Direct renin inhibitors: the dawn of a new era, or just a variation on a theme?

Numerous studies have demonstrated that the reninangiotensin-aldosterone system (RAAS) plays an important role in the progression of chronic kidney disease (CKD). Angiotensin (Ang) II generates intrarenal haemodynamic and inflammatory changes that promote proteinuria, growth of glomerular and tubular cells, inhibition of NO synthesis, stimulation of extracellular matrix synthesis and induction of chemokines, reactive oxygen species and apoptosis [1]. In addition, in animal models of renal diseases, aldosterone is also involved in endothelial dysfunction, inflammation, proteinuria and fibrosis [2]. In clinical trials, treatment with angiotensin-converting enzyme (ACE) inhibitors and Ang II AT1 receptor blockers (ARBs) was proved to slow down the evolution of both diabetic and non-diabetic nephropathies and, therefore, it is currently regarded as the cornerstone of what we call ‘nephroprotection’. A controversial issue is whether these agents are superior to other antihypertensive drugs in terms of nephroprotection—in other words, do they possess so-called ‘pleiotropic’ effects? A large meta-analysis [3] suggested that the benefit seen with ACE inhibitors was related to the blood pressure (BP) decrease alone. The truth, as Sarafidis et al. [4] pointed out in a very recent review, is that, indeed, ACE inhibitors exhibit a BP-independent renoprotective effect, but only in patients with proteinuria and advanced CKD (i.e. stage 3 or 4), and also that the higher the baseline urine protein excretion and its subsequent decrease, the more pronounced the beneficial effect of these drugs is likely to be [4]. However, it is not sufficiently appreciated that, due to the remarkable complexity of the RAAS, neither ACE inhibitors nor ARBs alone can completely suppress its activity (Figure 1). The main limitations of these agents in that regard can be summarized as follows: