title: Dual blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy: the role of aldosterone.
abstract: Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with both ACE inhibitors and angiotensin II receptor-blockers has been shown to reduce both albuminuria and blood pressure compared to either monotherapy. The mechanisms behind these beneficial effects are not known, and we hypothesized that the effect of dual RAAS blockade may be due to a more complete suppression of circulating aldosterone. We performed a combined analysis on three randomized, double-masked, cross-over trials where 51 type 1 diabetic patients suffering from diabetic nephropathy received 8 weeks of dual RAAS blockade using an angiotensin II receptor blocker in combination with an ACE inhibitor and 8 weeks of monotherapy with the same ACE inhibitor. Albuminuria, 24 h blood pressure, GFR, and plasma aldosterone were determined at the end of each treatment period. Compared to ACE inhibition alone, dual RAAS blockade lowered blood pressure by 7/5 mm Hg from 137/76 mm Hg, decreased albuminuria by 37% from 558 mg/24 hour, and reduced plasma aldosterone by 28% from 59 pg/ml and caused a reversible decline in GFR of 4 ml/min/1.73 m2 (p < or = 0.01 for all comparisons). There was and a significant correlation between changes in 24-hour diastolic blood pressure and changes in albuminuria. Furthermore, the antialbuminuric response to dual blockade was influenced by the ACE/ID polymorphism, that is, patients carrying the D-allele had a significantly lower reduction of 31% compared to the 55% in patients with the II genotype (p = 0.021). Multiple linear regression analysis revealed that ACE/ID genotypes and reduction in plasma aldosterone, diastolic blood pressure and GFR is associated with changes in albuminuria on dual blockade treatment (R2 (adjusted) = 0.57, p < 0.001). Dual RAAS blockade is a new treatment concept that may offer additional cardiovascular and renal protection in type 1 diabetic patients with diabetic nephropathy. The beneficial response may be influenced by genetic factors and reductions in blood pressure and plasma aldosterone concentrations.
authors.affiliation: Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark. kjos@steno.dk
authors.forename: K J
authors.initials: KJ
authors.lastname: Schjoedt
authors.forename: P
authors.initials: P
authors.lastname: Jacobsen
authors.forename: K
authors.initials: K
authors.lastname: Rossing
authors.forename: F
authors.initials: F
authors.lastname: Boomsma
authors.forename: H H
authors.initials: HH
authors.lastname: Parving
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000097:blood*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D006801:Humans; D008297:Male; D012084:Renin-Angiotensin System / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000450:Aldosterone