The renin–angiotensin–aldosterone system update: full-court press

Cardiovascular disease, blood pressure and the kidneys are inextricably linked by the renin-angiotensin-aldosterone system (RAAS).The RAAS plays a dominant role in the maintenance of basal blood pressure and the pathogenesis of hypertension, and exerts powerful effects on kidney function [1].The last 50 years could be dubbed the RAAS years, as manipulation of this system with pharmacologic inhibition has been the mainstay of therapy for a wide variety of diseases including hypertension, kidney disease, diabetes and heart disease.We review recent advances in how the RAAS is being used in a variety of ways in these disease states.We discuss the fate of dual RAAS blockade in diabetic kidney disease, neprilysin inhibition in heart failure (HF), the use of angiotensin (Ang) II in septic shock, Ang II vaccination for hypertension, the potential use of biased agonism of the type 1 Ang receptor and the renewed interest in blocking aldosterone in hypertension (Figure 1).The biologic exploitation of the RAAS in human disease started after the isolation of the first angiotensin-converting enzyme inhibitor (ACEi) from the venom of the Brazilian pit viper Bothrops jararaca [2].The next decade saw numerous randomized clinical trials utilizing RAAS blockade, demonstrating efficacy in patients with hypertension, HF and diabetic kidney disease.This also ushered the advent of a variety of pharmacologic inhibitors of the RAAS including the direct renin inhibitors and the angiotensin receptor blockers (ARBs), which demonstrated similar efficacy to ACEis but with diminished side effects including cough and angioedema.Since ACEis and ARBs have different targets, it was tempting to use these together for a potential synergistic effect.However, large clinical trials utilizing dual RAAS blockade in patients with diabetic nephropathy did not demonstrate an overwhelming kidney and cardiovascular benefit.In fact, they resulted in more adverse events such as hyperkalemia.Thus, the use of dual RAAS blockade is not a current strategy used in proteinuric kidney disease [3, 4].The RAAS plays an important role in the pathophysiology of HF with reduced ejection fraction (HFrEF) [5].Several randomized clinical trials have demonstrated efficacy of RAAS inhibition to improve mortality and morbidity [5].Recently, novel therapies have shown promise in patients with HFrEF.