Effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on accumulation of aliskiren in the kidney

Increased activity of the renin–angiotensin–aldosterone system (RAAS) plays an important role in the pathogenesis of chronic kidney disease (CKD) [1,2]. Inhibition of the RAAS with angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) has beneficial effects in slowing the progression of renal injury. However, these agents do not always prevent end-stage renal disease (ESRD) [3]. Inhibition of renin, the first rate-limiting enzyme acting at the point of activation of the RAAS cascade, may provide different renoprotective effects than other RAAS-blocking agents [4]. Therefore, dual therapy of a renin inhibitor with an ACEi or an ARB might be beneficial in preventing ESRD. Aliskiren is the first orally active, nonpeptide, low molecular weight, direct renin inhibitor approved for the treatment of hypertension [5]. The efficacy of aliskiren on blood pressure reduction has been evaluated in animal experiments [6,7], as well as in patients with CKD [8] and diabetes [9]. The antihypertensive effect of aliskiren remains relatively long, even after treatment withdrawal [7], and is comparable or superior with that of other antihypertensive agents at recommended doses [10]. In streptozotocin-induced diabetic (mRen-2)27 rats, aliskiren (10 mg/kg per day) does not reduce blood pressure as much as perindopril (0.2 mg/kg per day), but both drugs successfully reduce albuminuria and glomerulosclerosis [11]. Interestingly, aliskiren, but not perindopril, attenuates tubulointerstitial fibrosis, suggesting the significant renal tissue distribution of aliskiren [11]. Recently, we have also demonstrated that aliskiren augments antialbuminuric effects of an ARB in type 2 diabetic KKAy mice [12]. In clinical studies, aliskiren in combination with an ACEi or an ARB has proven to efficiently reduce proteinuria in diabetic patients without any safety concerns [13,14]. Moreover, a significant antiproteinuric effect of aliskiren remained 2 weeks after the withdrawal of treatment in CKD mice [15] and patients with diabetic nephropathy [16]. Importantly, however, this long-lasting effectiveness of aliskiren cannot be explained by the plasma half-life or by the pharmacokinetics of this agent [17]. Therefore, it is reasonable to speculate that the long-lasting renoprotective effects of aliskiren could be due to accumulation in the kidney, as shown by Feldman et al.[7] who demonstrated extensive accumulation of aliskiren in the rat kidney. Because aliskiren binds with the active site of renin and accumulates in secretory granules of the renin secretory cells [18], and in the glomeruli and vascular wall [7], aliskiren may also enter the juxtaglomerular cells of the afferent arterioles. Therefore, renin binding may modulate the accumulation of aliskiren in the kidney. In the current issue of the Journal of Hypertension, Lange et al.[19] tested the hypothesis that renal accumulation of aliskiren depends on the renin level. To test this hypothesis, they investigated the renal accumulation of aliskiren in AT1a receptor−/− mice. They showed that chronic treatment with aliskiren markedly increased renal renin levels in the wild-type mice as expected, but not in AT1a receptor–/– mice. Concentrations of aliskiren in plasma and the kidney of AT1a receptor–/– mice were similar to those of wild-type mice. Furthermore, aliskiren levels in plasma and the kidney were similar between wild-type control mice and Ren1c–/– mice, which have no renin in the kidney. Taken together, these findings clearly demonstrate that renin levels in the kidney do not contribute to renal accumulation of aliskiren. In addition to binding to renin, aliskiren binds to its precursor, prorenin [20], which enhances enzymatic activity by nonproteolytic activation through the (pro)renin receptor [21]. The interaction of prorenin with its receptor can be blocked by the handle region peptide [22]. To determine the role of prorenin in the renal accumulation of aliskiren, Lange et al.[19] investigated a pharmacological approach by using the handle region peptide and showed that it did not affect renal tissue levels of aliskiren. The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study has demonstrated that addition of aliskiren to conventional treatment, including an ARB, losartan, over a 6-month period, reduces proteinuria by 20% in patients with diabetic nephropathy [14]. Posthoc analysis of the AVOID trial also suggested that renal function was better preserved with aliskiren in patients with insufficient blood pressure control [13]. The Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial was proposed to determine whether aliskiren reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment (including ACEis and ARBs) [23]. However, aliskiren, in addition to an ACE inhibitor or an ARB, did not show any beneficial effect in the primary and secondary endpoints in type 2 diabetic patients who were at a high risk for cardiovascular and renal events [24]. Moreover, the aliskiren-treated group showed increased risks for hyperkalemia and hypotension, despite a significant reduction in proteinuria [24]. Although the results from the ALTITUDE study do not refute the efficiency of aliskiren in these high-risk patients with type 2 diabetic nephropathy, the precise mechanism by which the addition of aliskiren to ACEis or ARBs elicits hyperkalemia and hypotension is not clear. In this regard, Lange et al.[19] clearly showed that renin or prorenin is not a primary determinant of aliskiren accumulation in kidney. These data suggest that renal aliskiren accumulation is not affected by high renin levels during long treatment with ACEis and ARBs. Therefore, hyperkalemia and hypotension observed in the ALTITUDE study may not be simply explained by the authors’ assumption that aliskiren is accumulated in the kidney by binding to increased renin through ACEi or ARB treatment. Further studies and analyses are required to determine the mechanisms for how addition of aliskiren to ACEis or ARBs in patients with severe type 2 diabetic nephropathy elicits hyperkalemia and hypotension. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.