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International Journal of Nephrology and Renovascular Disease
open access to scientific and medical research Role of aliskiren in blood pressure control This article was published in the following Dove Press journal: International Journal of Nephrology and Renovascular Disease21 March 2011Number of times this article has been viewed Abstract: Patients with chronic renal disease are at increased risk for the development of
cardiovascular disease, which is the main cause of death in this growing population. Among the risk factors involved, hypertension and proteinuria are major contributors to kidney damage and, if not controlled, may eventually lead to the progression of renal failure and end-stage renal disease. Both proteinuria and hypertension can be primary pathologic events or can appear as
complications of other disease processes. Initially, these two factors may operate separately but,
as progression ensues, both processes generally combine, potentiating their effects and hastening
renal damage. Therefore, strategies to reduce blood pressure and proteinuria are essential in
order to slow the worsening of many nephropathies. Therapies that target the renin–angiotensin
system offer particular benefit, as hypertension and proteinuria can be precisely reduced with
angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers. However, with
this intervention, plasma renin activity remains high, and although primary endpoints may be
controlled, elevated renin concentration can contribute to cardiovascular damage. Aliskiren, a
direct renin inhibitor, is the first example of a novel class of antihypertensive drugs with potent
antiproteinuric effects, which, alone or combined, can contribute to delaying the progression
of kidney disease.
Keywords: aliskiren, proteinuria, hypertension, chronic kidney disease, renoprotection
Introduction to blood pressure management
and renoprotection
Hypertension and diabetes mellitus account for over 50% of cases of chronic kidney
disease. High blood pressure itself is a major risk factor for the progression of renal
disease, affecting approximately 30% of the adult population in Western countries.1
As pointed out by Ritz2 in an editorial regarding the 2007 World Kidney Day, “High
blood pressure, not necessarily the ‘disease’ hypertension according to current defini-
tions (JNC7), is a major killer …” If a subject presents a blood pressure of 140 mm
Hg systolic, the risk of stroke or myocardial infarction is double that of someone with
a blood pressure of 120 mm Hg systolic. However, with a systolic blood pressure of
120–130 mm Hg, rather than 120 mm Hg or lower, the risk of end-stage renal disease
is approximately 62% and rises to nearly 160% with a pressure of 130–140 mm Hg.3
Therefore, an aggressive approach to blood pressure reduction is mandatory. However, it is estimated that only a small percentage of hypertensive patients have adequate blood pressure control. This situation can, in part, explain the growing number of cases of chronic renal failure. According to the recently published United States Renal Data System (USRDS) report, in the general population, 31% of hypertensives are unaware submit your manuscript
International Journal of Nephrology and Renovascular Disease 2011:4 41–48 2011 Trimarchi, publisher and licensee Dove Medical Press Ltd. This is an Open Access article DOI: 10.2147/IJNRD.S6653
which permits unrestricted noncommercial use, provided the original work is properly cited.
of their diagnosis, 11% are aware but not treated, 24% are and blood pressure, either alone or combined.16 However, by treated but uncontrolled, and only 34% of subjects are aware, attenuating feedback inhibition of renin release, ACEIs and treated, and well controlled. Surprisingly, in patients with ARBs effects lead to an increase in plasma renin concentration chronic kidney failure stages 3–4 (glomerular filtration rate and activity, rendering incomplete inhibition of the RAAS 15–60 mL/min), 24% are unaware of being hypertensive, system.17,18 Moreover, inhibition of ACE causes an increase 6% are aware but not treated, 50% are aware but poorly in angiotensin I, which is then available for conversion to controlled, and only 20% have their blood pressure controlled angiotensin II by ACE-independent pathways not blocked (,130–180 mm Hg).4 In the same report, it is shown that by ACEIs, namely cathepsins and tonins.19–21 Consequently, 91.4% of chronic kidney patients are hypertensive.5 This despite adequate blood pressure control, angiotensin II levels grim reality may partially explain why the adjusted rate of increase aldosterone levels to certain degrees, rendering prevalent cases of end-stage renal disease in the US rose 1.9% these inflammatory molecules free to play an active role in in 2008 (the same rate growth as that seen in 2007) to 1699 tissue remodeling and scarring. Henceforth, it is tempting per million population. This rate is nearly 20% higher than and reasonable to assess the effects of a different pharma- that seen in 2000. The annual rate of increase has remained cologic strategy that blocks the RAAS upstream completely. stable between 1.9% and 2.3% since 2003.6 Aliskiren is the first known representative of a new class of Proteinuria is another relevant target, as it is a major risk nonpeptide orally active renin inhibitors that block the RAAS factor for renal disease progression.7–9 Proteinuria can be due at its rate-limiting step and induce a net reduction in plasma to primary glomerulopathies (focal and segmental glom- renin activity and angiotensin II and aldosterone levels.22–24 erulonephritis, membranous nephropathy, minimal change Aliskiren has been assessed in recent years as an efficient disease, Berger’s disease, membranoproliferative glomerulo- antihypertensive drug, either alone or in combination with nephritis), which are the third most likely cause of end-stage other drugs. Its antiproteinuric effects are notorious and may renal disease in the adult population and an important cause of be independent of its antihypertensive effects, showing that secondary hypertension, or to secondary glomerular damage aliskiren alone or combined can further decrease proteinuria as a result of primary hypertension, diabetes mellitus, reflux and the risk of renal disease progression.25 This suggests that nephropathy, or other causes of renal disease. A coexistent renin- or angiotensin-independent pathways may be involved diagnosis of hypertension and diabetes increases the risk of in inflammatory processes of which proteinuria is a disease adverse cardiovascular and renal outcomes. This increased activity marker and that aliskiren can abrogate.
risk extends to a diastolic blood pressure of $83 mm Hg and a systolic blood pressure of Review of aliskiren pharmacology,
proteinuria by .30% within the first 6–12 months of treat- mode of action, pharmacokinetics,
ment in patients with chronic kidney disease has been shown and effects on renal hemodynamics
to predict long-term renal and cardiovascular outcomes.8,12 The direct renin inhibitor aliskiren is an octanamide and a Moreover, the management of albuminuria in normotensive nonpeptide piperidine with high affinity and specificity for or hypertensive patients with diabetes may slow progression human renin,25 and it inhibits the enzyme renin by binding of diabetic nephropathy.13 Microalbuminuria itself, an early to its catalytic site, thus blocking the RAAS at its point of marker of kidney vascular dysfunction, is a strong prognostic activation.26 In this respect, angiotensin I, angiotensin II, indicator of mortality and cardiovascular disease in hyper- and aldosterone levels decrease, and their hemodynamic tension and diabetes mellitus.14,15 Therefore, one of the main and inflammatory effects are abolished. Therefore, aliskiren goals to slow the progression of renal disease is an adequate impedes efferent arteriolar vasoconstriction and diminishes and not unusually aggressive control of blood pressure and the glomerular filtration fraction, salt and water absorption, the reduction of proteinuria to its lowest possible level.
and angiotensin II-induced inflammatory actions. Moreover, In this regard, the pharmacological manipulation of the it blocks renin and prorenin activity while renin and prorenin renin–angiotensin–aldosterone system (RAAS) is an impor- tant tool to employ, as renin, angiotensin II, and aldosterone A recently discovered (pro)renin receptor activates are important molecules with hemodynamic and inflamma- when exposed to either renin or prorenin, the inactive form tory effects both systemically and locally, particularly in the of renin.27 The (pro)renin receptor, in turn, enhances renin kidney. Angiotensin-converting enzyme inhibitors (ACEIs) catalytic activity and allows prorenin to display catalytic and angiotensin receptor blockers (ARBs) reduce proteinuria activity without its proteolytic conversion to renin. This (pro) submit your manuscript |
International Journal of Nephrology and Renovascular Disease 2011:4 renin receptor-induced prorenin activation could explain how not major routes of aliskiren elimination.40,41 Following a prorenin exerts pathological effects in diabetic patients, where single oral 300 mg dose, aliskiren has an elimination half- prorenin represents approximately 95% of total circulating life of 40 hours in healthy volunteers.42 Excretion is almost renin.28 Interestingly, recent data have shown that renin and completely by the fecal route (91.5%), with 77.5% of the prorenin induce activation of the extracellular signal-regulated dose excreted as unchanged drug.43 The pharmacokinetics of kinase (ERK) pathway, independent of angiotensin II. In this aliskiren are not affected by sex,36,41 body mass index,36,41 or respect, aliskiren has no (pro)renin receptor-blocking action. race and are similar in Chinese, Japanese, and Caucasian44–46 Therefore, ACEIs, ARBs, and aliskiren all increase renin con- patients. The pharmacokinetics of aliskiren in patients with centration, which could conceivably induce (pro)renin recep- hepatic impairment, mild to severe renal disease,36,41 or type tor signaling without the involvement of angiotensin II, 2 diabetes42 are no different from those of healthy volunteers. suggesting that blockade of the (pro)renin receptor might Thus, initial dosage adjustments are not necessary in patients be an alternative or an adjunct to renin–angiotensin system inhibition, particularly in conditions with high renin and/or Aliskiren has a low potential for clinically relevant inter- prorenin levels.28 High prorenin levels are closely associated actions with other drugs.40,41 However, coadministration of with the severity of diabetic complications. In this respect, aliskiren with irbesartan decreased the aliskiren maximum in diabetics, increased prorenin levels have been shown to concentration by 50% after multiple dosing.36,41 The expo- be associated with microalbuminuria and with the develop- sure to aliskiren was not altered by coadministration of ment of nephropathy.29,30 However, aliskiren still blocks the furosemide.47 However, furosemide decreased by 28% and tissue renin–angiotensin system, because at the (pro)renin 49% with concomitant aliskiren administration. Although receptor level, activated prorenin can immediately be blocked the clinical significance of this is unclear, the effects of by aliskiren. The result would be angiotensin II production furosemide should be monitored.41 When aliskiren was not occurring.28 Interestingly, renin bound to the (pro)renin coadministered with rifampicin, the latter reduced aliskiren receptor presents much more enhanced catalytic activity concentration by 39%.48 Coadministration of aliskiren with than soluble renin.31 The cloning of a functional receptor potent P-glycoprotein inhibitors (cyclosporine, quinidine, for both renin and prorenin suggests that renin and prorenin and verapamil) is virtually contraindicated because aliskiren may exert direct angiotensin II-independent tissue-damaging plasma concentrations significantly increase, and aliskiren effects by increasing the expression of profibrotic pathways and moderate P-glycoprotein inhibitors (ketoconazole, itra- and molecules, such as transforming growth factor-β.32 conazole, clarithromycin, telithromycin, erythromycin, and Additionally, the receptor may amplify renin-induced angio- amiodarone) should be coadministered with caution. Grape- tensin II-dependent effects. Plasma renin activity is blocked fruit juice should not be taken together with aliskiren.41 only by aliskiren. Elevated baseline plasma renin activity in One concern is the potential adverse effect of high circu- untreated patients has been associated with end-organ damage, lating renin concentrations after aliskiren therapy. As men- such as left ventricular hypertrophy and renal dysfunction,33,34 tioned previously, aliskiren binds to the active site of renin, probably due to high angiotensin II levels. Renin inhibition reducing its activity (plasma renin activity) and angiotensin II with aliskiren therefore offers the chance of enhanced RAAS production. Diminished angiotensin II levels stimulate renin suppression and improved end-organ protection either alone secretion (plasma renin concentration). The potential nega- or in combination with other antihypertensive drugs.35 tive consequence of high renin concentration is that renin may Aliskiren is poorly absorbed, with an absolute oral bio- bind to a renin receptor and trigger yet unknown events.49 availability of 2.5% with maximum plasma aliskiren concen- However, an important contributor to the exaggerated renin trations reached within 1–3 hours of oral administration.36,37–39 response is interference by the renin inhibitor in the renin Although food has a big effect on the pharmacokinetics of assay causing overestimation of the renin concentration.50 aliskiren, the resulting decreases in aliskiren exposure are not Thus, this renin response may not actually represent an considered clinically relevant.40 Steady-state plasma concen- increase in enzymatically active renin molecules in plasma. trations are reached 5–8 days after once-daily oral administra- The question of whether this increase in renin concentra- tion of aliskiren.36,41 The half-life of oral aliskiren is around tion has any effect remains unanswered. Although aliskiren 24 hours;40 it is approximately 50% protein bound in human lowers plasma renin activity, renin concentration rises, and plasma, and protein binding is independent of aliskiren ACEIs and ARBs increase both.51,52 As mentioned previously, plasma concentration.41 Hepatic and renal metabolism are high levels of renin can activate the prorenin/renin receptor, International Journal of Nephrology and Renovascular Disease 2011:4 submit your manuscript
which aside from activating prorenin, can possibly initiate hypertension.63–67 The antihypertensive efficacy of aliskiren ERK1/2 signaling and transform growth factor-β activation monotherapy was also demonstrated in subgroups of patients, and other potentially serious complications.25,53 However, including diabetic and obese patients and those with meta- ACEIs and ARBs also leave these issues unresolved with a partial inhibition of angiotensin II concentration, despite good blood pressure control. Some authors have argued against renin inhibition, because plasma renin concentra- Across a number of trials in patients with hypertension, tions attained after aliskiren are higher than those obtained aliskiren monotherapy was generally as effective as hydro- after ARBs.54 However, in some studies in mice, ARBs have chlorothiazide, ramipril, lisinopril, irbesartan, atenolol, caused higher plasma renin concentrations than aliskiren. valsartan, and losartan at reducing blood pressure in short- This discrepancy could partly be due to the method employed term studies. In long-lasting, double-blind trials, aliskiren- to measure renin concentrations in mice and humans.55 based therapy was at least as effective as ramipril-based Plasma renin activity is blocked only by aliskiren. therapy69 and more effective than hydrochlorothiazide-based Elevated baseline plasma renin activity in untreated patients has been associated with end-organ damage, such as left Aliskiren 150–300 mg/day was more effective than ventricular hypertrophy and renal dysfunction,56,57 probably irbesartan 150–300 mg/day71 and generally as effective as due to high angiotensin II levels.58 Renin inhibition with valsartan 160–320 mg/day72 and losartan 100 mg/day73 in aliskiren therefore offers the chance of enhanced RAAS lowering blood pressure. Aliskiren did not differ significantly suppression and improved end-organ protection, either alone from atenolol in lowering systolic blood pressure in a study or in combination with other antihypertensive drugs.25,59 The in which patients received aliskiren 150 mg/day or atenolol kidney is an important site of the uptake of renin inhibitors, 50 mg/day for 6 weeks followed by 6 weeks on double the and aliskiren has been found in renal glomeruli, renal arter- initial dose of the agents.74 However, reductions in diastolic ies, and capillaries.60,61 Aliskiren may act directly on the blood pressure were significantly greater with atenolol than renin-secreting juxtaglomerular cell to influence prorenin with aliskiren at both 6 weeks and 12 weeks.
Efficacy studies and organ
The efficacy75–77 of aliskiren in combination with other protection
antihypertensives has been evaluated in randomized, double- blind or open-label, multicentre trials in which aliskiren The therapeutic efficacy of aliskiren will be outlined in this 150–300 mg/day was administered in combination with section at a dosage of 150 mg/day or 300 mg/day alone hydrochlorothiazide, valsartan, valsartan plus hydrochloro- and compared with placebo and ACEIs or ARBs and/or thiazide, amlodipine, amlodipine plus hydrochlorothiazide, combined with hydrochlorothiazide, valsartan, valsartan plus hydrochlorothiazide, amlodipine, amlodipine plus In patients with stage 1 to stage 2 hypertension, combined hydrochlorothiazide, ramipril, and atenolol. In general, adult strategies of aliskiren plus hydrochlorothiazide were more patients were enrolled in these trials with diastolic blood pres- effective than aliskiren, hydrochlorothiazide, or ramipril sures .90–95 mm Hg and ,110 mm Hg or mean systolic monotherapies, and at least as effective as amlodipine, in blood pressures between .160 mm Hg and ,200 mm Hg. reducing blood pressure in patients with stage 2 hyperten- Patients with secondary hypertension, severe cardiovascular sion, including patients with diabetes, patients with obesity, disease, uncontrolled diabetes mellitus, and hepatic or renal patients with metabolic syndrome, African American patients, disease were excluded from most studies. A concise, thor- and aged patients.78–83 Patients who received aliskiren plus ough, updated review has recently been published.62 valsartan had significantly greater blood pressure reductions than with either an individual component or placebo.84 The antihypertensive effect of the combination of aliskiren plus In the 8-week, placebo-controlled trials, monotherapy with valsartan was similar in patients with or without diabetes.36 aliskiren 150 mg/day or 300 mg/day reduced baseline sys- The antihypertensive effects of the aliskiren plus valsartan tolic and diastolic blood pressure to a significantly greater combination were diminished in African American patients, extent than placebo in patients with stage 1 to stage 2 as was the case with ACEIs, ARBs, and atenolol.36 submit your manuscript |
International Journal of Nephrology and Renovascular Disease 2011:4 Aliskiren in combination with amlodipine was effective in in Post-MI Patients to Reduce Remodelling [ASPIRE])92 are lowering BP in patients with stage 1 to stage 2 hypertension.62 First-line therapy with combination aliskiren 150 mg/day Aliskiren-based therapy demonstrated positive effects or 300 mg/day plus amlodipine 5–10 mg/day provided on the markers of cardiovascular and renal damage in significantly greater control than the respective monothera- hypertensive patients with type 2 diabetes and nephropa- pies in patients with stage 2 hypertension.85 Combination thy, reducing proteinuria independently of blood pressure therapy was also more effective than amlodipine monotherapy control88 in patients with reduced left ventricular hyper- as first-line therapy in African-American patients with stage trophy89 or in those with symptomatic heart failure and 2 hypertension.86 This was also observed irrespective of reduced plasma N-terminal probrain natriuretic peptide.90 age, sex, and the presence of diabetes or obesity.62 Finally, However, aliskiren therapy did not have a beneficial effect aliskiren in combination with ramipril led to a significantly on left ventricular remodeling after myocardial infraction.92 greater reduction in blood pressure than with each indi- Add-on aliskiren 300 mg/day had no significant beneficial vidual component in hypertensive patients with type 1 effect on left ventricular end-systolic volume compared with or 2 diabetes.84 In a study combining aliskiren 150 mg/day placebo (ASPIRE).92 Further studies are currently under way with atenolol 50 mg/day, there were greater reductions to evaluate the effect of aliskiren on the following clini- in blood pressure than with aliskiren monotherapy after cal outcomes: reduction of cardiovascular death and heart failure rehospitalization events within 6 months in patients with congestive heart failure hospitalized for an episode of Safety and tolerability
acute decompensated heart failure (Aliskiren Trial on Acute Aliskiren was generally well tolerated at doses of 150 or Heart Failure Outcomes [ASTRONAUT]),93 morbidity and 300 mg/day62 and resulted in an incidence of adverse events mortality in patients with type 2 diabetes and pre-existing similar to placebo.41 Adverse events, including uncontrolled cardiovascular disease and/or kidney disease (Aliskiren Trial hypertension (2.2%),36 have generally been mild and have in Type 2 Diabetes Using Cardio-renal Disease Endpoints infrequently led to discontinuation of therapy.41 The most [ALTITUDE]),94 and morbidity and mortality in patients with common adverse events reported are headache (5.8%), chronic heart failure (Aliskiren Trial to Minimize Outcomes nasopharyngitis (2.6%), and diarrhea (1.4%).62 Aliskiren was in Patients with Heart Failure [ATMOSPHERE]).95 The also associated with a few cases of cough (1.1%), although, potential benefit of aliskiren on long-term outcomes is cur- compared with ACEIs, the rate of cough was approximately rently being evaluated as part of the larger ASPIRE HIGHER one-third to one-half that reported with ramipril or lisinopril.36 Although aliskiren has rarely been associated with changes in laboratory parameters, it is still prudent to monitor hemo- globin concentration and serum levels of creatinine, urea, Aliskiren can be employed in patients with hypertension, and potassium, uric acid, and creatine kinase.36,41,62 in particular in subjects with proteinuria. Despite the possibil-ity of an occasional forgotten dose (missing dose), it exerts protection beyond 24 hours due to its long half-life. This In respect of organ protection, although blood pressure- feature is not associated with a higher risk of hypotension.41 lowering effects with aliskiren are well established, its An important advantage is that aliskiren does not need to effects on cardiovascular morbidity and mortality are yet to be adjusted in patients with hepatic or renal disease. As an be determined. A clinical program is under way to assess the antihypertensive drug, aliskiren is equivalent to any other potential benefits of aliskiren in clinical outcomes. Details drug and may not present major differences in blood pressure on studies on the renoprotective and cardioprotective effects control when used as monotherapy, particularly at 300 mg/day. of aliskiren in hypertensive, diabetic subjects with nephropa- However, in hypertensive patients with proteinuria, it may thy (Aliskiren in the Evaluation of Proteinuria in Diabetes present some advantages. It can be used alone or in combina- [AVOID]),88 reduced left ventricular hypertrophy (Aliskiren tion with other drugs to achieve low protein urinary excretion. in Left Ventricular Hypertrophy [ALLAY]),89 symptomatic Although aliskiren does not present a renal route of elimi- heart failure (Aliskiren Observation in Heart Failure Treat- nation and would potentially be useful at any stage of renal ment [ALOFT]),90 acute coronary symptoms,91 and postmyo- disease, there is still not enough information to recommend cardial infarction with low ejection fraction (Aliskiren Study its use in chronic renal failure stages 4 or 5. Patients with International Journal of Nephrology and Renovascular Disease 2011:4 submit your manuscript
renin-dependent hypertension are a target population. In 2. Ritz E. Hypertension. The kidney is the culprit even in the absence of these cases, potassium levels must be monitored periodically. kidney disease. Kidney Int. 2007;71:371–372.
3. Levington S, Clarke R, Qizilbash N. Age-specific relevance of usual blood Diabetics appear to benefit from aliskiren, independently pressure to vascular mortality: a meta-analysis of individual data for one of being normotensive or hypertensive, normoalbuminuric, million adults in 61 prospective studies. Lancet. 2002;360:1903–1913.
4. United States Renal Data System 2010 Annual Data Report, CD microalbuminuric, or proteinuric. Aliskiren can block prorenin Vol 1, Chapter 1, Table ei, page 48.
activity, which is increased in diabetic subjects and associated 5. United States Renal Data System 2010 Annual Data Report, CD with inflammatory processes systemically. Although plasma Vol 1, Chapter 2, Table 19i, page 61.
6. United States Renal Data System 2010 Annual Data Report, CD renin activity is suppressed by aliskiren, plasma renin concen- Vol 2, Chapter 2, Table 2 10ii, page 258.
tration remains high, and the eventual consequences of this 7. Bakris GL. Slowing nephropathy progression: focus on proteinuria reduction. Clin J Am Soc Nephrol. 2008;3 Suppl 1:S3–S10.
phenomenon are still unknown in the adult population.25 8. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, protei- In patients with primary or secondary glomerulopathies, nuria, and the progression of renal disease. The Modification of Diet in such as lupus nephritis, in which immunosuppression is Renal Disease Study. Ann Int Med. 1995;123:754–762.
9. De Zeew D, Remuzzi G, Parving HH, et al. Proteinuria, a target for the mainstay of treatment, once the acute process has been renoprotection in patients with type 2 diabetic nephropathy:Lessons approached and renal function stabilized, aliskiren could be from RENAAL. Kidney Int. 2004;65:2309–2320.
10. Chobanian AV, Bakris GL, Black HR. Seventh Report of the Joint used alone or in combination with ARBs, ACEIs, or other anti- National Committee on Prevention, Detection, Evaluation, and Treat- hypertensive drugs to inhibit angiotensin II-induced inflamma- ment of High Blood Pressure. Hypertension. 2003;42:1206–1252.
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5.2.5 Interdisziplinäres Zentrum für Suchtforschung (IZSW)Prof. Dr. med. Andreas Fallgatter (Vorsitzender)findung“ wird die suchtspezifische Frage untersucht, wie die kognitiv-emotionalen ze auf das individuel e Verlangen zu Rau-ten „Interdisziplinären Würzburger BMBF- chen und als Prädiktoren eines Rückfal s in Suchtforschungsverbund“ zu neurobiologi-E-mail: Fallgatter_A@klini

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April 3, 2009 Klas Center, Hamline University The Food, Drug, and Cosmetic Act – Searching for the Crossroads of Safety and Innovation In a 2008 U.S. Supreme Court decision, Riegel v. Medtronic , the opportunity to bring state tort claims against medical device manufacturers that make FDA-approved devices diminished significantly due to a preemption clause in the Medical Dev

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