Dual RAS-blockade by ACE-inhibition and AT1 receptor blockade, role of the ACE I/D genotype and low sodium diet in non-diabetic proteinuric patients.

The DUAAAL study is a double blind, randomized, crossover study to study whether the gene environment interaction between the ACE genotype, dietary sodium intake and the response to ACE inhibition which is present in healthy subjects, is also present in a clinically relevant setting, in renal patients. Moreover, we study if this assumed therapy resistance in the DD genotype, could be overcome by the addition of an ARB and whether this assumed additional effect is dependent on the genotype and dietary sodium intake. 56 patients with a stable non-diabetic proteinuria will be included, who will, after a run-in period of 6 weeks where lisonopril 40 mg will be prescribed, treated with either placebo or valsartan 320 mg (160 mg 1dd2)for 6 weeks on top of their ACEi treatment in randomized order on both a low and a high sodium diet.

The recently found gene-environment interaction between dietary sodium intake and the ACE genotype with sodium-induced therapy resistance to ACE inhibition in DD homozygotes (that was absent in II and ID subjects) is present in the renal patient as well. With regard to the pathophysiological mechanism, we hypothesise that a high dietary sodium intake induces an increase in tissue ACE activity, which is stronger in the DD homozygotes, resulting in a worse therapy response to ACEi. The alleged sodium-induced therapy resistance of the DD homozygotes may therefore be overcome by addition of AT1 receptor blockade, since AT1 receptor blockers act “downstream” of the ACE.
Moreover, we hypothesize that low dietary sodium intake has additional effects on proteinuria and blood pressure on top of dual RAS blockade in patients with non-diabetic proteinuria.

Lisinopril 40 mg, with the addition of valsartan 320 mg (160 mg 1dd2) or placebo, both during low dietary sodium intake and high dietary sodium intake in randomised order.