Direct Renin Inhibition with Aliskiren in Hypertension and Target Organ Damage

Mini-Review

Dominik N. Mu¨ller and Friedrich C. Luft Medical Faculty of the Charite´, Max Delbru¨ck Center for Molecular Medicine, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Berlin, Germany

The Joint National Committee and the World Health Organization are in agreement that hypertension in most patients who are treated is controlled inadequately and that rates of cardiovascular morbidity remain high. Additional pharmacologic treatments could ameliorate this situation. The renin-angiotensin-aldosterone system has been a highly successful pharmacologic target, as the system is strongly implicated in the development of hypertension-related target organ damage. However, compensatory increases in plasma renin levels that lead to adjustments in angiotensin production and conversion present limitations for existing renin-angiotensin-aldosterone system inhibitors. A once-daily, orally effective, small-molecule renin inhibitor, aliskiren, is now available to address angiotensin production directly at its rate-limiting step. Studies in humans attest to an effective BP-lowering effect, a side effect profile no different from AT1 receptor blockers, and the option of combination therapies. A novel animal model of high human renin hypertension in the rat attest to target organ protection. Because angiotensin receptor blockade, angiotensin-converting enzyme inhibition, calcium channel blockade, and diuretic therapy all lead to sharp increases in plasma renin activity, aliskiren offers a novel circumvention. Clin J Am Soc Nephrol 1: 221–228, 2006. doi: 10.2215/CJN.01201005

he National High Blood Pressure Education Program countries were on average lower than in North America (3). For recently presented its seventh report prepared by the the European countries, on average only 8% of hypertensive T Joint National Committee (1). The report indicated that individuals had their condition controlled. 50 million or more Americans have BP levels that warrant These data do not inspire confidence. The rate of decline in treatment. Worldwide prevalence estimates for hypertension hypertension-related morbidity has slowed in the past de- approach 1 billion individuals, and approximately 7.1 million cade; however, the incidence of chronic heart failure and deaths per year are attributed to hypertension. The World ESRD is now increasing (1). Various explanations have been Health Organization estimates that poor BP control is largely suggested. Possibly, poor compliance on the part of the responsible for two thirds of strokes and half of ischemic heart patients is responsible. Another possibility is that awareness disease. A recent European review of essential hypertension of prevention strategies and their implementation by pri- drew a similar picture (2). Effective medical treatment has been mary physicians may not always be optimal. Finally, some available to lower BP for almost 50 years. Indeed, treatment of lay the blame at the feet of the health care system or third- hypertension has been credited with the decline in stroke and party payers. Undoubtedly, all of these factors play a role. heart attack rates observed in North America and Europe over However, an additional explanation might be that we need the past few decades. Awareness of hypertension has increased better drugs for patients with essential hypertension. The in the United States from approximately 50% of people who current therapeutic strategy is aimed at volume regulation have hypertension to 70%. Similarly, the percentage of hyper- with diuretics, sympathetic nervous system activity suppres- tensive people who are receiving treatment has increased from sion by means of peripheral adrenergic receptor blockers or 31 to 59%. The European figures are similar in kind (2). Nev- centrally acting drugs, vascular smooth muscle cell tone ertheless, the control rates are unacceptable. Twenty years ago, reduction by means of ion channel manipulation, and inhi- the control rate in the United States was 29% of those who were bition of the renin-angiotensin-aldosterone system (RAAS). receiving treatment. The current value is 34%. A recent epide- In any given patient, several concomitant pharmacologic miologic investigation of six European countries, Canada, and targets must be addressed. Indeed, patients who require four the United States reported that across all age groups examined, or more classes of drugs to achieve the current treatment BP levels were the lowest in the United States and the highest guidelines are no rarity. in Germany. Rates of hypertension treatment in the European Novel antihypertensive therapies that offer the potential for improved targeting of the mechanisms that underpin organ

Published online ahead of print. Publication date available at www.cjasn.org. damage in hypertension and cardiovascular disease would be of great value. One potential target for which effective inhibi- Address correspondence to: Dr. Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, Berlin 13125, Germany. Phone: ϩ49-30-9417-2202; Fax: ϩ49-30-9417- tors have been sought for several decades is renin, the enzyme 2206; E-mail: [email protected] that catalyzes the rate-limiting step of the RAAS.

RAAS Inhibition to Approach Hypertension block the Ang II AT1 receptor directly, was expected to settle RAAS activity is initiated by the cleavage of the peptide the RAAS issue by inhibiting all of the negative effects of RAAS angiotensinogen to the decapeptide angiotensin I (Ang I) by the activation. After all, actions of Ang II such as salt retention, enzyme renin; the key product of the renin system is the oc- aldosterone release, vascular smooth muscle cell contraction, tapeptide hormone angiotensin II (Ang II), which is formed and growth factor activity all involve activation of the AT1 from Ang I by the angiotensin-converting enzyme (ACE; Figure receptor. However, the introduction of this drug class, although 1). RAAS plays a key role in volume regulation and the main- of undoubted clinical benefit, still may not block the RAAS tenance of BP. However, excessive activity of the renin system satisfactorily (8). is associated with hypertension and target organ damage, mediated largely through the actions of Ang II on the angiotensin ACE Inhibitors and ARB Provide Incomplete

AT1 receptor. The introduction of ACE inhibitors ushered in a RAAS Suppression new era of therapeutic possibilities for patients with hyperten- Suppression of the RAAS after treatment with either ACE sion, heart failure, and renal failure. However, physicians soon inhibitors or ARB remains incomplete (9). A key reason for this learned that in terms of lowering BP, ACE inhibitors were no is that these therapies stimulate a reactive increase in renin more effective than existing antihypertensives as a mono- activity (10), because they disrupt the short feedback loop therapy and, like existing drugs, still had to be combined with (Figure 1) by which Ang II normally inhibits the release of renin other treatments, particularly diuretics, to achieve BP control. from the kidney (11). Bernstein et al. (12) used mouse models to The Antihypertensive and Lipid-Lowering Treatment to pre- demonstrate the central role of renin in the control of BP. They vent Heart Attack (ALLHAT) investigators recently substanti- showed that mice with gene disruptions involving angio- ated this fact (4). The poorer levels of BP control achieved in the tensinogen, renin, ACE, and the AT1 receptor all display a ACE inhibitor arm of ALLHAT may reflect, at least in part, that similar phenotype, with a 35-mmHg reduction in BP. These ACE inhibitor/diuretic combinations were not allowed by the experiments underscore that the RAAS is central to BP control. trial protocol (5). This design feature probably also resulted in Importantly, whereas ACE Ϫ/Ϫ mice had barely detectable the notably poorer BP control that was observed in the black Ang II levels, ACE Ϫ/ϩ mice had normal Ang II levels but patient subgroup of the trial. showed higher Ang I levels so that their Ang II/Ang I ratio was Patients who receive ACE inhibitors initially have lower approximately half normal. Thus, the compensatory mecha- circulating Ang II levels; however, the levels commonly in- nism in these mice was to increase Ang I levels so that Ang II crease to earlier baseline concentrations (6,7). The same situa- levels were sustained. These data suggest that normal BP was tion is also true for circulating aldosterone concentrations. The maintained in these animals through the regulated production phenomenon has been termed “escape.” The introduction of of renin. Indeed, mice with one, two, three, or four copies of the the angiotensin receptor blockers (ARB), a drug class that can ACE gene exhibited BP levels that were indistinguishable from those of wild-type mice, showing that it was the activity of renin (not ACE) that was the key regulator of BP. A second issue with ACE inhibitors and perhaps ARB is that they may not provide effective inhibition of tissue RAAS activity (13). Crowley et al. (14) recently demonstrated the impor-

tance of extrarenal AT1 receptors. They performed difficult Ϫ Ϫ cross-transplantation experiments in AT1 receptor / and

wild-type mice. The authors found that when the AT1A receptor was deleted in the recipient animal, even transplantation of

a wild-type donor kidney that expressed the AT1A receptor did not restore normal BP; this discrepancy could not be explained by altered aldosterone generation. These data cast some doubt on the prevailing dogma of the kidney as the sole, final com-

mon pathway of BP regulation and suggest that AT1 receptor actions in systemic tissues such as the vascular and/or the central nervous system make nonredundant contributions to BP regulation. It is interesting that the group further showed

that interruption of the AT1 receptor–mediated short feedback Figure 1. Schematic representation of the renin-angiotensin- loop in the kidney was not sufficient to explain the marked aldosterone system (RAAS) is shown. RAAS activity is nor- stimulation of renin production induced by global AT receptor mally regulated by compensatory feedback inhibition by the 1 deficiency or by receptor blockade. Nevertheless, this finding angiotensin AT1 receptor on the release of renin, the rate- limiting step of the system. Angiotensin-converting enzyme underscores the multiplicity of mechanisms that stimulate re- (ACE) inhibitors and angiotensin receptor blockers (ARB) dis- nin responses. rupt this feedback loop, stimulating increased renin activity, The reactive plasma renin stimulation by ACE inhibitors or and thus increase angiotensin I (Ang I) generation. Only a renin ARB gives rise to numerous explanations for why current inhibitor can effectively block this cycle. RAAS inhibitors are sometimes suboptimal or not effective. A Clin J Am Soc Nephrol 1: 221–228, 2006 Renin Inhibition with Aliskiren in Hypertension and Target Organ Damage 223 problem with ACE inhibitors is that the reactive increase in two catalytic aspartic residues. Unlike other aspartic proteases, plasma renin activity may ultimately lead to increased Ang II renin has only one known substrate, angiotensinogen, which it generation by ACE-independent pathways such as dipepti- cleaves to form Ang I. An inactive form of renin exists; the dases, which are found in several tissues, including the kidney biosynthetic precursor of renin is termed prorenin and is 5 kD (15). The gradual Ang II level increase in the face of ACE larger, with a 43–amino acid N-terminus that covers the enzy- inhibitor therapy has been termed “ACE escape” (9). Clinical matic cleft and obstructs access to the active site. Prorenin studies have confirmed that this phenomenon is associated circulates in plasma at 100-fold higher concentrations than re- with deteriorating control of BP in patients with hypertension nin and can be activated by proteolytic activity or by low pH (6) and with poorer prognosis in patients with heart failure (7). and low temperatures. In the body, proteolytic activation oc- The evidence that the reactive rise in renin activity may limit curs almost exclusively in the kidney by various processing the therapeutic benefits of ARB treatment is less clear-cut. enzymes. However, recent clinical trials in patients with heart failure Several renin receptors have been identified. These recep- have indicated that twice-daily treatment with an ARB may be tors also recognize prorenin and should probably be desig- necessary to provide effective blockade of the effects of Ang II nated as (pro)renin receptors. The mannose-6-phosphate re- (16,17), a possible indication that the renin increase may be ceptor, identical to the IGF receptor II, binds and internalizes clinically relevant in patients with considerable neurohormonal prorenin and renin and may serve a clearance function. activation. Indeed, increased plasma renin activity could result Nguyen et al. (27) and Sealey et al. (28) demonstrated renin in actions independent of the AT1 receptor. ARB therapy leaves receptors in human mesangial cells and in membranes pre- the AT2 receptor open for occupancy in the face of increased pared from rat tissues, respectively. The receptor described Ang II levels. This state of affairs is viewed as salubrious by by Nguyen et al., which was cloned from a human kidney some but by no means all investigators. Thus, whereas some library, is a 350–amino acid protein that has a single trans- preclinical studies have shown that AT2 receptor activation membrane domain and no homology with any known pro- may be associated with beneficial effects, such as vasodilation tein. Binding is specific for renin and prorenin; as a matter of and inhibition of renin release (18), other studies have sug- fact, the receptor acts as a (pro)renin co-factor on the cell gested that AT2 receptor–mediated signaling pathways could surface by enhancing renin catalytic activity and unmasks lead to harmful effects such as vascular cell proliferation receptor-bound prorenin catalytic activity. This activity (19,20). Furthermore, in the face of ARB therapy, various Ang would allow local, circulation-independent, Ang II produc- fragments, such as Ang 1-7, Ang III, and Ang IV, may appear in tion. Also important is the finding that the binding of (pro- greater concentrations. Preclinical studies have shown that Ang )renin to the receptor triggers intracellular signaling; in vitro IV may upregulate the prothrombotic plasminogen activator studies on cultured mesangial cells indicate that binding of inhibitor-1 and thereby lead to prothrombotic, vasoconstrictor, renin to the receptor may stimulate activation of the intra- or undesired trophic effects. The fragments are an area of cellular mitogen-activated protein kinase pathway (27), sug- intense study; however, there is some doubt as to the clinical gesting that such binding may have profibrotic conse- importance of these fragments (21). quences. Although research into this area is at a very early High plasma renin activity per se may represent a cardiovas- stage, this signaling was the first demonstration of Ang cular risk factor. A study of 2902 hypertensive patients showed II–independent renin-related effects and underscores the po- that pretreatment plasma renin activity was independently and tential for increased renin levels to exert important effects on directly associated with the risk for myocardial infarction, even tissues that would not be inhibited by ACE inhibitor or ARB though the patients subsequently achieved BP control with treatment. antihypertensive therapy (22). It should be noted, however, that Although prorenin and renin generally are closely correlated, this study did not investigate whether the effects of plasma there are states when prorenin levels far exceed those of renin; renin activity were independent of Ang II. Nevertheless, ele- a physiologic example is pregnancy. A pathologic example is vated plasma renin activity has also been associated with the diabetes, in which active renin is suppressed. The existence of presence of target organ damage, including renal dysfunction receptors for renin and prorenin may provide an explanation (23) and left ventricular hypertrophy (24). Alderman et al. (25) for the long-standing observation that renin and prorenin levels recently reported that although black individuals, the elderly, are markers of microvascular complications in patients with individuals with diabetes, and women are said to exhibit more diabetes, particularly those involving the eye (29). Indeed, in- commonly low-renin hypertension, this was by no means the creases in prorenin are associated with the development of case. These findings indicate that the use of a renin inhibitor to retinopathy (29,30) and may also predict the onset of mi- suppress the reactive rise in renin activity, alone or in combi- croalbuminuria in patients with diabetes (31). Although at nation with ACE inhibitors or ARB, may have considerable present there is no clinical evidence that prorenin levels per se potential for the prevention of end organ damage in hyperten- represent anything more than a marker, Veniant et al. (32) sion. generated a transgenic rat that expresses prorenin in the liver and reported that these animals developed cardiomyocyte hy- Properties of Renin pertrophy and renal lesions, despite normal BP values. The Renin is an aspartic protease that has two homologous lobes clinical significance of these observations is currently uncertain; (26). The cleft between the lobes contains the active site with with regard to the potential effects of renin inhibitors, prorenin 224 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 221–228, 2006 and renin binding to the (pro)renin receptor is independent of pocket. However, the new inhibitors also interacted with a the cleavage site, and signaling seems to occur even if the renin hitherto unrecognized large, distinct, subpocket of the enzyme receptor is occupied by the renin inhibitor remikiren (Mu¨ller et that extends from the S3-binding site toward the hydrophobic al., unpublished observations). core of the enzyme. Binding to this S3(sp) subpocket was essential for high binding affinity. This unprecedented binding Direct Renin Inhibition mode guided the drug-design process in which the mostly Renin is the rate-limiting step in Ang II production and hydrophobic interactions within subsite S3(sp) were optimized. thus represents the most logical target for inhibition of the The investigators’ design approach led to compounds with renin system. Whereas angiotensinogen is present at plasma high in vitro affinity and specificity for renin, favorable bio- concentrations of approximately 500 to 600 pmol, Ang I is availability, and excellent oral efficacy in lowering BP in pri- present in the 50- to 100-fmol range and Ang II at approxi- mates. One of these compounds was aliskiren (Figure 2). Wood mately half that. From a pharmacologist’s perspective, the et al. (40) expanded these investigations on aliskiren further in renin step would be the one earning the target focus, as it is the marmoset and in humans. They found that aliskiren de- the step with the largest step down in concentration. Work creased BP in sodium-depleted marmosets and increased by Smithies et al. (33) using gene-dosing strategies showed plasma immunoreactive renin levels, whereas plasma renin that increased copies of the angiotensinogen gene increase activity was reduced through inhibition. Initial ambulatory BP BP, whereas increased copies of the ACE gene do not. Thus, monitoring studies in eight hypertensive patients, who in- blocking the conversion of angiotensinogen to Ang I has a gested 75 or 150 mg of the compound, showed daytime and particular rationale. nighttime BP-lowering effects. Higher doses, up to 640 mg, Potent renin inhibitors are not new. The early compounds caused more complete renin inhibition but no side effects. were peptide inhibitors, such as isovaleryl-His-Pro-Phe-His- Nussberger et al. (41) tested aliskiren in normal volunteers

Sta-Leu-Phe-NH2 (SCRIP), that contained the amino acid sta- and found that the drug produced dose-dependent and long- tine (34). SCRIP was as effective as the ACE inhibitor enalapri- lasting decreases in aldosterone levels and Ang II concentra- lat in alleviating acute left ventricular failure (35). Similarly, tions; the 160 mg dose of aliskiren provided similar effects to Neisius et al. (36) studied a synthetic peptide renin inhibitor, an the ACE inhibitor enalapril at a dose of 20 mg. Natriuresis was antirenin antibody, and enalaprilat in the marmoset. All three enhanced by aliskiren, whereas potassium excretion was not compounds increased renal blood flow to a similar degree. The influenced. Stanton et al. (42) tested four doses of aliskiren up to synthesis of peptide analogs of the angiotensinogen N-terminal 300 mg/d in patients with mild to moderate hypertension. BP amino acid sequence produced competitive renin inhibitors, including several compounds that were effective in the nano- molar range. The best of these agents, remikiren and enalkiren, were very potent but had an oral bioavailability only of the order of 1 to 2%. Nevertheless, remikiren was shown effectively to reduce plasma renin activity and Ang I and Ang II levels in a dose-dependent manner when given orally to healthy humans (37). Hollenberg et al. (8) performed studies of considerable physiologic interest with these early renin inhibitors. They mea- sured changes in renal plasma flow in healthy volunteers who were given a 10-mmol/d sodium diet after ACE inhibition and renin inhibition. The three ACE inhibitors tested all increased renal blood flow by approximately 90 ml/min per 1.73 m2.By contrast, the renin inhibitors enalkiren and zankiren increased renal blood flow to a significantly greater degree, namely 150 ml/min per 1.73 m2. El-Amrani et al. (38) confirmed these findings in the guinea pig, an animal with renin that is suscep- tible to human renin inhibitors. The greater increase in renal blood flow stimulated by renin inhibitors is the result of greater suppression of intrarenal RAAS activity and reflects the inabil- ity of ACE inhibitors to block ACE-independent pathways for the generation of Ang II.

Aliskiren, First in a New Class of Oral Figure 2. General view of aliskiren (ball-and-stick representa- Renin Inhibitors tion, with all bonds to carbon atoms shown in purple) in the Rahuel et al. (39) used crystal structure analysis of renin- binding complex with human renin; the enzyme ␤ strands are inhibitor complexes combined with computational methods to represented as arrows and ␣ helices as ribbons. Inset shows the design inhibitors that bound as predicted to the renin S1/S3 chemical structure of aliskiren. Clin J Am Soc Nephrol 1: 221–228, 2006 Renin Inhibition with Aliskiren in Hypertension and Target Organ Damage 225 and plasma renin activity were reduced satisfactorily. The BP effectively suppressed the rise in renin activity that would responses were similar to those observed with a 100 mg/d dose normally be stimulated by an ARB. of the ARB losartan (the current maximum approved daily dose for the treatment of hypertension). Recently, Gradman et al. (43) Preclinical Target Organ Protection Studies reported the results of a multicenter study involving 652 pa- with Renin Inhibitors tients. The patients were randomly assigned to receive double- The species specificity of renin is such that human renin blind treatment with once-daily oral aliskiren (150, 300, and 600 inhibitors can be tested practicably only in the marmoset and mg), the ARB irbesartan 150 mg, or placebo. Aliskiren treat- the guinea pig. The former is a primitive primate, and the ment reduced systolic BP by 11.4, 15.8, and 15.7 mmHg (at latter has no tail, and neither is ideal for hypertension- doses of 150, 300, and 600 mg, respectively), whereas diastolic related studies. To get around this problem, Ganten, Mullins, BP fell by 9.3, 11.8, and 11.5 mmHg, respectively, compared Murakami, and others (45) generated two transgenic rat with a reduction of 5.3/6.3 mmHg (systolic/diastolic BP) for strains. One strain harbors the human renin gene with its placebo and 12.5/8.9 mmHg for irbesartan 150 mg. Thus, once- own promoter; the second harbors the human angiotensino- daily oral treatment with aliskiren lowered BP effectively (Fig- gen gene with an albumin promoter. Rat renin will not cleave ure 3), with a safety and tolerability profile comparable to that human angiotensinogen, and human renin will not cleave rat of irbesartan and placebo, in patients with mild to moderate angiotensinogen. Thus, the double-transgenic (dTGR) off- hypertension. Aliskiren 150 mg was as effective as irbesartan spring are under the influence of two transgenes that gener- 150 mg (the recommended starting dose of irbesartan for the ate large quantities of Ang II in the circulation, the vascula- treatment of hypertension) in lowering BP. ture, the heart, and the kidneys. Untreated dTGR die of Because a key theoretical advantage of renin inhibitors is cardiac cachexia, while in renal failure, at age 8 wk. The their ability to suppress the reactive rise in renin activity stim- model is ideal to test human renin inhibitors, particularly in ulated by other RAAS blockers, Azizi et al. (44) investigated the terms of elucidating mechanisms of target organ damage and possibility that aliskiren might find utility when combined with subsequent repair. an ARB. Twelve mildly depleted normotensive individuals In our first study, 6-week-old dTGR were matched by albu- were studied in this double-blind, placebo-controlled, random- minuria (2 mg/d) and divided into five groups (46). Untreated ized, four-period, crossover study. Aliskiren 300 mg decreased dTGR were compared with aliskiren-treated (3 and 0.3 mg/kg plasma renin activity and Ang I and Ang II levels for 48 h. per day) and valsartan-treated (10 and 1 mg/kg per day) rats. Importantly and in contrast to valsartan 160 mg treatment, an The purpose of the low-dose valsartan group was to prolong aliskiren 150 mg ϩ valsartan 80 mg combination did not in- survival sufficiently to permit the animals to be studied after 7 crease plasma renin activity or plasma angiotensin levels, even wk. Treatment was from week 6 through week 9. At week 6, all though the plasma concentrations of renin were increased. The groups had elevated systolic BP. Untreated dTGR showed in- investigators noted that a renin inhibitor and ARB combination creased BP (202 Ϯ 4 mmHg), serum creatinine, and albumin- could provide synergistic effects on RAAS hormone levels, and uria (34 Ϯ 5.7 mg/d) at week 7. By week 9, both doses of it is also important to note that the presence of a renin inhibitor aliskiren lowered BP (115 Ϯ 6 and 139 Ϯ 5 mmHg) and albuminuria (0.4 Ϯ 0.1 and 1.6 Ϯ 0.6 mg/d) and normalized serum creatinine. Mortality was 100% in untreated dTGR and 26% in low-dose valsartan–treated (1 mg/kg per day) rats, whereas in all other groups, survival was 100%; BP levels were similar to those expected for a normal nontransgenic rat. dTGR that were treated with low-dose valsartan had cardiac hypertrophy (4.4 Ϯ 0.1 mg/g), increased left ventricular wall thickness, and diastolic dysfunction. We concluded that in dTGR, equieffective antihypertensive doses of valsartan or aliskiren attenuated end- organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR. In our second study that included aliskiren, we assessed complement expression, as well as C-reactive protein (CRP) production, in this dTGR model (47). We found that CRP elevation, macrophages, T cells, TNF-␣, C1q, C3, C3c, and C5b-9 expression all preceded albuminuria in untreated dTGR. Figure 3. Aliskiren, the orally effective renin inhibitor, provides C1q, C3, C3c, and C5b-9 were observed in the dTGR vessel antihypertensive efficacy at least equivalent to the ARB irbesartan in patients with hypertension. Bars indicate placebo- media. C5b-9 co-localized with IL-6. Aliskiren and the ARB ␣ corrected reductions from baseline in mean sitting diastolic BP losartan reduced albuminuria, TNF- , CRP, and complement (DBP) after once-daily treatment for 8 wk with either aliskiren C1q, C3, C3c, and C5b-9 expression to control levels. The effect (f) or irbesartan (o). *P Ͻ 0.05 versus irbesartan 150 mg. Re- of aliskiren on C3c and C5b-9 is shown in Figure 4. Our data produced from reference (43) with permission. showed that in this Ang II–induced model, complement acti- 226 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 221–228, 2006

Detection, Evaluation, and Treatment of High Blood Pres- sure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Commit- tee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42: 1206–1252, 2003 2. Staessen JA, Wang J, Bianchi G, Birkenhager WH: Essential hypertension. Lancet 361: 1629–1641, 2003 3. Wolf-Maier K, Cooper RS, Banegas JR, Giampaoli S, Hense HW, Joffres M, Kastarinen M, Poulter N, Primatesta P, Rodriguez-Artalejo F, Stegmayr B, Thamm M, Tuomilehto J, Vanuzzo D, Vescio F: Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA 289: 2363–2369, 2003 4. ALLHAT Officers and Coordinators for the ALLHAT Col- Figure 4. The human renin inhibitor aliskiren reduces comple- laborative Research Group: Major outcomes in high-risk ment C3c and C5b-9 in Ang II–induced renal damage. hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treat- ment to Prevent Heart Attack Trial (ALLHAT). JAMA 288: vation is a major participant and suggested further that TNF-␣ 2981–2997, 2002 and CRP may play a role in its induction. Blockade of the RAAS 5. Laragh JH, Sealey JE: Relevance of the plasma renin hor- either by inhibiting renin directly or by blocking the AT1 re- monal control system that regulates blood pressure and ceptor ameliorates target organ damage in this model. This sodium balance for correctly treating hypertension and for novel model of human RAAS-induced malignant hypertension evaluating ALLHAT. Am J Hypertens 16: 407–415, 2003 in the rat promises to enable investigation of the effect of 6. Borghi C, Boschi S, Ambrosioni E, Melandri G, Branzi A, human renin inhibitors on a host of pathologic vascular pro- Magnani B: Evidence of a partial escape of renin-angioten- cesses and related repair mechanisms. sin-aldosterone blockade in patients with acute myocardial infarction treated with ACE inhibitors. J Clin Pharmacol 33: Perspectives 40–45, 1993 Hypertension-induced cardiovascular diseases are the 7. Roig E, Perez-Villa F, Morales M, Jimenez W, Orus J, Heras M, Sanz G: Clinical implications of increased plasma an- most common cause of death worldwide. BP control is still giotensin II despite ACE inhibitor therapy in patients with woefully inadequate in all countries. The RAAS has been a congestive heart failure. Eur Heart J 21: 53–57, 2000 superb target. However, adequate RAAS blockade cannot be 8. Fisher NDL, Hollenberg NK: Renin inhibition: What are achieved with ACE inhibitors or ARB because of counter- the therapeutic opportunities? J Am Soc Nephrol 16: 592– regulatory mechanisms. The primary rate-limiting step in the 599, 2005 RAAS now can be pharmacologically inhibited directly. Re- 9. Azizi M, Menard J: Combined blockade of the renin-angio- nin inhibition may offer protection of target organs such as tensin system with angiotensin-converting enzyme inhibi- the kidney and the eye beyond what can be achieved with tors and angiotensin II type 1 receptor antagonists. Circu- current antihypertensive therapies, thereby addressing the lation 109: 2492–2499, 2004 most common causes of organ damage, such as ESRD and 10. Bing J: Rapid marked increase in plasma renin in rats blindness. Renin inhibition could be combined with ACE treated with inhibitors of the renin system. Effects of 1-sar- 8-ala-angiotensin II and of a synthetic converting enzyme inhibition or AT receptor blockade to inhibit both Ang II 1 inhibitor (nonapeptide, SQ 20.881) on normal and adrena- and aldosterone generation. Clinical studies investigating lectomized rats. Acta Pathol Microbiol Scand [A] 81: 376–378, benefits of renin inhibition are in progress, but the promising 1973 results obtained with renin inhibitors in animal models of 11. Vander AJ, Greelhoed GW: Inhibition of renin secretion by end-organ damage suggest that this drug class may have Ang II. Proc Soc Exp Biol Med 120: 339–403, 1965 great potential. 12. Bernstein KE, Xiao HD, Frenzel K, Li P, Shen XZ, Adams JW, Fuchs S: Six truisms concerning ACE and the renin- Acknowledgments angiotensin system educed from the genetic analysis of The Deutsche Forschungsgemeinschaft and Novartis supported the mice. Circ Res 96: 1135–1144, 2005 studies by D.N.M. and F.C.L. F.C.L. has served as a consultant for 13. Dzau VJ, Bernstein K, Celermajer D, Cohen J, Dahlof B, Novartis. D.N.M. is a fellow of the Hermann von Helmoltz Gemein- Deanfield J, Diez J, Drexler H, Ferrari R, Van Gilst W, schaft. Hansson L, Hornig B, Husain A, Johnston C, Lazar H, Lonn E, Luscher T, Mancini J, Mimran A, Pepine C, Ra- belink T, Remme W, Ruilope L, Ruzicka M, Schunkert H, References Swedberg K, Unger T, Vaughan D, Weber M: Pathophys- 1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green iologic and therapeutic importance of tissue ACE: A con- LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT sensus report. Cardiovasc Drugs Ther 16: 149–160, 2002 Jr, Roccella EJ: Joint National Committee on Prevention, 14. Crowley SD, Gurley SB, Oliverio MI, Pazmino AK, Grif- Clin J Am Soc Nephrol 1: 221–228, 2006 Renin Inhibition with Aliskiren in Hypertension and Target Organ Damage 227

fiths R, Flannery PJ, Spurney RF, Kim HS, Smithies O, Le mellitus. A marker of microvascular complications. N Engl TH, Coffman TM: Distinct roles for the kidney and sys- J Med 312: 1412–1417, 1985 temic tissues in blood pressure regulation by the renin- 30. Davies L, Fulcher GR, Atkins A, Frumar K, Monaghan J, angiotensin system. J Clin Invest 115: 1092–1099, 2005 Stokes G, Clifton-Bligh P, McElduff A, Robinson B, Stiel J, 15. Hollenberg NK, Fisher ND, Price DA: Pathways for angio- Twigg S, Wilmsurst E: The relationship of prorenin values tensin II generation in intact human tissue: Evidence from to microvascular complications in patients with insulin- comparative pharmacological interruption of the renin sys- dependent diabetes mellitus. J Diabetes Complications 13: tem. Hypertension 32: 387–392, 1998 45–51, 1999 16. Cohn JN, Tognoni G: A randomized trial of the angioten- 31. Chiarelli F, Pomilio M, De Luca FA, Vecchiet J, Verrotti A: sin-receptor blocker valsartan in chronic heart failure. Plasma prorenin levels may predict persistent microalbu- N Engl J Med 345: 1667–1675, 2001 minuria in children with diabetes. Pediatr Nephrol 16: 116– 17. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober 120, 2001 L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, 32. Veniant M, Menard J, Bruneval P, Morley S, Gonzales MF, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske Mullins J Vascular damage without hypertension in trans- S, Sellers MA, Califf RM; Valsartan in Acute Myocardial genic rats expressing prorenin exclusively in the liver. Infarction Trial Investigators: Valsartan, captopril, or both J Clin Invest 98: 1966–1970,1996 in myocardial infarction complicated by heart failure, left 33. Smithies O: Theodore Cooper Memorial Lecture. A mouse ventricular dysfunction, or both. N Engl J Med 349: 1893– view of hypertension. Hypertension 30: 1318–1324, 1997 1906, 2003 34. Boger J, Lohr NS, Ulm EH, Poe M, Blaine EH, Fanelli GM, 18. Siragy HM, Xue C, Abadir P, Carey RM: Angiotensin sub- Lin TY, Payne LS, Schorn TW, LaMont BI, Vassil TC, type-2 receptors inhibit renin biosynthesis and angiotensin Stabilito II, Veber DF, Rich DH, Bopari AS: Novel renin II formation. Hypertension 45: 133–137,2005 inhibitors containing the amino acid statine. Nature 303: 19. Zhang X, Lassila M, Cooper ME, Cao Z: Retinal expression 81–84, 1983 of vascular endothelial growth factor is mediated by an- 35. Sweet CCS, Ludden CT, Frederick CM, Bush LR, Ribeiro giotensin type 1 and type 2 receptors. Hypertension 43: LGT: Comparative hemodynamic effects of MK-422, a converting enzyme inhibitor, and a renin inhibitor in dogs 276–281, 2004 with acute left ventricular heart failure. J Cardiovasc Phar- 20. Skurk T, van Harmelen V, Hauner H: Angiotensin II stim- macol 6: 1067–1075, 1984 ulates the release of interleukin-6 and interleukin-8 from 36. Neisius D, Wood JM, Hofbauer KG: Renal vasodilatation cultured human adipocytes by activation of NF-kappaB. after inhibition of renin or converting enzyme in marmo- Arterioscler Thromb Vasc Biol 24: 1199–1203, 2004 set. Am J Physiol 251: H897–H902, 1986 21. Plovsing RR, Wamberg C, Sandgaard NC, Simonsen JA, 37. Camenzind E, Nussberger J, Juillerat L, Munafo A, Fischli Holstein-Rathlou NH, Hoilund-Carlsen PF, Bie P: Effects W, Coassolo P, van Brummelen P, Kleinbloesem CH, Wae- of truncated angiotensins in humans after double blockade ber B, Brunner HR. Effect of the renin response during of the renin system. Am J Physiol Regul Integr Comp Physiol renin inhibition: Oral Ro 42-5892 in normal humans. J Car- 285: R981–R991, 2003 diovasc Pharmacol 18: 299–307, 1991 22. Alderman MH, Ooi WL, Cohen H, Madhavan S, Sealey JE, 38. el Amrani AI, Menard J, Gonzales MF, Michel JB: Effects of Laragh JH: Plasma renin activity: A risk factor for myocar- blocking the angiotensin II receptor, converting enzyme, dial infarction in hypertensive patients. Am J Hypertens 10: and renin activity on the renal hemodynamics of normo- 1–8, 1997 tensive guinea pigs. J Cardiovasc Pharmacol 22: 231–239, 23. Kehoe B, Keeton GR, Hill C. Elevated plasma renin activity 1993 associated with renal dysfunction. Nephron 44: 51–57,1986 39. Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, 24. Malmqvist K, Ohman KP, Lind L, Nystrom F, Kahan T: Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood JM, Grutter Relationships between left ventricular mass and the renin- MG: Structure-based drug design: The discovery of novel angiotensin system, catecholamines, insulin and leptin. nonpeptide orally active inhibitors of human renin. Chem J Intern Med 252: 430–439, 2002 Biol 7: 493–504, 2000 25. Alderman MH, Cohen HW, Sealey JE, Laragh JH: Plasma 40. Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC, renin activity levels in hypertensive persons: Their wide Rasetti V, Ruger H, Goschke R, Stutz S, Fuhrer W, Schilling range and lack of suppression in diabetic and in most W, Rigollier P, Yamaguchi Y, Cumin F, Baum HP, Schnell elderly patients. Am J Hypertens 17: 1–7, 2004 CR, Herold P, Mah R, Jensen C, O’Brien E, Stanton A, 26. Danser AHJ, Deinum J: Renin, prorenin, and the putative Bedigian MP: Structure-based design of aliskiren, a novel (pro)renin receptor. Hypertension 46: 1069–1076, 2005 orally effective renin inhibitor. Biochem Biophys Res Com- 27. Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer mun 308: 698–705, 2003 JD: Pivotal role of the renin/prorenin receptor in angioten- 41. Nussberger J, Wuerzner G, Jensen C, Brunner HR: Angio- sin II production and cellular responses to renin. J Clin tensin II suppression in humans by the orally active renin Invest 109: 1417–1427, 2002 inhibitor Aliskiren (SPP100): Comparison with enalapril. 28. Sealey JE, Catanzaro DF, Lavin TN, Gahnem F, Pitarresi T, Hypertension 39: E1–E8, 2002 Hu LF, Laragh JH: Specific prorenin/renin binding 42. Stanton A, Jensen C, Nussberger J, O’Brien E: Blood pres- (ProBP). Identification and characterization of a novel sure lowering in essential hypertension with an oral renin membrane site. Am J Hypertens 9: 491–502, 1996 inhibitor, aliskiren. Hypertension 42: 1137–1143, 2003 29. Luetscher JA, Kraemer FB, Wilson DM, Schwartz HC, 43. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Bryer-Ash M: Increased plasma inactive renin in diabetes Chiang Y, Bedigian MP: Aliskiren, a novel orally effective 228 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 221–228, 2006

renin inhibitor, provides dose-dependent antihypertensive specificity of renin kinetics in transgenic rats harboring the efficacy and placebo-like tolerability in hypertensive pa- human renin and angiotensinogen genes. Proc Natl Acad tients. Circulation 111: 1012–1018, 2005 Sci U S A 89: 7806–7810, 1992 44. Azizi M, Menard J, Bissery A, Guyenne TT, Bura-Riviere A, 46. Pilz B, Shagdarsuren E, Wellner M, Fiebeler A, Dechend R, Vaidyanathan S, Camisasca RP: Pharmacologic demonstra- Gratze P, Meiners S, Feldman DL, Webb RL, Garrelds IM, tion of the synergistic effects of a combination of the renin Jan Danser AH, Luft FC, Muller DN: Aliskiren, a human inhibitor aliskiren and the AT1 receptor antagonist valsar- renin inhibitor, ameliorates cardiac and renal damage in tan on the angiotensin II-renin feedback interruption. JAm double-transgenic rats. Hypertension 46: 569–576, 2005 Soc Nephrol 15: 3126–3133, 2004 47. Shagdarsuren E, Wellner M, Braesen JH, Park JK, Fiebeler 45. Ganten D, Wagner J, Zeh K, Bader M, Michel JB, Paul M, A, Henke N, Dechend R, Gratze P, Luft FC, Muller DN: Zimmermann F, Ruf P, Hilgenfeldt U, Ganten U, Kaling M, Complement activation in angiotensin II-induced organ Bachmann S, Fkuamizu A, Mullins JJ, Murakami K: Species damage. Circ Res 97: 716–724, 2005

While pharmacological renin inhibition is an exciting approach to reducing target organ damage and progression of chronic kidney disease, Heinze et al. in this month’s JASN (889–899) have shown that conventional blockade of the renin-angiotensin system with ACE inhibitors or AT1 receptor blockers enhances renal allograft patient and graft survival, emphasizing the importance of the renin-angiotensin system in renal disease progression.