More Work to Do on Renin-Angiotensin System Blockade

Y. Z. Lit
2006 American Society of Nephrology. Clinical Journal  
T hree articles in this month's issue of CJASN are concerned with the use of renin-angiotensin system (RAS) blocking drugs to slow the progression of renal disease. Together they suggest that after two decades of productive research we are still a long way from knowing how best to prescribe these agents. Kanno et al. (1) address the important question of whether the progression of renal disease can be slowed by adding an angiotensin receptor blocker (ARB) to an angiotensin-converting enzyme
more » ... nverting enzyme inhibitor (ACEi). They carried out an open-label, prospective trial over 3 yr in 90 subjects, mostly nondiabetic, who had baseline proteinuria Ͼ1 g/d and serum creatinine between 1.2 and 5.0 mg/dl while receiving either benazepril 2.5 to 10 mg daily or trandolapril 2 to 4 mg daily. Subjects were randomly assigned to receive added candesartan, 2 to 12 mg daily, or to continue on the ACEi without any ARB. Over 3 yr, the subjects receiving the ARB exhibited a larger reduction in proteinuria (1.78 g/d to 0.55 g/d as compared with 1.61 g/d to 1.21 g/d) and a lesser increase in serum creatinine. Doubling of the serum creatinine was observed in no patients receiving the ARB ϩ ACEi as compared with seven patients receiving an ACEi alone. It should be emphasized, however, that the average ACEi dose was the same in the two groups and was considerably less than the maximum approved ACEi dose in the patients receiving benazepril. The findings of Kanno et al. thus strongly suggest that, at least up to some point, more RAS blockade is better than less RAS blockade, but they do not show that adding an ARB achieves benefit that could not be obtained by increasing the dose of ACEi. The way we commonly consider the ACEi ϩ ARB question has been strongly influenced by the history of drug development. Logically, the question should be expressed ACEi, ARB, or both. But the ACEi were discovered first, shown effective first, and have gone off patent first, which has lowered their cost. In uncomplicated patients, most physicians therefore use an ACEi first and then consider adding an ARB. It is harder to explain why we have only more recently addressed the question of adding a mineralocorticoid receptor antagonist. One reason may be that the side effects of spironolactone, which was for many years the only available mineralocorticoid antagonist, were considered to be unacceptable. Another may be that investigators considered spironolactone unlikely to be renoprotective as a single agent and then ignored the question of whether it would be useful in combination with other RAS blocking drugs. It should be noted that the assumption that mineralocorticoid antagonism cannot duplicate the effects of ACE inhibition or angiotensin receptor blockade has not been directly tested in human renal disease. But animal studies and theoretical considerations suggest that this assumption would prove correct. Aldosterone contributes to the progression of glomerular injury in the rat remnant kidney, but spironolactone cannot not replicate the protective effect of lisinopril and losartan in this model (2) . Presumably this is because while an ACEi or ARB limits the activity of both angiotensin II and aldosterone, a mineralocorticoid receptor antagonist limits only the activity of aldosterone and leaves unchecked any reflex increase in the activity of angiotensin II. The assumption that mineralocorticoid antagonists would be ineffective if used as the sole RAS blocking agents in human kidney disease, however, does not imply they can have no benefit when used in combination with an ACEi and/or ARB. As reviewed by Ponda and Hostetter (3), mineralocorticoid receptor antagonism could add to the protective effect of other RAS blocking agents either by limiting aldosterone-mediated distal nephron sodium reabsorption or by blocking various, imperfectly defined actions of aldosterone at the glomerulus and other sites. The evidence summarized by Ponda and Hostetter is amply sufficient to justify further research but not routine clinical use of mineralocorticoid receptor antagonists in patients with renal insufficiency. The most important practical question to be addressed is whether mineralocorticoid receptor antagonists have any advantage over diuretic agents, which tend to reduce rather than elevate the serum potassium. If they do not, the mineralocorticoid receptor antagonists will presumably continue to be used only in those rare patients who have renal insufficiency and a low potassium level. The papers by Kanno et al. and Ponda and Hostetter both indicate that further trials are needed. The analysis of Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study data by Keane et al. (4) is intended to facilitate the design of such trials. RENAAL was a placebo-blinded trial of the effect of losartan on the progression of nephropathy in patients with type 2 diabetes. A total of 1513 Published online ahead of print. Publication date available at
doi:10.2215/cjn.01670506 pmid:17699265 fatcat:672faq6ft5benge22qz7uzox4e