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1.
Plasma Renin Concentration is Associated With Hemodynamic Deficiency and Adverse Renal Outcome in Septic Shock.
Nguyen, M, Denimal, D, Dargent, A, Guinot, PG, Duvillard, L, Quenot, JP, Bouhemad, B
Shock (Augusta, Ga.). 2019;(4):e22-e30
Abstract
BACKGROUND In septic shock, both systemic vasodilatation and glomerular arteriole dilatation are responsible for the drop in glomerular filtration observed in early acute kidney injury. Angiotensin II has been shown to act on both mechanisms. Our objective was to evaluate the impact of renin angiotensin system activation, on hemodynamic deficiency and renal outcome in patient with septic shock and to assess whether urinary sodium could be a reliable test for high plasma renin concentration screening. METHODS This was a prospective and observational study. Inclusion criteria were early septic shock (first episode), dose of norepinephrine ≥ 0.25 μg/kg/min, before the start of substitutive corticosteroids. Plasma renin concentration, plasma aldosterone concentration, and urinary sodium were measured at inclusion. Renal outcome, organ deficiency, and 28-day survival were followed. RESULTS Plasma renin concentration was associated with worse hemodynamic deficiency and adverse renal outcome. Natriuresis was associated with shock severity but was not associated with renal outcome. Low natriuresis (< 20 mM) was associated with higher renin concentration. Those two variables were only weakly correlated. CONCLUSION Plasma renin concentration is associated with adverse renal outcome, probably through shock severity and insufficient glomerular efferent arterioles vasoconstriction. An association was observed between low natriuresis and high plasma renin concentration.
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2.
Liraglutide Treatment May Affect Renin and Aldosterone Release.
Sedman, T, Heinla, K, Vasar, E, Volke, V
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2017;(1):5-9
Abstract
Nowadays, GLP-1 receptor agonists are widely used as effective and safe antidiabetic medications. In addition to glucose-dependent insulin secretion, their effects reach beyond glucose control. Previously, it has been shown that acute administration of GLP-1 receptor agonists increases circulating glucocorticoid and mineralocorticoid levels in both humans and rodents. So far, no studies have reported the effects of chronic administration of GLP-1 receptor agonists on the hypothalamic-pituitary-adrenal axis in humans. The aim of the current study was to examine the effects of acute and chronic treatment with the GLP-1 receptor agonist liraglutide on adrenal function in humans. Ten healthy volunteers were recruited into a single group open-label clinical trial. Each participant was tested for baseline levels, and after acute and chronic treatment with 0.6 mg liraglutide daily. A graded glucose infusion test was performed 3 times. We found that aldosterone tended to be suppressed (albeit not statistically different) after acute administration of liraglutide, and increased after chronic dosing; the difference was statistically significant when compared between acute and chronic dosing. Changes in aldosterone levels followed the changes in renin concentrations and the aldosterone-to-renin ratio remained stable. No statistically significant differences were observed in ACTH or cortisol levels. In conclusion, we have shown that a low dose of GLP-1 receptor agonist may interfere with renin and aldosterone release. Further studies in a larger patient sample and with higher doses of GLP-1 receptor agonists are warranted to corroborate this finding. The study protocol was registered at clinical.trials.gov (NCT02089256) and EU Clinical Trial Register (2014-000238-43).
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3.
Does Extremely Low Birth Weight Predispose to Low-Renin Hypertension?
Raaijmakers, A, Zhang, ZY, Claessens, J, Cauwenberghs, N, van Tienoven, TP, Wei, FF, Jacobs, L, Levtchenko, E, Pauwels, S, Kuznetsova, T, et al
Hypertension (Dallas, Tex. : 1979). 2017;(3):443-449
Abstract
UNLABELLED Low birth weight and prematurity are risk factors for hypertension in adulthood. Few studies in preterm or full-term born children reported on plasma renin activity (PRA). We tested the hypothesis that renin might modulate the incidence of hypertension associated with prematurity. We enrolled 93 prematurely born children with birth weight <1000 g and 87 healthy controls born at term, who were all examined at ≈11 years. Renal length and glomerular filtration rate derived from serum cystatin C were 0.28 cm (95% confidence interval, 0.09-0.47) and 11.5 mL/min per 1.73 m2 (6.4-16.6) lower in cases, whereas their systolic/diastolic blood pressure (BP) was 7.5 mm Hg (4.8-10.3)/4.0 mm Hg (2.1-5.8) higher (P<0.001 for all). The odds of having systolic prehypertension or systolic hypertension associated with extreme low birth weight were 6.43 (2.52-16.4; P<0.001) and 10.9 (2.46-48.4; P=0.002). Twenty-four hours of urinary sodium excretion was similar in cases and controls (102.1 versus 106.8 mmol; P=0.47). Sodium load per nephron was estimated as sodium excretion divided by kidney length (mmol/cm). PRA was 0.54 ng/mL per hour (0.23-0.85; P=0.001) lower in cases. PRA, systolic BP, and sodium load were available in 43 cases and 56 controls. PRA decreased with systolic BP (slope -0.022 ng/mL per hour/-mm Hg; P=0.048), but was unrelated to sodium load (slope +0.13 mmol/cm-mm Hg; P=0.54). The slope of PRA on systolic BP was similar (P=0.17) in cases and controls. In conclusion, extremely low birth weight predisposes young adolescents to low-renin hypertension, but does not affect the inverse association between PRA and BP. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147457.
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4.
Obesity and the diagnostic accuracy for primary aldosteronism.
Tirosh, A, Hannah-Shmouni, F, Lyssikatos, C, Belyavskaya, E, Zilbermint, M, Abraham, SB, Lodish, MB, Stratakis, CA
Journal of clinical hypertension (Greenwich, Conn.). 2017;(8):790-797
Abstract
The effects of body mass index on the diagnostic accuracy of primary aldosteronism (PA) are inconsistent and yet important considering the high prevalence and frequent co-occurrence of obesity and hypertension. The current study included 59 adult patients who underwent a stepwise evaluation for PA, using aldosterone to renin ratio for case detection and plasma aldosterone concentration after saline suppression test and/or 24-hour urinary aldosterone after oral sodium loading for case confirmation. Body mass index had a quadratic (U-shaped) correlation with plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, and plasma aldosterone concentration after saline suppression test. Among patients with a body mass index ≥30 kg/m2 , the aldosterone to renin ratio yielded lower case detection accuracy of PA. We conclude that obesity results in a nonlinear correlation with plasma aldosterone concentration, plasma renin activity, and aldosterone to renin ratio, which affects the accuracy of case detection for PA. Patients with a body mass index ≥30 kg/m2 are less accurately identified as having PA when saline suppression and/or oral salt loading tests are used for case confirmation.
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5.
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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6.
Effect of the Arg389Gly β₁-adrenoceptor polymorphism on plasma renin activity and heart rate, and the genotype-dependent response to metoprolol treatment.
Petersen, M, Andersen, JT, Jimenez-Solem, E, Broedbaek, K, Hjelvang, BR, Henriksen, T, Frandsen, E, Forman, JL, Torp-Pedersen, C, Køber, L, et al
Clinical and experimental pharmacology & physiology. 2012;(9):779-85
Abstract
1. A gene-drug interaction has been indicated between β₁-adrenoceptor-selective beta-blockers and the Arg389Gly polymorphism (rs1801253) in the adrenergic beta-1 receptor gene (ADRB1). In the present study, we investigated the effect of the ADRB1 Arg389Gly polymorphism on plasma renin activity (PRA) and heart rate (HR), as well as genotype-dependent responses to metoprolol and exercise. 2. Twenty-nine healthy male subjects participated in two treatment periods (placebo and 200 mg/day metoprolol). A 15 min submaximal exercise test was performed after each treatment period and PRA and HR were measured before and after exercise. 3. Before exercise, median PRA was lower in Gly/Gly subjects than in Arg/Arg subjects after both placebo (P = 0.030) and metoprolol (P = 0.020) treatment. After placebo, the exercise-induced increase in PRA was greater in Gly/Gly than Arg/Gly and Arg/Arg subjects (P = 0.033). The linear association between log(PRA) and log(metoprolol concentration) varied significantly between genotypes (P = 0.024). In Gly/Gly subjects, PRA decreased significantly with metoprolol concentration before (P = 0.025) and after exercise (P < 0.001), whereas in Arg/Gly and Arg/Arg subjects metoprolol concentration had no effect on PRA. The effect of metoprolol concentration on PRA in Gly/Gly subjects was enhanced by exercise (P = 0.044). No significant differences in HR were seen between genotype groups. 4. Resting PRA was lower in Gly/Gly than Arg/Arg subjects and the effect of exercise and metoprolol concentration on PRA was stronger in Gly/Gly subjects than with the other two genotypes. Thus, Gly/Gly heart failure patients may require lower doses of metoprolol than other patients to block neurohumoral hyperactivity.
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7.
Validation of a therapeutic scheme for the treatment of resistant hypertension.
Segura, J, Cerezo, C, Garcia-Donaire, JA, Schmieder, RE, Praga, M, de la Sierra, A, Ruilope, LM
Journal of the American Society of Hypertension : JASH. 2011;(6):498-504
Abstract
We tested the hypothesis that a therapeutic strategy of substituting the diuretic (most commonly hydrochlorothiazide) with chlorthalidone (50 mg/day), and, if needed, the calcium channel blocker with the highest dose of the most commonly used calcium antagonist (amlodipine 10 mg), and adding on top a direct renin inhibitor (aliskiren 300 mg) is effective to treat resistant hypertensive patients not responding to spironolactone. The scheme was tested in a group of 76 patients who had true treatment resistant hypertension (24-hour mean blood pressure ≥130/80 mm Hg while receiving three or more drugs). An effective response to spironolactone was defined as 24-hour ambulatory systolic blood pressure (SBP) drop by more than 20 mm Hg, and was obtained with 25-50 mg in 60 patients (78.9%). In patients with inadequate response to spironolactone (n = 16), we administered the triple combination plus the remaining therapy, a mean decrease of 29 mm Hg (95% CI 11-48; P = .004) for SBP and 12 mm Hg (95% CI: 4-20 mm Hg) for diastolic BP were observed. In only 1 of 16 patients (6%), the response was considered as insufficient. These data indicate the need for further testing this scheme that looks really promising to treat resistant hypertensive patients not responding to spironolactone.
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8.
25-Hydroxyvitamin D is associated with plasma renin activity and the pressor response to dietary sodium intake in Caucasians.
Vaidya, A, Forman, JP, Hopkins, PN, Seely, EW, Williams, JS
Journal of the renin-angiotensin-aldosterone system : JRAAS. 2011;(3):311-9
Abstract
INTRODUCTION Concentrations of 1,25-hydroxyvitamin D have been positively associated with dietary sodium and salt sensitivity (SS) of blood pressure (BP), and inversely with plasma renin activity (PRA). We investigated the association between PRA and 25-hydroxyvitamin D (25OHD), the most clinically relevant vitamin D metabolite, and whether 25OHD associates with SS of BP in renin phenotypes of hypertension. METHODS We performed cross-sectional analyses on 223 Caucasian subjects with hypertension maintained in high and low dietary sodium balance. Subjects were distinguished as having low-renin (LR) or normal-renin (NR) hypertension. Multivariable linear regression was used to evaluate adjusted relationships. RESULTS Increasing 25OHD concentrations were inversely associated with PRA (p < 0.05) on both salt diets. Furthermore, 25OHD was associated with SS of BP in LR hypertension (b = 0.62, p = 0.04), but not in NR hypertension (b = 0.06, p = 0.59). In an adjusted multivariable interaction model, renin status (LR vs. NR) was a significant effect modifier of the relationship between 25OHD and SS of BP (p = 0.04). CONCLUSIONS Our findings suggest that 25OHD is inversely associated with PRA and positively associated with SS of BP in LR hypertension subjects. These results extend and support prior evidence indicating an interaction between dietary sodium, the RAS, and vitamin D that influences BP in hypertension.
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9.
Normotensive sodium loading in normal man: regulation of renin secretion during beta-receptor blockade.
Mølstrøm, S, Larsen, NH, Simonsen, JA, Washington, R, Bie, P
American journal of physiology. Regulatory, integrative and comparative physiology. 2009;(2):R436-45
Abstract
Saline administration may change renin-angiotensin-aldosterone system (RAAS) activity and sodium excretion at constant mean arterial pressure (MAP). We hypothesized that such responses are elicited mainly by renal sympathetic nerve activity by beta1-receptors (beta1-RSNA), and tested the hypothesis by studying RAAS and renal excretion during slow saline loading at constant plasma sodium concentration (Na+ loading; 12 micromol Na+.kg(-1).min(-1) for 4 h). Normal subjects were studied on low-sodium intake with and without beta1-adrenergic blockade by metoprolol. Metoprolol per se reduced RAAS activity as expected. Na+ loading decreased plasma renin concentration (PRC) by one-third, plasma ANG II by one-half, and plasma aldosterone by two-thirds (all P < 0.05); surprisingly, these changes were found without, as well as during, acute metoprolol administration. Concomitantly, sodium excretion increased indistinguishably with and without metoprolol (16 +/- 2 to 71 +/- 14 micromol/min; 13 +/- 2 to 55 +/- 13 micromol/min, respectively). Na+ loading did not increase plasma atrial natriuretic peptide, glomerular filtration rate (GFR by 51Cr-EDTA), MAP, or cardiac output (CO by impedance cardiography), but increased central venous pressure (CVP) by approximately 2.0 mmHg (P < 0.05). During Na+ loading, sodium excretion increased with CVP at an average slope of 7 micromol.min(-1).mmHg(-1). Concomitantly, plasma vasopressin decreased by 30-40% (P < 0.05). In conclusion, beta1-adrenoceptor blockade affects neither the acute saline-mediated deactivation of RAAS nor the associated natriuretic response, and the RAAS response to modest saline loading seems independent of changes in MAP, CO, GFR, beta1-mediated effects of norepinephrine, and ANP. Unexpectedly, the results do not allow assessment of the relative importance of RAAS-dependent and -independent regulation of renal sodium excretion. The results are compatible with the notion that at constant arterial pressure, a volume receptor elicited reduction in RSNA via receptors other than beta1-adrenoceptors, decreases renal tubular sodium reabsorption proximal to the macula densa leading to increased NaCl concentration at the macula densa, and subsequent inhibition of renin secretion.
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10.
A study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with allopurinol, celecoxib and cimetidine in healthy subjects.
Ayalasomayajula, S, Tchaloyan, S, Yeh, CM, Bizot, MN, Dieterich, HA, Howard, D, Dole, WP
Current medical research and opinion. 2008;(3):717-26
Abstract
OBJECTIVE Aliskiren is the first in a new class of orally effective direct renin inhibitors approved for the treatment of hypertension. This multiple-dose study investigated the potential for pharmacokinetic interactions between aliskiren and three drugs, each predominantly eliminated by a different clearance/metabolic pathway: allopurinol (glomerular filtration), celecoxib (cytochrome P450 metabolism) and cimetidine (P-glycoprotein and organic anion/cation transporters). RESEARCH DESIGN AND METHODS Three open-label, multiple-dose studies in healthy subjects investigated possible pharmacokinetic interactions between aliskiren 300 mg od and allopurinol 300 mg od (n = 20), celecoxib 200 mg bid (n = 22), or cimetidine 800 mg od (n = 22). Subjects received aliskiren alone or co-administered with allopurinol, celecoxib or cimetidine. Allopurinol and celecoxib were also administered alone and in combination with aliskiren. Plasma drug concentrations were determined by LC/MS/MS. RESULTS Co-administration of aliskiren with allopurinol had no effect on allopurinol AUC(tau) (ratio of geometric means 0.93 [90% CI, 0.88, 0.98]) or oxypurinol AUC(tau) (mean ratio 1.12 [90% CI, 1.08, 1.16]) and C(max) (mean ratio 1.08 [90% CI, 1.04, 1.13]), with 90% CI within the bioequivalence range 0.80-1.25, and a minor effect on allopurinol C(max) (mean ratio 0.88 [90% CI, 0.78, 1.00]). Aliskiren co-administration had no effect on AUC(tau) or C(max) of celecoxib (mean ratios and 90% CI within range 0.80-1.25). Neither allopurinol nor celecoxib significantly altered aliskiren AUC(tau) or C(max) (geometric mean ratios 0.88-1.02 with 90% CI including 1.00, but with some 90% CI outside the 0.80-1.25 range due to high variability). Co-administration of aliskiren with cimetidine increased aliskiren AUC(tau) by 20% (mean ratio 1.20 [90% CI, 1.07, 1.34]) and C(max) by 25% (mean ratio 1.25 [90% CI, 0.98, 1.59]). CONCLUSIONS In this multiple-dose study, aliskiren showed no clinically relevant pharmacokinetic interactions when co-administered with allopurinol, celecoxib or cimetidine in healthy subjects.