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Effects of Direct Renin Blockade on Renal & Systemic Hemodynamics and on RAAS Activity, in Weight Excess and Hypertension: A Randomized Clinical Trial.
Kwakernaak, AJ, Roksnoer, LC, Lambers Heerspink, HJ, van den Berg-Garrelds, I, Lochorn, GA, van Embden Andres, JH, Klijn, MA, Kobori, H, Danser, AH, Laverman, GD, et al
PloS one. 2017;(1):e0169258
Abstract
AIM: The combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension. METHODS A randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15). RESULTS Mean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m2) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m2) was increased in response to DRI (320 (14) mL/min/1.73m2, P = 0.012) and ACEi (317 (15) mL/min/1.73m2, P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9-42] mg/d) was reduced by DRI only (12 [5-28] mg/d, P = 0.030). CONCLUSIONS In men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension. TRIAL REGISTRATION Dutch trial register, registration number: 2532 www.trialregister.nl.
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Long-term effects of a renin inhibitor versus a thiazide diuretic on arterial stiffness and left ventricular diastolic function in elderly hypertensive patients.
Okada, Y, Shibata, S, Fujimoto, N, Best, SA, Levine, BD, Fu, Q
American journal of physiology. Regulatory, integrative and comparative physiology. 2017;(4):R400-R409
Abstract
Arterial stiffness and cardiac function are important predictors of cardiovascular events in patients with hypertension, even with adequate blood pressure (BP) control. We evaluated whether a direct renin inhibitor, aliskiren, reduces arterial stiffness and modulates left ventricular function compared with a diuretic, hydrochlorothiazide, in elderly hypertensive patients. Twenty-one hypertensive patients [67 ± 14 (SD) yr] were randomly assigned to receive 6-mo aliskiren (n = 11) or hydrochlorothiazide (n = 10)-based therapy. We assessed β-stiffness of the local arteries, arterial elastance (Ea), and echocardiographic variables, including early (E) and late (A) mitral inflow velocity, deceleration time of E, early (E') and late (A') diastolic mitral annular velocity, and left ventricular end-systolic elastance (Ees) before and after treatment. BP decreased similarly (P < 0.001) after both therapies. β-Stiffness of the carotid artery decreased after aliskiren but increased after hydrochlorothiazide treatment (aliskiren: 6.42 ± 2.34 pre vs. 5.07 ± 1.29 post; hydrochlorothiazide: 5.05 ± 1.78 vs. 7.25 ± 2.68, P = 0.001 for interaction). β-Stiffness of the femoral and radial arteries were not different after either treatment. Different from aliskiren, E decreased (73 ± 16 vs. 67 ± 14 cm/s, P = 0.026), and the deceleration time was prolonged (218 ± 40 vs. 236 ± 35 ms, P = 0.032) after hydrochlorothiazide therapy, whereas the E/A, and E' remained unchanged after both treatments. Ea and Ees decreased after aliskiren therapy (both P < 0.05), whereas the Ea/Ees (ventricular-arterial coupling) was maintained after both treatments. Thus, aliskiren decreased the stiffness of carotid artery and left ventricular end-systolic elastance with maintenance of ventricular-arterial coupling without any effects on diastolic filling, while hydrochlorothiazide increased carotid arterial stiffness and slowed early diastolic filling in elderly hypertensive patients.
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Aliskiren, Enalapril, or Aliskiren and Enalapril in Heart Failure.
McMurray, JJ, Krum, H, Abraham, WT, Dickstein, K, Køber, LV, Desai, AS, Solomon, SD, Greenlaw, N, Ali, MA, Chiang, Y, et al
The New England journal of medicine. 2016;(16):1521-32
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Abstract
BACKGROUND Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction. METHODS After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure. RESULTS After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001). CONCLUSIONS In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).
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Aldosterone-to-renin ratio acts as the predictor distinguishing the primary aldosteronism from chronic kidney disease.
Chen, WG, Zhou, TT, Zhou, P, Li, XW, Wu, Z, Zhang, KY, Xing, JC
International journal of clinical and experimental pathology. 2015;(6):6901-9
Abstract
Aldosterone-to-renin ratio (ARR) is a screening test for primary aldosteronism, but it was impacted by a bunch of clinical covariates. The ARR is associated with chronic kidney disease (CKD), renal artery stenosis, renin adenoma. This study aims to investigate relationship between ARR and primary aldosteronism in CKD patients. A retrospective observational analysis involves 253 attendees from Urology Department of Chengdu Military General Hospital (China), comprising 146 patients with confirmed primary aldosteronism, 56 patients with essential hypertension, and 55 patients with chronic kidney disease accounting for primary kidney disease. Blood samples were drawn from patients with particular restriction for measuring serum aldosteronism, plasma renin activity, and serum potassium. Receiver operating characteristic (ROC) curve of ARR was tested to establish cutoff values and to assess sensitivity and specificity. The results showed that LogARR values were significantly higher (P < 0.001), and PRA and serum potassium values were significantly lower (P < 0.001) in primary aldosteronism patients. By contrast, significantly higher serum aldosterone and plasma renin were observed in CKDs compared with the other two groups (P < 0.001). There was a significantly positive correlation between LogARR and serum potassium (r = -0.0345, P < 0.001, R(2) = 0.093). The AUC for plasma renin activity, logARR, and serum aldosterone are 0.855, 0.84, and 0.501, respectively. ROC curve of logARR and plasma renin activity in detection of primary aldosteronism with higher sensitivity and specificity. In conclusion, this study indicated that the ARR act as the biomarker for the primary aldosteronism, and could distinguish from chronic kidney disease.
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Aliskiren attenuates oxidative stress and improves tubular status in non-diabetic patients with chronic kidney disease-Placebo controlled, randomized, cross-over study.
Renke, M, Lizakowski, S, Tylicki, L, Rutkowski, P, Knap, N, Heleniak, Z, Sławińska-Morawska, M, Aleksandrowicz-Wrona, E, Januszczyk, J, Wójcik-Stasiak, M, et al
Advances in medical sciences. 2014;(2):256-60
Abstract
PURPOSE Pharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) may have a beneficial impact on proteinuria and chronic kidney diseases (CKD) progression. Despite recent progress by means of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), there is still no optimal therapy which can stop progression of the nephropathy. Recently introduced aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. The purpose was to evaluate the extent of oxidative stress and tubular injury after the direct renin inhibitor, aliskiren compared with placebo and perindopril in patients with non-diabetic chronic kidney disease (NDCKD). MATERIAL/METHODS A randomized, double-blind, cross-over trial was performed in 14 patients receiving 300mg aliskiren, 10mg perindopril and placebo in random order. The end point was a change in the urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and α1-microglobulin (α1m) and 15-F(2α)-isoprostane. RESULTS Aliskiren reduced excretion of 15-F(2α)-isoprostane (p=0.03) and α1m (p=0.01) as compared to placebo. There were no differences between aliskiren and perindopril in this regard. NAG urine excretion did not change after aliskiren and perindopril. CONCLUSIONS Aliskiren attenuates oxidative stress and may improve functional status of tubules in patients with NDCKD.
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Clinical pharmacology of single- and multiple-ascending doses of ACT-178882, a new direct renin inhibitor, and its pharmacokinetic interaction with food and midazolam.
Dingemanse, J, Nicolas, L, Binkert, C
Fundamental & clinical pharmacology. 2013;(6):698-710
Abstract
This study investigated the tolerability, safety, pharmacokinetics, and pharmacodynamics of ACT-178882, a new direct renin inhibitor, as well as its interaction with food and midazolam. Healthy male subjects received either single (10-1000 mg) or multiple doses (30-600 mg) administered once daily for 14 days of ACT-178882, placebo, or 20 mg enalapril in the fasted state. Following a 2-week washout, the single dose of 30 mg ACT-178882 was also administered in the fed state. In the multiple-ascending-dose part, subjects were dosed with midazolam on days -2, 2, and 12 to investigate interactions with CYP3A4. Dizziness and headache were the most frequently reported adverse events. No clinically relevant changes occurred for body weight, vital signs, clinical laboratory variables, and ECG although both enalapril and ACT-178882 tended to decrease systolic blood pressure. Following single doses of ACT-178882, t1/2 and tmax varied from 18.7 to 24.7 h and from 3 to 5 h, respectively, and food had no significant effect. Steady-state conditions were achieved after 4-6 days of dosing and accumulation was minimal. ACT-178882 pharmacokinetics were dose proportional. ACT-178882 but not enalapril dose-dependently increased Cmax and area under the concentration-time curve of midazolam. Single and multiple doses of ACT-178882 dose-dependently increased active renin and decreased plasma renin activity, whereas enalapril increased both variables. No effects on urinary excretion of creatinine, potassium, and the 6β-hydroxycortisol/cortisol ratio were observed, whereas sodium and aldosterone excretion was decreased by both ACT-178882 and enalapril. The current results with ACT-178882 warrant further clinical investigation of this renin inhibitor in hypertensive patients.
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Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects.
Vaidyanathan, S, Reynolds, C, Yeh, CM, Bizot, MN, Dieterich, HA, Howard, D, Dole, WP
Journal of clinical pharmacology. 2007;(4):453-60
Abstract
This open-label, multicenter study compared the pharmacokinetics and safety of the oral direct renin inhibitor aliskiren in 29 elderly (>or=65 years) and 28 young (18-45 years) healthy subjects. Plasma drug concentrations were determined for up to 168 hours following a single 300-mg oral dose of aliskiren. In elderly compared with young subjects, AUC(0-infinity) was 57% higher (ratio of geometric means 1.57, 90% confidence interval: 1.19, 2.06; P = .008) and C(max) was 28% higher (1.28, 90% confidence interval: 0.91, 1.79; P=.233). Other parameters, including t(max) and Vd/F, were similar between age groups. No differences in aliskiren exposure were observed between subjects ages 65 to 74 years (n=16) and >or=75 years (n=13). Aliskiren was well tolerated by all age groups, including the very elderly. In conclusion, aliskiren exposure is modestly increased in elderly subjects. Based on its wide therapeutic index and shallow dose response for blood pressure lowering, no initial dose adjustment should be needed for elderly patients.
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The spironolactone, amiloride, losartan, and thiazide (SALT) double-blind crossover trial in patients with low-renin hypertension and elevated aldosterone-renin ratio.
Hood, SJ, Taylor, KP, Ashby, MJ, Brown, MJ
Circulation. 2007;(3):268-75
Abstract
BACKGROUND There is continuing variation in diagnosis and estimated prevalence of primary hyperaldosteronism. The higher estimates encourage search for adrenal adenomas in patients with elevated ratios of plasma aldosterone to renin. However, it is more likely that patients with normal plasma K+ and aldosterone belong to the polygenic spectrum of low-renin hypertension rather than have the same monogenic syndrome as classic Conn's. Our primary hypothesis was that in low-renin patients with normal plasma K+ and aldosterone, a thiazide diuretic, bendroflumethiazide, would be as effective as spironolactone in overcoming the Na+ retention and lowering blood pressure. Secondary objectives were to compare the dose response for each diuretic and to evaluate amiloride as an alternative to spironolactone. METHODS AND RESULTS Fifty-seven patients entered and 51 patients completed a placebo-controlled, double-blind, randomized crossover trial. Entry criteria included low plasma renin, normal K+, elevated aldosterone-renin ratio, and a previous systolic blood pressure response to spironolactone of > or = 20 mm Hg. Two doses each of spironolactone and bendroflumethiazide were compared. The crossover also included amiloride and losartan. Outcome measures were blood pressure, plasma renin, and other biochemical markers of diuretic action. Spironolactone 100 mg and bendroflumethiazide 5 mg caused similar falls in systolic blood pressure, whereas bendroflumethiazide 2.5 mg was 5/2 mm Hg less effective in reducing blood pressure than either bendroflumethiazide 5 mg or spironolactone 50 mg (P<0.005). Amiloride 40 mg was as effective as the other diuretics. Biochemical indices of natriuresis showed bendroflumethiazide to be less effective than either spironolactone or amiloride; plasma renin rose 4-fold on spironolactone but only 2-fold on bendroflumethiazide (P=0.003). CONCLUSIONS In hypertensive patients with a low plasma renin but normal K+, bendroflumethiazide 5 mg was as effective as spironolactone 100 mg in lowering blood pressure, despite patients being selected for a previous large fall in blood pressure on spironolactone. Because this result differs from that expected in primary hyperaldosteronism, our finding argues against low-renin hypertension including a large, undiagnosed pool of primary hyperaldosteronism. However, spironolactone was the more effective natriuretic agent, suggesting that inappropriate aldosterone release or response may still contribute to the Na+ retention of low-renin hypertension.
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Is there an association between ACE and CKMM polymorphisms and cycling performance status during 3-week races?
Lucía, A, Gómez-Gallego, F, Chicharro, JL, Hoyos, J, Celaya, K, Córdova, A, Villa, G, Alonso, JM, Barriopedro, M, Pérez, M, et al
International journal of sports medicine. 2005;(6):442-7
Abstract
In this paper, we examine the association between polymorphisms of the angiotensin-converting enzyme (ACE) and muscle-specific creatine kinase (CKMM) genes, and the actual performance status observed in professional cyclists capable of completing a classic tour stage race such as the Giro d'Italia, Tour de France, or Vuelta a España. To accomplish this, we compared the frequencies of the ACE and CKMM genotypes/alleles in 50 top-level Spanish professional cyclists that have completed at least one of these events to 119 sedentary controls, and 27 elite (Olympic-class) Spanish runners. The genetic polymorphism at the CK-MM locus was detected with the NcoI restriction endonuclease. The results of our study showed that the proportion of the DD genotype was higher in cyclists (50.0 %) than in the other two groups (p<0.05), the proportion of the ID genotype was higher in controls (46.2 %) than in the other two groups (p<0.05), and the proportion of the II genotype was higher in runners (40.7 %) than in the other two groups (p<0.05). The proportion of the D allele was higher in both cyclists (65.0 %) and controls (57.6 %) than in runners (46.3 %) (p<0.001), whereas the proportion of the I allele was higher in runners than in the other two groups (p<0.001). No statistical differences were found for CKK-MM- NcoI. We conclude that in top-level professional cyclists capable of completing a classic 3-wk tour race, the frequency distribution of the D allele and the DD genotype seems to be higher than in other endurance athletes such as elite runners (in whom the I allele is especially frequent).
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Endothelin-aldosterone interaction and proteinuria in low-renin hypertension.
Elijovich, F, Laffer, CL, Schiffrin, EL, Gavras, H, Amador, E
Journal of hypertension. 2004;(3):573-82
Abstract
OBJECTIVE To investigate whether endothelin and aldosterone participate in the increased prevalence and severity of nephrosclerosis in human low-renin hypertension, analogous to observations in experimental hypertension. DESIGN Comparison of endothelin, aldosterone and their relationships with proteinuria, in hypertensive patients with high aldosterone : renin ratios (HARR group, n = 14) or normal aldosterone : renin ratios (NARR group, n = 15). METHODS Urine protein and radioimmunoassay measurements of plasma renin activity, endothelin and aldosterone were carried out in individuals taking their usual diet, and after salt loading and salt depletion. RESULTS Compared with the NARR group, patients in the HARR group had higher blood pressure, greater salt sensitivity of their blood pressure, significantly greater urine protein and lower serum potassium concentrations, lower renin activities [0.14 +/- 0.03 ng AngiotensinI (AI)/l per s compared with 0.76 +/- 0.16 ng AI/l per s; P < 0.005], blunted renin-aldosterone responses to salt loading and salt depletion, enhanced catecholamine responses to salt depletion, and increased plasma endothelin (5.1 +/- 0.5 fmol/ml compared with 3.7 +/- 0.3 fmol/ml; P < 0.03). In the HARR group, endothelin and aldosterone concentrations were highly correlated, and both correlated with blood pressure and urine protein. In contrast, in the NARR group, endothelin and aldosterone did not correlate between them or with blood pressure, and only endothelin, not aldosterone, correlated with urine protein. Multivariate regression confirmed that the interaction between aldosterone and endothelin was the major predictor of urine protein in the HARR group (r = 0.442), whereas endothelin, renin and their interaction were predictors in the NARR group (r = 0.467). CONCLUSIONS Our results concur with experimental evidence for participation of endothelin in renal damage of angiotensin-dependent hypertension and for that of an endothelin-aldosterone interaction in low-renin hypertension. We propose that combined pharmacological antagonism of endothelin and aldosterone may confer renal protection beyond blood pressure reduction in patients with low-renin hypertension, a population at high risk for hypertensive nephrosclerosis.