Aliskiren in the treatment of renal disease; a narrative review (original) (raw)
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Direct Renin inhibitor: aliskiren in chronic kidney disease
Nephro-urology monthly, 2013
The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression and its increased complications such as hypertension (HT) and cardiovascular diseases (CVD). Previous studies suggested that aliskiren a direct renin inhibitor, blocks RAAS and may be effective for the management of CKD and its complications. This review focuses on the effects of aliskiren on CKD.
Polish Archives of Internal Medicine, 2013
INTROduCTION Various methods of combination renin-angiotensin-aldosterone system blockade help achieve more potent antiproteinuric effects, but may be associated with higher risk of side effects. Therapies involving direct renin inhibitor, aliskiren, may promote renal fibrosis by stimulating (pro)renin receptor due to increased renin levels. ObjECTIvEs The aim of the study was to compare the effects of combination treatment with angiotensin receptor blockers, telmisartan (80 mg/d) and aliskiren (300 mg/d) with those of combination treatment with 80 mg/d telmisartan and mineralocorticoid receptor blocker (50 mg/d eplerenone) and telmisartan (160 mg/d) alone on the urinary excretion of transforming growth factor β 1 (TGF-β 1), renal function, and serum potassium levels. PATIENTs ANd mEThOds A randomized open-label controlled cross-over study was performed in 18 white patients (7 women and 11 men; mean age, 42.4 ±1.9 years) with proteinuric nondiabetic chronic kidney disease and estimated glomerular filtration rate of 85.2 ±4.6 ml/min. REsuLTs The urinary excretion of TGF-β 1 was stable despite a significant increase in plasma renin levels after treatment with telmisartan and aliskiren. There were no differences in renal function and serum potassium levels between the compared treatments. Moreover, there were no episodes of hypotension or acute renal impairment. CONCLusIONs Combination therapy with telmisartan and aliskiren may be safe in young nondiabetic patients with normal renal function at low vascular risk. This treatment may be an alternative for a subset of patients in whom standard RAA system blockade is ineffective.
Medicinski arhiv, 2009
The renin-angiotensin system (RAS) plays a crucial role in development of hypertension, heart failure, as well as in the whole process of nephropathy, particularly of diabetic nephropathy, with or without proteinuria. Blockade of RAS plays the key role in the management of hypertension and other cardiovascular diseases. Angiotensin-converting enzyme (ACE) inhibitors do not provide the full blockade of angiotensin II because it is produced through alternative pathways. Angiotensin receptor blockers (ARBs) also block the negative feedback of angiotensin II upon renin like ACE inhibitors, leading to a several fold increase in angiotensin II levels. Aliskiren is an orally-active, nonpeptidic, direct inhibitor of renin which simultaneously reduces angiotensin I, angiotensin II and plasma renin activity (PRA). This is the main point of action of aliskiren, making it completely different from ACE inhibitors and ARBs. Aliskiren introduces a new concept into the management of hypertension. H...
Aliskiren, the future of renin–angiotensin system blockade?
Expert Review of Cardiovascular Therapy, 2007
The suppression of the renin-angiotensin system by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been proven in many studies to treat hypertension and reduce cardiovascular events; however, reducing angiotensin I receptor stimulation results in the loss of the negative-feedback signal, leading to increased plasma renin activity. Numerous direct renin inhibitors were synthesized, but abandoned owing to low potency, poor bioavailability and short half-life. Aliskiren, a direct renin inhibitor of a novel structural class, inhibits the activity of the renin produced and, thus, its capacity to form angiotensin I, as measured by plasma renin activity. Aliskiren has been recently shown to be efficacious in hypertensive patients at once-daily oral dosing with favorable pharmacokinetics and the potential to improve end-organ protection.
Renal and Hormonal Responses to Direct Renin Inhibition With Aliskiren in Healthy Humans
Circulation, 2008
Background-Pharmacological interruption of the renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF Ϸ95 mL · min Ϫ1 · 1.73 m Ϫ2 ), greater renal vasodilation with angiotensin receptor blockers (Ϸ145 mL · min Ϫ1 · 1.73 m Ϫ2 ) suggested more effective blockade. We predicted that blockade with the direct oral renin inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Methods and Results-Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197Ϯ27 mL · min Ϫ1 · 1.73 m Ϫ2 ) and exceeded responses to captopril (92Ϯ20 mL · min Ϫ1 · 1.73 m Ϫ2 ; PϽ0.01). Furthermore, significant residual vasodilation was observed 48 hours after each dose (PϽ0.01). The RPF response on a high-sodium diet was also higher than expected (47Ϯ17 mL · min Ϫ1 · 1.73 m Ϫ2 ). Plasma renin activity and angiotensin levels were reduced in a dose-related manner. As another functional index of the effect of aliskiren, we found significant natriuresis on both diets.
Combination renin-angiotensin system blockade with the renin inhibitor aliskiren in hypertension
Journal of Renin-Angiotensin-Aldosterone System, 2009
Combining an angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) lowers blood pressure (BP) by 4/3 mmHg compared to either agent alone, although this additive effect may be abolished with maximal monotherapy dosing. The recent ONTARGET study showed no reduction in primary outcomes when an ACE-I-ARB combination was compared to an ACE-I alone, despite 2.4/1.4 mmHg lower BP in the former group. In proteinuric chronic kidney disease, an ACE-I-ARB combination reduces proteinuria and disease progression more than monotherapy, but the ONTARGET study showed an increase in renal endpoints in the combined group. Aliskiren offers a novel approach to renin-angiotensin system (RAS) inhibition. As monotherapy in hypertension, aliskiren is of similar efficacy to thiazides, calcium channel blockers and ARBs. In combination with other RAS inhibitors at maximal dosage aliskiren has a small synergistic effect on BP (additional 4/2 mmHg reduction). Early data suggest a role for aliskiren in preventing end-organ damage but, considering the ONTARGET results with an ACE-I-ARB combination, outcome studies are needed before the use of aliskiren can be recommended in combination with other RAS inhibitors. As monotherapy, aliskiren should probably be reserved for use as an alternative to ACE-Is or ARBs, where these are ineffective or poorly tolerated.
Aliskiren: the first direct renin inhibitor available for clinical use
Journal of Nephrology, 2011
The idea of blocking the renin-angiotensin system (RAS) with the inhibition of the enzymatic activity of renin has been pursued for half a century, but it became a reality only recently, with the synthesis of aliskiren, the first direct renin inhibitor available for clinical use. The upstream blockade of the system induced by aliskiren, in combination with its unique pharmacological properties (inhibiting potency, high plasma concentration, long half-life and preferential partitioning in the kidney) makes this compound the ideal tool to achieve a complete blockade of the RAS. Consistent with expectations, present evidence indicates that aliskiren, at the licensed dosages of 150-300 mg/day, lowers blood pressure to the same extent as other first-line antihypertensive agents, with the additional advantage of a longer duration of action which persists for several days after the cessation of treatment. Moreover, aliskiren was found to act synergically not only with diuretics but also with other drug classes, including angiotensinconverting enzyme inhibitors and angiotensin II receptor antagonists. In addition, results of recent clinical trials have shown that aliskiren possesses cardiovascular and renal protective properties which may contribute to the beneficial effects of this drug beyond the reduction of blood pressure. Finally, aliskiren has an excellent, placebo-like tolerability profile, a feature which is very relevant for improving compliance of patients.
International Urology and Nephrology, 2015
with the progression of the disease. In Europe, non-diabetic glomerulonephritis is the third leading cause of end-stage renal disease (ESRD). IgA glomerulonephritis (IgA GMN), membranous glomerulonephritis (MB GMN), lupus nephritis (LN) and focal and segmental glomerulosclerosis (FSGS) are the most progressive forms [1]. The common therapeutic approach is aimed at countering proteinuria, and renin-angiotensin-aldosterone system (RAAS) inhibition is the treatment of choice for slowing the progression of the renal damage [2]. However, despite the remarkable handling of anti-RAAS agents acquired by nephrologists, they often fail to achieve the desired clinical targets for renal protection. Both ACE-is and ARBs, being final inhibitors of RAAS, involve the up-regulation of prorenin and renin. The intrarenal effects of prorenin and renin are therefore not inhibited by these drugs, but even exalted [3]. Many studies conducted on animals evidenced that elevated plasma levels of prorenin and renin are independently associated with the chronic activation of a profibrotic cascade in the renal tissue [4-6]. Approved in 2007 by the Food and Drug Administration (FDA), aliskiren is the first drug acting as direct inhibitor of plasmatic renin activity [3], also possibly able to interfere with the 'prorenin and renin profibrotic escape'. The present literature review is aimed at assessing the potential efficacy and safety of aliskiren in the treatment of non-diabetic glomerulopathies. From intrarenal RAAS to aliskiren pharmacodynamics RAAS is a pleiotropic system presiding to the regulation of blood pressure, extracellular volume and vascular tone, with several complex mechanisms. Although RAAS components are ubiquitously expressed throughout the Abstract Non-diabetic glomerulonephritis is a frequent cause of end-stage renal disease. The use of renin-angiotensin-aldosterone system blockers is a fundamental therapeutic approach. However, converting enzyme inhibitors (ACE-is) and angiotensin receptor blockers do not always achieve the desired target of proteinuria. The induction of the prorenin and renin up-regulation is a possible explanation. Aliskiren is the first drug acting as direct inhibitor of plasmatic renin activity, also able to interfere with the prorenin and renin profibrotic escape. We aimed at reviewing the literature for the assessment of potential efficacy and safety of aliskiren in the treatment of non-diabetic glomerulonephritis. The data on this topic are limited; however, we concluded for a possible usefulness of aliskiren. The renal safety profile appears potentially acceptable in non-diabetic patients although extreme carefulness, particularly with respect to long-term renal and cardiovascular tolerability, is recommended.