENSIVE NEPHROPATHY

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Abstract

The aldosterone/mineralocorticoid receptor (MR) pathway regulate renal excretory function and control BP. Notably, we identified Rac1 as a novel ligand-independent modulator of MR (Nat Med 2008), and found involvement of the Rac1-MR pathway in rodent models of salt-sensitive hypertension (JCI 2011). In the clinical trial (EVALUATE study), effects of MR antagonist on urinary albumin excretion were assessed in 304 hypertensive CKD patients receiving renin-angiotensin system (RAS) inhibitors and sub-grouped according to the estimated dietary salt intake (Lancet Endo & Diabetes 2014). During the 52-week treatment period, albuminuria tended to increase with excessive dietary salt intake in patients receiving placebo, despite standard RAS inhibitor therapy, suggesting salt-induced resistance to RAS inhibitors. The greater suppression of residual albuminuria by MR blockade in patients with higher salt intake, independent of baseline plasma aldosterone, suggests that the ligand-independent activation of MR contributes to high salt-induced resistance to RAS blockade. Thus, add-on therapy of MR antagonists is efficacious for CKD patients receiving RAS inhibitors and taking high salt.

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