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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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Low-Renin Hypertension.
Athimulam, S, Lazik, N, Bancos, I
Endocrinology and metabolism clinics of North America. 2019;(4):701-715
Abstract
Low-renin hypertension affects 30% of hypertensive patients. Primary hyperaldosteronism presents with low renin and aldosterone excess. Low-renin, low-aldosterone hypertension represents a wide spectrum of disorders that includes essential low-renin hypertension, hereditary forms of hypertension, and hypertension secondary to endogenous or exogenous factors. This review addresses the different conditions that present with low-renin hypertension, discussing an appropriate diagnostic approach and highlighting the genetic subtypes within familial forms.
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Efficacy and Safety of Dual Blockade of the Renin-Angiotensin-Aldosterone System in Diabetic Kidney Disease: A Meta-Analysis.
Feng, Y, Huang, R, Kavanagh, J, Li, L, Zeng, X, Li, Y, Fu, P
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2019;(3):259-286
Abstract
INTRODUCTION Current guidelines recommend renin-angiotensin-aldosterone system (RAAS) inhibitors in the treatment of diabetic kidney disease (DKD). However, evidence suggests that the combined use of RAAS blockers may be associated with increased rates of adverse events. OBJECTIVES Our objective was to examine the efficacy and safety of dual blockade of the RAAS in patients with DKD. METHODS This was a systematic review and meta-analysis of randomized controlled trials (RCTs) published between January 1990 and January 2018 sourced via the PubMed, EMBASE, and Cochrane Library databases. RCTs were included if they investigated the efficacy and safety of dual blockade therapy compared with monotherapy in patients with DKD. Random effects models were used in meta-analysis to account for heterogeneities in effect sizes across the reviewed studies. Analyses were stratified by blood pressure and albuminuria. We further conducted subgroup analyses by considering various combinations of RAAS inhibitors. RESULTS Based on 42 RCTs with 14,576 patients, dual RAAS blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup. The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria. CONCLUSION Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction, though such superiority does not translate into improvements in longer-term outcomes, such as reduced progression to ESRD, all-cause mortality, and cardiovascular mortality. An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD, and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria.
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P-glycoprotein influences urinary excretion of aldosterone in healthy individuals.
Marques, P, Courand, PY, Gouin-Thibault, I, Zhygalina, V, Bergerot, D, Salem, JE, Funck-Brentano, C, Loriot, MA, Azizi, M, Blanchard, A
Journal of hypertension. 2019;(11):2225-2231
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OBJECTIVES P-glycoprotein (P-gp), the product of the ABCB1 gene, is involved in the transport of aldosterone and cortisol in adrenal cells in vitro but its physiological role in humans remains controversial. Our objective was to test the influence of P-gp polymorphisms on aldosterone. METHODS We evaluated plasma aldosterone concentration (PAC), urinary aldosterone, and blood pressure in a cohort of white normotensive men at baseline on diets unrestricted for sodium and potassium and after a 5-day treatment with 500 mg b.i.d. clarithromycin, a P-gp inhibitor. Included were 20 homozygous wild-type (P-gp0), 20 heterozygous (P-gp1), and 20 individuals with combined 2677G>T/A-3435C>T loss-of-function polymorphism of the ABCB1 gene (P-gp2). RESULTS At baseline, PAC, urinary aldosterone, urinary free cortisol to urine creatinine ratios, and blood pressure did not differ in the three genotypes. After clarithromycin administration, the urinary aldosterone to creatinine ratio increased by an average of 30% in the entire cohort (P < 0.001, n = 60). Increases were pronounced in P-gp1 (+40%; P = 0.014) and P-gp2 individuals (+50%; P = 0.020) but lesser and were NS in P-gp0 individuals (+10%; P = 0.259). PAC also increased from baseline after clarithromycin treatment in all individuals (+19%, P = 0.050); however, the increase in PAC was NS when the three genotypes were analyzed separately. CONCLUSION In our experimental conditions, the interaction between P-gp inhibition and the ABCB1 genotype, suggests that aldosterone is indeed a physiological endogenous substrate of P-gp in humans and that P-gp interferes with the net equilibrium between aldosterone secretion and elimination processes in humans.Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01627665.
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Change in renal function associated with drug treatment in heart failure: national guidance.
Clark, AL, Kalra, PR, Petrie, MC, Mark, PB, Tomlinson, LA, Tomson, CR
Heart (British Cardiac Society). 2019;(12):904-910
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Inhibitors of the renin-angiotensin-aldosterone (RAAS) system are cornerstones of the management of patients with heart failure with reduced left ventricular ejection fraction (HFrEF). However, RAAS inhibitors may cause decline in renal function and/or hyperkalaemia, particularly during initiation and titration, intercurrent illness and during worsening of heart failure. There is very little evidence from clinical trials to guide the management of renal dysfunction. The Renal Association and British Society for Heart Failure have collaborated to describe the interactions between heart failure, RAAS inhibitors and renal dysfunction and give clear guidance on the use of RAAS inhibitors in patients with HFrEF. During initiation and titration of RAAS inhibitors, testing renal function is mandatory; a decline in renal function of 30% or more can be acceptable. During intercurrent illness, there is no evidence that stopping RAAS inhibitor is beneficial, but if potassium rises above 6.0 mmol/L, or creatinine rises more than 30%, RAAS inhibitors should be temporarily withheld. In patients with fluid retention, high doses of diuretic are needed and a decline in renal function is not an indication to reduce diuretic dose: if the patient remains congested, more diuretics are required. If a patient is hypovolaemic, diuretics should be stopped or withheld temporarily. Towards end of life, consider stopping RAAS inhibitors. RAAS inhibition has no known prognostic benefit in heart failure with preserved ejection fraction. Efforts should be made to initiate, titrate and maintain patients with HFrEF on RAAS inhibitor treatment, whether during intercurrent illness or worsening heart failure.
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Dual RAAS Blockade with Aliskiren in Patients with Severely Impaired Chronic Kidney Disease.
Rasche, FM, Joel, C, Ebert, T, Frese, T, Barinka, F, Busch, V, Rasche, WG, Lindner, TH, Schneider, J, Schiekofer, S
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2018;(1):39-52
Abstract
Dual renin-angiotensin-aldosterone blockade (dRAASb) is purposed in the prevention of the cardiorenal syndrome (CRS). However, all attempts with dRAASb even in patients with moderate impaired chronic kidney disease (CKD) were terminated due to the typical severe adverse events (SAE), e. g., hyperkalemia and rise of serum creatinine. The aim of our study with the direct renin inhibitor aliskiren was to evaluate the effect of dRAASb with a washout phase in patients with severely advanced CKD. We have studied 45 patients (G3b to 4, A2 and >A3; median glomerular filtration rate (GFR) CKD-EPI 31 (23-40) ml/min per 1.73 m² BSA (body surface area), albumin-creatinine-ratio in urine (UACR) (0.413 (0.164 to 1.39) g/g) and proteinuria (0.5 (0.2 to 0.9) g/l) before, with and without aliskiren (150 respectively 300 mg per day) added to an angiotensin-converting enzyme inhibitor (ACEi) or an AT1-receptor blocker (ARB) over 4 ½ years. The dRAASb with aliskiren showed a significant decrease of proteinuria (0.5 to 0.38 g/l), especially in patients with an UACR≥350 mg/g and in the subgroup analysis e. g., in patients with diabetes, but proteinuria increased in the washout phase again. The blood pressure (130/80 mm Hg), serum potassium (4.9 to 5.0 mmol/l) and GFR remained nearly constant (31 to 29.5 ml/min per 1.73 m2 BSA). A more than 30% increase in serum creatinine was associated with an UACR>300 mg/g. The dRAASb has beneficial effects on proteinuria and is safe in patients with severely advanced CKD. However, in patients with high UACR (>300 mg/g) raise of creatinine and potassium have to be controlled.
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The relationship between plasma renin activity and serum lipid profiles in patients with primary arterial hypertension.
Pizoń, T, Rajzer, M, Wojciechowska, W, Wach-Pizoń, M, Drożdż, T, Wróbel, K, Gruszka, K, Rojek, M, Kameczura, T, Jurczyszyn, A, et al
Journal of the renin-angiotensin-aldosterone system : JRAAS. 2018;(4):1470320318810022
Abstract
INTRODUCTION The aim of the study was to evaluate clinical and biochemical differences between patients with low-renin and high-renin primary arterial hypertension (AH), mainly in reference to serum lipids, and to identify factors determining lipid concentrations. MATERIALS AND METHODS In untreated patients with AH stage 1 we measured plasma renin activity (PRA) and subdivided the group into low-renin (PRA < 0.65 ng/mL/h) and high-renin (PRA ⩾ 0.65 ng/mL/h) AH. We compared office and 24-h ambulatory blood pressure, serum aldosterone, lipids and selected biochemical parameters between subgroups. Factors determining lipid concentration in both subgroups were assessed in regression analysis. RESULTS Patients with high-renin hypertension ( N = 58) were characterized by higher heart rate ( p = 0.04), lower serum sodium ( p < 0.01) and aldosterone-to-renin ratio ( p < 0.01), and significantly higher serum aldosterone ( p = 0.03), albumin ( p < 0.01), total protein ( p < 0.01), total cholesterol ( p = 0.01) and low-density lipoprotein cholesterol (LDL-C) ( p = 0.04) than low-renin subjects ( N = 39). In univariate linear regression, only PRA in the low-renin group was in a positive relationship with LDL-C ( R2 = 0.15, β = 1.53 and p = 0.013); this association remained significant after adjustment for age, sex, and serum albumin and aldosterone concentrations. CONCLUSIONS Higher serum levels of total and LDL-C characterized high-renin subjects, but the association between LDL-C level and PRA existed only in low-renin primary AH.
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Renin-Angiotensin-Aldosterone Profiles in Pregnant Women With Chronic Hypertension.
Malha, L, Sison, CP, Helseth, G, Sealey, JE, August, P
Hypertension (Dallas, Tex. : 1979). 2018;(2):417-424
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Pregnant women with chronic hypertension are at risk for increased blood pressure and superimposed preeclampsia (SPE) in late pregnancy. Alterations in the renin-aldosterone system are a feature of normal pregnancy; however, their role in chronic hypertension with and without SPE is less clear. We performed a prospective, longitudinal trial of 108 women with chronic hypertension and measured plasma renin activity (PRA), 24-hour urine sodium, urine potassium, and urine aldosterone (Ualdo) at 12, 20, 28, and 36 weeks and postpartum. SPE developed in 34% of pregnancies. PRA was lower in women who developed SPE at weeks 28 (5.99 versus 6.22 ng/mL per hour; P<0.001) and 36 (5.71 versus 7.74 ng/mL per hour; P=0.002). Ualdo was lower in women with SPE compared with those without SPE at 28 weeks (59.6 versus 81.3 μg/d; P=0.039). Mean arterial pressure was inversely related to both PRA (r=-0.23; P<0.0001) and Ualdo (r=-0.11; P=0.029). PRA and Ualdo were positively associated with each other (r=0.5327; P<0.0001) after adjusting for urine potassium, urine sodium, serum potassium, and mean arterial pressure. PRA and Ualdo were lower in women of black race compared with other racial groups (P<0.001). Our results demonstrate that in women with chronic hypertension PRA and Ualdo increase in early pregnancy and subsequently decrease in women who develop SPE. These findings are consistent with the hypothesis that sodium retention may contribute to the elevation in blood pressure in SPE.
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Effect of Vitamin D therapy on urinary albumin excretion, renal functions, and plasma renin among patients with diabetic nephropathy: A randomized, double-blind clinical trial.
Liyanage, P, Lekamwasam, S, Weerarathna, TP, Liyanage, C
Journal of postgraduate medicine. 2018;(1):10-15
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BACKGROUND Despite different management strategies, progression of proteinuria occurs in a sizable category of patients with diabetic nephropathy (DN). Increase in serum renin levels induced by the renin-angiotensin system (RAS) may contribute to this. Vitamin D therapy is found to have an inhibitory effect on the RAS. We aimed to study the effects of Vitamin D therapy on renal functions of patients with DN. METHODS This was a double-blind, randomized, placebo-controlled study. Patients with DN (urinary albumin [UA] >30 mg/g of creatinine) whose estimated glomerular filtration rate (eGFR) was more than 30 mL/min were selected and their plasma renin, parathyroid hormone, serum Vitamin D, serum calcium, serum creatinine, fasting blood sugar were done as baseline measurements. Subjects were randomized into two groups and treatment group was given Vitamin D, 50000 IU (0.25 ml) intramuscularly (IM) monthly for 6 months; control group received distilled water IM. Investigations were repeated after 6 months of therapy. RESULTS Of 155 patients invited, 85 were randomly assigned to two groups. After 6 months, mean reduction of UA to creatinine ratio in the treatment and control group was 51.8 mg/g (95% confidence interval [CI]; 66.1--37.5, P ≤ 0.001); 22.4 mg/g (95% CI; -45.7-0.8, P = 0.06), respectively (between group difference P = 0.001). Significant increase in the eGFR observed in the treatment group while eGFR remained unchanged in the control group (P = 0.03 for the between-group difference). Mean reduction in plasma renin in treatment group and control group was 5.85 pg/mL (95% CI; -6.7--4.6) (P < 0.001) and 0.95 pg/mL (95% CI; -1.4--0.14, P = 0.02), respectively. CONCLUSIONS Vitamin D 50000 IU given IM monthly for 6 months reduces urine albumin, serum creatinine, and renin levels in patients with DN.
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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).