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

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1 Nephrol Dial Transplant (2007) 22: doi: /ndt/gfm363 Advance Access publication 7 June 2007 Editorial Review Direct renin inhibitors: the dawn of a new era, or just a variation on a theme? Liviu Segall 1, Adrian Covic 1 and David J. A. Goldsmith 2 1 Nephrology, Dialysis and Renal Transplantation Center, C. I. Parhon University Hospital, B-dul Carol I No. 50, Iasi , Romania and 2 Renal Unit, Guy s Hospital, London SE1 9RT, UK Keywords: chronic kidney disease; direct renin inhibitors; renin-angiotensin-aldosterone system Renin-angiotensin-aldosterone system (RAAS) inhibitors in chronic kidney disease (CKD): benefits and limitations 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 Correspondence and offprint requests to: Dr Liviu Segall, MD, Nephrology, Dialysis and Renal Transplantation Center, C. I. Parhon University Hospital, B-dul Carol I No. 50, Iasi , Romania. livsegall@yahoo.com 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: (i) A substantial proportion of Ang II is generated in the kidneys from Ang I via non-ace pathways, such as chymase [5], which are not susceptible to the actions of ACE inhibitors. (ii) ACE inhibition and ARB, by interrupting negative feedback-loops, result in high plasma (and most likely tissue-) renin concentrations and high plasma renin activity (PRA), which may overcome the drugs effectiveness. The reactivation of Ang II (or Ang II escape ) has been described with both ACE inhibitors and ARBs [6]; however, its clinical significance is not yet fully understood. (iii) Renin can also bind to specific receptors in the mesangium and in the subendothelium of the renal arteries. This binding leads on one hand, to a substantial increase in the catalytic efficiency of conversion of angiotensinogen to Ang I, and, on the other hand, to stimulation of mitogenactivated protein kinases, ERK-1 and ERK-2 [7]. In animal models of nephrotic syndrome, treatment with ACE inhibitors was associated with a reduction in glomerular injury and proteinuria, but also with tubulo-interstitial lesions [8]. These findings support a direct profibrotic role for renin, independent of its Ang-generating effect. (iv) ACE inhibitors induce an acute decrease in plasma aldosterone. This effect, however, is often only transient and followed by a progressive rise in aldosterone levels that ultimately, with long-term ACE inhibition, can reach normal or even elevated concentrations. This aldosterone ß The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 2436 L. Segall et al. Fig. 1. The renin-angiotensin-aldosterone system. Black arrows show stimulation and gray arrows show inhibition. Dotted lines show alternative pathways mainly documented in experimental studies. aˆ blockers, renin inhibitors, inhibitors of angiotensin-converting enzyme (ACE) and angiotensin II type-1 receptor blockers (ARB) reduce the activity of the renin-angiotensin system (RAS). AT-R ¼ angiotensin receptor; EP ¼ endopeptidases; EC ¼ endothelial cells. (Reproduced with permission from ref. 21). escape is not well explained, but it might be the result of aldosterone secretion stimulation by high potassium levels induced by ACE inhibition. Aldosterone breakthrough also occurs during long-term ARB treatment, through an AT2-dependent mechanism [9]. (v) The ARBs leave the AT2 receptors unblocked, and some experimental data suggest that these receptors are involved in renal inflammation, by activation of NF-kB in mesangial and endothelial cells and induction of chemokines [6]. Taking all of these mechanisms together, one can see that there is at least the potential for additional benefit from alternative or complementary approaches to RAAS blockade. Combination therapy: more effective, more risks One way in which this last point has been addressed is by dual RAAS blockade with ACE inhibitors and ARBs together. This stratagem is now advocated by many nephrologists, as it has been shown to decrease proteinuria and slow kidney disease progression more effectively than using each of the two drug classes alone [6]. However, such combination therapy carries, undoubtedly, an increased risk of side effects, particularly in certain patients such as the elderly, the saltdepleted, those receiving cyclooxygenase inhibitors, those with renal artery stenosis and during anaesthetic induction [10]. In the CHARM-Added trial, patients with congestive heart failure treated with an ARB and an ACE inhibitor experienced significantly more episodes of hypotension, acute renal failure and hyperkalaemia, compared with those receiving an ACE inhibitor alone [11]. The risk of hyperkalaemia was also increased when the baseline glomerular filtration rate was <35 ml/min [12]. Another useful combination could be the addition of an aldosterone receptor antagonist to patients already receiving an ACE inhibitor or an ARB [13]. In small studies (reviewed by Sarafidis et al. [4]), the use of either spironolactone or eplerenone, on top of ACE inhibitors or ARBs, further decreased proteinuria. However, it is not known whether the addition of an aldosterone antagonist can retard the long-term progression of CKD to end-stage renal failure, but

3 Direct renin inhibitors 2437 promising data have been recently published by Bianchi et al. [14]. On the other hand, such combinations may dangerously increase the serum potassium levels in CKD patients [14]. Direct renin inhibition: an old new strategy of RAAS blockade A new and promising development in RAAS blockade has been initiated with the introduction of the first direct renin inhibitor (DRI), aliskiren, recently approved by the USA Food and Drug Administration for the treatment of hypertension. While this is indeed an exciting progress, it should not be forgotten that beta-blockers (BBs) also induce a significant reduction in plasma renin synthesis, by about one-third. However, as it has been recently discussed at length, their other properties may not make them first-line therapy choices for hypertensive patients [15]. Research on DRIs started over 30 years ago and several agents have been synthesized over this period, but low efficacy, lack of oral availability and high cost prevented their therapeutic application [16]. Aliskiren is the only orally active DRI that progressed to phase- III clinical trials and, is in fact the first new treatment for hypertension since the introduction of ARBs in As there is only one such compound that has undergone significant clinical trial exposure, we are restricted to discussing this to try to understand the potential effects, benefits and safety-concerns of DRIs, but it should be borne in mind that there will most likely be other DRIs in time. Unlike ACE inhibitors and ARBs, DRIs induce a marked and sustained reduction in PRA, and, as a result, the serum levels of Ang I, Ang II and aldosterone dramatically decrease [16]. DRIs do not block other Ang I-releasing enzymes, such as cathepsin D or tonins, but these enzymes appear to be of minor physiological importance [17]. Several studies in animal models by Fisher et al. [18] showed that DRIs cause a significantly higher increase in renal plasma flow than ACE inhibitors, despite similar BP falls, which suggests a more complete inhibition of the renal RAAS. In clinical trials, the addition of aliskiren to PRA-increasing drugs like diuretics, ACE inhibitors and ARBs was shown to prevent the raise or even to lower the PRA [19]. Suppressing the RAAS at the earliest stage with DRIs may be expected to limit the Ang II and the aldosterone escape phenomena, by avoiding the accumulation of their precursors [20]. Although BBs are also capable of reducing the PRA, their influence on Ang I, Ang II and aldosterone is unknown [21]. However, most BBs either decrease (non-selective BBs) or have no influence (b-1-selective BBs) on the renal blood flow and the glomerular filtration rate [22]. Aliskiren s average half-life of 24 h [23] and its 98% trough to peak ratio [24] makes it appropriate for a once daily administration. Since <1% of the drug is excreted by the kidneys [16], there is no need for adjustment of the starting dose in patients with renal insufficiency. Aliskiren concentrations in the kidneys are particularly high and persistent up to 3 weeks after discontinuation of the drug, suggesting that long-term effects could be derived at the tissue level [25]. Aliskiren monotherapy demonstrated significant, dose-dependent antihypertensive effects in several placebo-controlled clinical trials [23]. Compared with other drugs, the BP lowering effect of aliskiren 150 mg/day was similar to that of irbesartan 150 mg/day [26] and hydrochlorothiazide 12.5 mg/day [27], whereas at a dose of 300 mg/day, aliskiren was as potent as hydrochlorothiazide [27], but more effective than ramipril 10 mg/day [28]. Combinations of aliskiren with diuretics [27], calcium-channel blockers [29], ACE inhibitors [28] and ARBs [30] provided greater reductions in BP than any of these drugs alone. Aliskiren is, generally, well tolerated by hypertensive patients. In contrast to ACE inhibitors, it does not induce accumulation of substance P or bradykinin, therefore side effects like cough and angiooedema are implausible [16]. Angiooedema does not occur more often with aliskiren than with placebo, and whereas the incidence of cough is slightly increased with aliskiren, it is still much lower than with ACE inhibitors [23]. Increases in serum potassium >5.5 mmol/l were seldom reported with aliskiren alone; however, when used in combination with an ACE inhibitor in a diabetic population, hyperkalaemia was more frequent [23]. Minor increases in blood urea nitrogen or serum creatinine were observed in <7% of patients treated with aliskiren alone, vs 6% on placebo [23]. Yet, since subjects with significant renal dysfunction, dialysis, nephrotic syndrome or renovascular hypertension were excluded from clinical trials of aliskiren in hypertension, caution is required when prescribing the drug in such patients [23]; clearly, there is an urgent need to investigate DRIs in these special conditions. Better renoprotection with renin inhibitors? From a nephrologist s point of view, renin inhibition seems an interesting new approach for preventing the progression of CKD. Just like ACE inhibitors and ARBs, DRIs were shown to diminish renal vascular resistance and increase renal blood flow. On the other hand, by predominantly dilating the efferent arteriole, the net result is a decrease in the filtration fraction, without a change (or even an increase) in the glomerular filtration rate and the fractional sodium excretion. These effects were seen in animals [31 33], as well as in humans [34,35], and may provide renoprotective benefits, similar to ACE inhibitors and ARBs. Moreover, particular advantages may result from direct renin inhibition, if the Ang-independent profibrotic role of renin (discussed earlier) is considered relevant.

4 2438 L. Segall et al. Direct evidence of favourable effects of renin inhibitors on kidney disease is very scarce; however, a few experimental and clinical trials have yielded notable results. Several researchers studied the renal effects of aliskiren in double transgenic rats, which carry human renin and angiotensinogen genes and spontaneously develop malignant hypertension, leading to multiple organ damage and death, if left untreated. In these animals, aliskiren significantly lowered the BP and albuminuria, in a dose-dependent manner, and normalized the serum creatinine [36]. The antiproteinuric effect of aliskiren persisted even 2 weeks after stopping the treatment [37]. The drug reduced intrarenal inflammation (cell infiltration, C-reactive protein, tumour necrosis factor-a and complement) and fibrosis, to the same extent as losartan did [38]. In six patients with renal dysfunction, a short-acting renin inhibitor, remikiren, reduced proteinuria by 27% (P < 0.01) from a median baseline level of 5.8 g/day [35]. Preliminary data from an ongoing clinical study indicate a more substantial reduction in microalbuminuria with aliskiren ( 61%) compared with ramipril ( 50%) [39]. Conclusion DRIs may have a significant future as renoprotective agents, besides their utility as antihypertensives. The ability to decrease renin concentration and PRA, the more complete inhibition of the RAAS, the expected limitation of Ang II and aldosterone escape phenomena, and the prevention of possible renal-damaging direct effects of renin make DRIs appealing drugs for nephrologists. Certainly though, DRIs have a very long way to go before eventually overtaking the wellestablished ACE inhibitors and ARBs, with their long track record of reducing not just the intermediate endpoint proteinuria, but also the progression of CKD, and conferring cardioprotection and increased survival to many groups of patients with heart failure, diabetes or myocardial infarction. To start with, DRIs may find their place as adjunctive therapies, in combinations with ACE inhibitors or ARBs, or less commonly still, in patients intolerant to these. In the next few years, the results of the first phase III trials with aliskiren in patients with CKD will become available. The ongoing AVOID study (Aliskiren in the Evaluation of Proteinuria in Diabetes) is a 6-month study of aliskiren in addition to losartan in 496 patients with controlled hypertension, type 2 diabetes and proteinuria, with the change in urinary albumin to creatinine ratio as primary endpoint. ALTITUDE (Aliskiren Trial in Type 2 Diabetic Nephropathy) is a type 2 diabetes outcomes study that will be carried out in approximately 6000 subjects, to determine whether aliskiren delays time to diabetic complications in patients with diabetes mellitus and nephropathy [39]. Finally, other DRIs are expected to join aliskiren in clinical use in the years to come, since some of these new agents are currently undergoing animal and pre-clinical investigation [21]. Acknowledgements. The authors wish to address special thanks to Dr Jan A. Staessen, MD, PhD, FESC, FAHA, Laboratory of Hypertension, Leuven, Belgium, for granting them the permission to reproduce the picture The renin-angiotensin-aldosterone system [21]. Conflict of interest statement. Dr D.J.A.G. receives honoraria and speaker fees from Novartis, Astellas, Shire, Genzyme, Roche, Amgen and Abbott. Dr A.C. is a member of the speakers bureau for Hoffman La Roche and member of the advisory board of Fresenius Medical Care. Dr L.S. has no conflict of interests to declare. References 1. Ru ster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol 2006; 17: Nishiyama A, Abe Y. Molecular mechanisms and therapeutic strategies of chronic renal injury: Renoprotective effects of aldosterone blockade. J Pharmacol Sci 2006; 100: Casas JP, Chua W, Loukogeorgakis S et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005; 366: Sarafidis PA, Khosla N, Bakris GL. Antihypertensive therapy in the presence of proteinuria. Am J Kidney Dis 2007; 49: Hollenberg NK, Fisher NDL. Renal circulation and blockade of the renin-angiotensin system. Hypertension 1995; 26: Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int 2005; 67: Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer J-D. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 10: Hamming I, Navis G, Kocks MJ, van Goor H. ACE inhibition has adverse renal effects during dietary sodium restriction in proteinuric and healthy rats. J Pathol 2006; 209: Naruse M, Tanabe A, Sato A et al. Aldosterone breakthrough during angiotensin II receptor antagonist therapy in strokeprone spontaneously hypertensive rats. Hypertension 2002; 40: Azizi M, Menard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 2004; 109: McMurray JJ, Ostergren J, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-convertingenzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362: Ruilope LM, Aldigier JC, Ponticelli C et al. Safety of the combination of valsartan and benazepril in patients with chronic renal disease: European Group for the Investigation of Valsartan in Chronic Renal Disease. J Hypertens 2000; 18: Covic A, Gusbeth-Tatomir P, Goldsmith DJ. Is it time for spironolactone therapy in dialysis patients? Nephrol Dial Transplant 2006; 21: Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 2006; 70:

5 Direct renin inhibitors Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005; 366: Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor aliskiren (SPP100). Comparison with enalapril. Hypertension 2002; 39: e1 e8 17. Phillips MI, Speakman EA, Kimura B. Levels of angiotensin and molecular biology of the tissue renin angiotensin systems. Regul Pept 1993; 43: Fisher NDL, Hollenberg NK. Renin inhibition: what are the therapeutic opportunities? J Am Soc Nephrol 2005; 16: O Brien E, Barton J, Nussberger J et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension 2007; 49: Athyros VG, Mikhailidis DP, Kakafika AI, Tziomalos K, Karagiannis A. Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution? Expert Opin Pharmacother 2007; 8: Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet 2006; 368: Bakris GL, Hart P, Ritz E. Beta blockers in the management of chronic kidney disease. Kidney Int 2006; 70: Tekturna (aliskiren). Prescribing information ( Mitchell J, Oh B, Herron J et al. Once-daily aliskiren provides effective, smooth 24-hour blood pressure control in patients with hypertension. J Clin Hypertens 2006; 8 [5 Suppl. A]:A93(P-209). Poster presented at ASH Feldman DL, Persohn E, Schutz H et al. Renal localization of the renin inhibitor aliskiren. J Clin Hypertens 2006; 8 [Suppl. A]: A Gradman AH, Schmieder RE, Lins RL et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005; 111: Villamil A, Chrysant S, Calhoun D et al. The novel oral renin inhibitor aliskiren provides effective blood pressure control in patients with hypertension when used alone or in combination with hydrochlorothiazide. J Clin Hypertens 2006; 8 [Suppl. A]: A Uresin Y, Taylor A, Kilo C et al. Aliskiren, a novel rennin inhibitor, has greater BP lowering than ramipril and additional BP lowering when combined with ramipril in patients with diabetes and hypertension. J Hypertens 2006; 24 [Suppl. 4]: S Munger MA, Drummond W, Essop MR et al. Aliskiren as addon to amlodipine provides significant additional blood pressure lowering without increased oedema associated with doubling the amlodipine dose. Abstract presented at WCC/ESC, Barcelona, Spain, 2 6 September, 2006 (P784) 30. Pool JL, Schmieder RE, Azizi M et al. Aliskiren, an orally effective rennin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 2007; 20: Clozel JP, Veniant MM, Qiu C, Sprecher U, Wolfgang R, Fischli W. Renal vascular and biochemical responses to systemic rennin inhibition in dogs at low renal perfusion pressure. J Cardiovasc Pharmacol 1999; 34: Verburg KM, Kleinert HD, Chekal MA, Kadam JRC, Young GA. Renal hemodynamic and excretory responses to renin inhibition induced by A J Pharmacol Exp Ther 1990; 252: El Amrani AIK, Me nard J, Gonzales MF, Michel JB. Effects of blocking the angiotensin II receptor, converting enzyme, and rennin activity on the renal hemodynamics of normotensive Guinea pigs. J Cardiovasc Pharmacol 1993; 22: Fisher NDL, Allan D, Kifor I et al. Responses to converting enzyme and renin inhibition: role of angiotensin II in humans. Hypertension 1994; 23: van Paassen P, de Zeeuw D, Navis G, de Jong PE. Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function. Nephrol Dial Transplant 2000; 15: Pilz B, Shagdarsuren E, Wellner M et al. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in doubletransgenic rats. Hypertension 2005; 46: Feldman D, Jin L, Miserindinomoltini R, Xuan H, Luft F, Muller D. Aliskiren, a human renin inhibitor induces persistent renoprotection comparable to ACE inhibition in double transgenic rats (dtgr). Am J Hypertens 2005; 18: A Shagdarsuren E, Wellner M, Braesen JH et al. Complement activation in angiotensin II-induced organ damage. Circ Res 2005; 97: Chris Jensen J. SPP100 (Aliskiren). The journey from the laboratory bench to market. Received for publication: Accepted in revised form:

Scientific conclusions and detailed explanation of the scientific grounds for the differences from the PRAC recommendation

Scientific conclusions and detailed explanation of the scientific grounds for the differences from the PRAC recommendation Annex I Scientific conclusions, grounds for variation to the terms of the marketing authorisations and detailed explanation of the scientific grounds for the differences from the PRAC recommendation 1