Plasma Renin Activity Concentration Research Articles

The effect of spironolactone versus eplerenone on blood pressure targets in resistant hypertension patients

Abstract Objective to evaluate different effects on blood pressure (BP) control in two treatment options spironolactone (SPIR) versus eplerenone (EPL) as an add-on therapy in resistant hypertensive (RAH) patients. Design and methods: We studied 208 patients with true RAH confirmed by the office and ambulatory BP monitoring (ABPM) despite the use of 3 antihypertensive medications including a calcium channel blocker, a blocker of the renin-angiotensin system, and a thiazide diuretic with maximally tolerated doses for at least 3 months. Patients were randomized into 2 groups throughout 12 weeks of once-daily treatment with SPIR (25–50 mg) or EPL (25-50 mg) in addition to their baseline triple-combination and then rotated with drugs. BP was measured in the office and by ABPM. Changes in laboratory tests were also studied. The predictive values of plasma aldosterone, active renin concentration (ARC), aldosterone-renin ratio (ARR), and serum potassium were analyzed to determine the antihypertensive response. Results There were no significant differences in the reduction of average office BP, average systolic 24-h, daytime, and nighttime BP by SPIR and EPL. SPIR reduced average diastolic 24-h BP by 7.3 mm Hg, diastolic daytime BP by 7.2 mm Hg, and diastolic nighttime BP by 7.5 mm Hg compared with a reduction of 5.6 mm Hg (P = 0.01), 5.6 mm Hg (P = 0.03) and 4.2 mm Hg (P = 0.0001) with EPL, respectively. Overall, 40.7 % RAH patients achieved targets of clinical BP and 24-h ABPM levels on SPIR and 33.3 % on EPL (Р = 0.002). After 12 weeks of treatment mean plasma potassium concentrations increased by 7.1 (P = 0.0001) on SPIR and by 5.0 % (Р = 0.0001) on EPL, but eGFR did not significantly change on the two drugs. Plasma aldosterone (β = 0.498, Р = 0.02) and ARC (β= -0.374, Р = 0.04) were predictors of the BP-lowering effect of SPIR and plasma aldosterone (β = 0.453, Р = 0.04) was a predictor of reduction BP for EPL in multivariate modeling. Breast pain or tenderness, changes in sex drive, and irregular menstrual cycles or spotting were more often by SPIR than by EPL (5.2 % vs 1.9 %, respectively, P = 0.04). Conclusions The greater antihypertensive effect of SPIR is related to aldosterone status, ARS level in resistant hypertension. EPL may be recommended for RAH patients who have high serum potassium levels that cannot tolerate spironolactone and for people with systolic resistant hypertension.

The effect of age, sex and BMI on the aldosterone-to-renin ratio in essential hypertensive individuals.

The aldosterone-to-renin ratio (ARR) is widely used as a screening test for primary aldosteronism, but its determinants in patients with essential hypertension are not fully known. The purpose of the present investigation is to identify the impact of age, sex and BMI on renin, aldosterone and the ARR when measured under strict, standardized conditions in hypertensive patients without primary aldosteronism. We analysed the data of 423 consecutive hypertensive patients with no concomitant cardiac or renal disorders from two different hospitals (Rotterdam and Maastricht) who had been referred for evaluation of their hypertension. Those who were diagnosed with secondary causes of hypertension, including primary aldosteronism, were excluded from analysis. Patients who used oral contraceptives or had hormonal replacement therapy were excluded as well. Plasma aldosterone concentration (PAC), active plasma renin concentration (APRC) and the ARR were measured under standardized conditions. All measurements were taken in the supine position at 10.00 h in the morning, with one subgroup of patients adhering to a sodium-restricted diet (55 mmol/day) for no less than 3 weeks, and the other subgroup maintaining an ad libitum diet. In those who were receiving antihypertensive treatment, all medications were discontinued at least 3 weeks before testing. In neither group did aldosterone correlate with age. Renin, however, was inversely related to age both during low-salt diet ( P < 0.001) and during ad lib salt intake ( P = 0.05). This resulted in a significant positive correlation between age and the ARR in both groups. Although on both dietary regimens, PAC and APRC were significantly higher in men when compared with women, the ARR was not significantly different between the two sexes. The age-relationships of renin and the ARR were comparable in men and women on both diets, albeit with greater variability in women. There was an upward trend between BMI and the ARR, which reached statistical significance only in men on low-salt diet. In multivariable regression analysis, age remained the only independent determinant of the ARR. In our essential hypertensive population, the ARR increased significantly with age but was not affected by sex or BMI.

Renin Trajectories and Outcome in Stable Heart Failure with Reduced Ejection Fraction (HFrEF) on Contemporary Therapy: A Monocentric Study from an Austrian Tertiary Hospital Outpatient Clinic

Introduction. The renin-angiotensin system (RAS) is the main target of neurohumoral therapy in heart failure with reduced ejection fraction (HFrEF) effectively reducing mortality. Reasonably, renin might serve as a biomarker for risk prediction and therapy response. Renin indeed bears some additional value to clinical risk models, albeit the effect is not pronounced. Whether assessing renin trajectories can overcome the weaknesses of single renin measurements has not been reported. Methods. A total of 505 patients with stable HFrEF were enrolled prospectively and followed through routine clinical visits. Active plasma renin concentration was documented up to 5 years. Changes in renin were analyzed throughout the disease course, and survival was compared for different renin trajectories within the first year. Results. Baseline renin levels were not related to all-cause mortality (crude HR for an increase of 100 μiE/ml: 1.01 (95% CI: 0.99–1.02), [Formula: see text]) but associated with unplanned HF hospitalizations (crude HR: 1.01 (95% CI: 1.00-1.02), [Formula: see text]). Renin increased during the disease course from baseline to 1-year and 2-year FUP (122.7 vs. 185.6 μIU/ml, [Formula: see text], and 122.7 vs. 258.5 μIU/ml, [Formula: see text]). Both survival and unplanned HF hospitalization rates were comparable for different renin trajectories at 1-year FUP ([Formula: see text], [Formula: see text]). Conclusions. Intriguingly, renin is not a good biomarker to indicate prognosis in HF, while renin trajectories over a 1-year period do not have an additional value. Rapid physiologic plasma renin variations, but also opposing effects of angiotensinogen-derived metabolites under presence of RAS blockade, might obscure the predictive ability of renin.

Temporal evolution of the key neurohumoral regulator renin in chronic stable HFrEF

Abstract Background Renin is the enzyme catalyzing the rate-limiting step of the Renin-Angiotensin-System (RAS) generating Angiotensin II (AngII). RAS inhibitors are a main pillar of current heart failure with reduced ejection fraction (HFrEF). Although used since over 30 years in clinical routine, the studied effects of RAS-inhibitors on renin level changes during the course of HFrEF and its impact on patient outcomes, especially under current guideline directed medical therapy (GDMT), are lacking. Methods Consecutive patients with stable chronic HFrEF and GDMT were enrolled prospectively from the our outpatient unit of heart failure between 06/2013 and 08/2021. Active plasma renin concentration (ARC) was documented for all patients consecutively at first measurement, i.e. baseline (BL), and at follow-up (FUP) visits at 12, 24, 36, 48 and 60 months, respectively. BL renin was correlated with N-terminal pro B-type natriuretic peptide (NT-proBNP) and compared between NYHA class, HF medication use and renin levels between baseline and FUP timepoints. To assess the effect of changes in renin levels, patients were categorized into three groups based on the change of renin from baseline within the first year of observation: decrease = change &amp;gt;−50%, undulating=change between −50 to 50%, increase=change&amp;gt;50% and survival curves were displayed as Kaplan-Meier plots and compared for different ARC categories by the log-rank test. Results A total of 491 patients were included in the study. BL characteristics are shown in Table1. Renin levels showed no relationship with HF severity reflected by a lack of correlation with NT-proBNP [rs=−0.05, p=0.273] and comparable levels between NYHA groups [p=0.753] (Figure 1A). Renin levels were further comparable for different RAS inhibitors and patients with and without beta blockers, however higher in patients with mineralocorticoid receptor antagonists (MRA) [189 μIE/ml vs. 59 μIE/ml, p=0.0001] and SGLT2-inhibitors [280 μIE/ml vs. 100 μIE/ml, p=0.004] (Figure 1B). Renin levels at different yearly FUP timepoints are displayed in Figure 1C. There was no significant difference in renin levels between BL and 1-year FUP, while renin concentration was increased at 2-year FUP [126 μIE/ml vs. 243 μIE/ml, p=0.002]. Baseline renin levels were not associated with survival [crude HR for an increase of 100μiE/ml 1.014 (95% CI: 0.997–1.032), p=0.102]. Within one year following BL, renin decreased in 77 (27.6%), was undulating in 74 (26.5%) and increased in 128 (45.9%) patients. Kaplan-Meier suggests worse survival for patients with increasing renin though the difference was statistically not significant [p=0.2573] (Figure 1D). Conclusion Renin was elevated in patients with MRA and/or SGLT2-inhibitors. Renin tends to increase over time in stable HFrEF. Although RAS is the main target of HFrEF therapy, surprisingly there seems to be no strong association between RAS activation and thereby potential effectivity of achieved RAS-blockade and outcome. Funding Acknowledgement Type of funding sources: None.

Variability of aldosterone, renin and the aldosterone-to-renin ratio in hypertensive patients without primary aldosteronism.

The aldosterone-to-renin ratio (ARR) is commonly used in the screening of primary aldosteronism. However, limited information is available with regard to the intra-patient variability in this ratio. Our objective is to determine whether ARR measurements are reliably consistent over both the short- and long-term. We assessed the short-term variability of the aldosterone-to-renin ratio in 116 unmedicated, essential hypertensive participants who had two blood samples taken in the morning of the same day for measurement of aldosterone and active plasma renin concentration. Long-term variability was studied in 22 unmedicated, essential hypertensive participants who had two blood samples taken approximately 1 year apart. All samples were taken under highly standardized conditions. Our data show that renin, aldosterone and the aldosterone-to-renin ratio show marked variations, both when measured on the same day and when assessed at a longer interval. The ARR becomes increasingly variable as its mean value increases. Its degree of variability is similar in both the short-term and the long-term. Based on our findings, we conclude that the aldosterone-to-renin has acceptable short-term variability in the lower ranges, but increasingly dubious reliability as aldosterone-to-renin values rise. Thus, in a clinical context, great caution should be taken in interpreting point-measurements of moderate to high aldosterone-to-renin ratio values.

Association of renin and aldosterone with glucose metabolism in a Western European population: the KORA F4/FF4 study

IntroductionPrimary aldosteronism is associated with impaired glucose tolerance. Whether plasma aldosterone and/or renin concentrations are associated with type 2 diabetes and continuous measures of glucose metabolism in the general population...

Renal Hemodynamics and Renin-Angiotensin-Aldosterone System Profiles in Patients With Heart Failure

Understanding cardiorenal pathophysiology in heart failure (HF) is of clinical importance. We sought to characterize the renal hemodynamic function and the transrenal gradient of the renin-angiotensin-aldosterone system (RAAS) markers in patients with HF and in controls without HF. In this post hoc analysis, the glomerular filtration rate (GFRinulin), effective renal plasma flow (ERPFPAH) and transrenal gradients (arterial-renal vein) of angiotensin converting enzyme (ACE), aldosterone, and plasma renin activity (PRA) were measured in 47 patients with HF and in 24 controls. Gomez equations were used to derive afferent (RA) and efferent (RE) arteriolar resistances. Transrenal RAAS gradients were also collected in patients treated with intravenous dobutamine (HF, n = 11; non-HF, n = 11) or nitroprusside (HF, n = 18; non-HF, n = 5). The concentrations of PRA, aldosterone and ACE were higher in the renal vein vs the artery in patients with HF vs patients without HF (P < 0.01). In patients with HF, a greater ACE gradient was associated with greater renal vascular resistance (r = 0.42; P 0.007) and greater arteriolar resistances (RA: r = 0.39; P = 0.012; RE: r = 0.48; P = 0.002). Similarly, a greater aldosterone gradient was associated with lower GFR (r = -0.51; P = 0.0007) and renal blood flow (RBF), r = -0.32; P = 0.042) whereas greater PRA gradient with lower ERPF (r = -0.33; P = 0.040), GFR (r = -0.36; P = 0.024), and RBF (r = -0.33; P = 0.036). Dobutamine and nitroprusside treatment decreased the transrenal gradient of ACE (P = 0.012, P < 0.0001, respectively), aldosterone (P = 0.005, P = 0.030) and PRA (P = 0.014, P = 0.002) in patients with HF only. A larger transrenal RAAS marker gradient in patients with HF suggests a renal origin for neurohormonal activation associated with a vasoconstrictive renal profile.

SHORT-TERM VARIABILITY OF THE ALDOSTERONE-TO-RENIN RATIO IN AN ESSENTIAL HYPERTENSIVE POPULATION

Objective: The aldosterone-to-renin ratio (ARR) is a commonly used metric in the screening of primary aldosteronism. However, insufficient high-quality research evaluating its precision and accuracy is available. In particular, limited information is known with regard to intra-patient short-term variability in the ARR. Highly variable intra-patient values could severely hamper the ability of the ARR to effectively screen for primary aldosteronism. Design and method: 68 unmedicated, essential hypertensive participants (female n = 26, male n = 42), had two blood samples taken in the morning measuring plasma aldosterone and active plasma renin concentration within a 2-hour time window under strictly standardised conditions and while consuming a regulated sodium intake (3 g/day). Bland-Altman plots, mountain plots and correlation analysis were performed, comparing the mean values per participant with the difference between their measurements. Results: Using Bland-Altman plots, we found that renin, aldosterone and the ARR become increasingly variable as their mean values increase. Correlation analysis of the absolute difference in aldosterone-to-renin ratio values between measurements and their mean resulted in an R-squared value of 34.7% (p-value &lt; 0.000)). This trend was also noted for plasma aldosterone (R-squared 9.6%; p-value 0.010) and active plasma renin concentration (R-squared 7.9%; p-value 0.021) separately. Taking an ARR value above 30 as abnormally high, 29.4% of the participants with a mean value above 30, had one measurement below 30. Conversely, 3.9% of those with mean values below 30 had one measurement above 30. Conclusions: Based on our findings, it can be concluded that spot measurements of the aldosterone-to-renin ratio have acceptable short-term variability in the lower ranges, but have increasingly doubtful reliability as aldosterone-to-renin values rise. Thus, in a clinical context, great caution should be taken in interpreting spot measurements of moderate to high aldosterone-to-renin ratio values, in particular when values are mildly elevated.

THE EFFECT OF THE MENSTRUAL CYCLE ON RENIN, ALDOSTERONE AND ALDOSTERONE-TO-RENIN RATIO IN FORMERLY PREECLAMPTIC AND HEALTHY WOMEN

Abstract Objective: The aldosterone-to-renin ratio (ARR) is widely used as a screening test for primary aldosteronism (PA) in patients with hypertension. The purpose of the present original investigation is to identify the impact hormonal changes have on renin, aldosterone, and the ARR during the menstrual cycle of premenopausal women when measured in strict standardised conditions. Design and method: We analysed 59 women with a history of preeclampsia and 6 healthy parous controls. Blood values were determined during both follicular and luteal phases of the menstrual cycle (days 1 and 14 respectively). Plasma aldosterone, active plasma renin concentration (APRC) and the ARR were measured under standardised conditions. All measurements were taken in the supine position at 9am, all patients maintained a standardised sodium diet (100 mmol/day) for no less than two weeks. In those who were receiving antihypertensive medications (n = 2), all medications were discontinued at least 1 week prior to screening. Results: When performing the Friedman's Test and the Wilcoxon signed rank test in formerly preeclamptic women (n = 59), aldosterone and renin were both significantly elevated in the luteal phase (mean rank aldosterone 1.2 and 1.8 p0.000 Z-4.7, mean rank renin 1.23 and 1.77 p0.000 Z -4.5, respectively), however the ARR values did not significantly differ between phases (mean rank 1.53 and 1.47 p0.7 Z-0.14). When performing the Friendman's Test in the control group (n = 6), the difference in aldosterone, renin and the ARR between the follicular and luteal phase was not significant (p0.059 for all parameters). Wilcoxon signed test revealed a significant difference in aldosterone (Z-2.02 p0.04), but the difference in renin and the ARR remained insignificant (p0.06). Conclusions: In this study of premenopausal women we found that both renin and aldosterone are significantly affected by the menstrual cycle. However the resulting ARR was not statistically significantly altered. Our study indicates that it is not necessary to take the menstrual phase of patients into account when performing and interpreting the ARR as a screening test for PA in patients with a history of preeclampsia.

CONTROL OF ANTIHYPERTENSIVE EFFECT MEDIATED BY SMALL INTERFERING RNA TARGETING ANGIOTENSINOGEN

Objective: A single dose of small interfering ribonucleic acids (siRNA) targeting angiotensinogen (AGT) provides a strong and durable antihypertensive effect, lasting weeks to months in preclinical models. Here, we investigated whether conventional vasopressors can elevate arterial pressure under conditions of AGT depletion and reverse RNAi-mediated blood pressure lowering. Design and method: Spontaneously hypertensive rats on a low-salt diet (&lt;0.03% NaCl) were treated for 4 weeks with siRNA (10 mg/kg fortnightly; s.c.), supplemented with fludrocortisone (6 mg/kg/day; s.c.), midodrine (4 mg/kg/day; s.c.) or a high-salt diet (4% NaCl) during the final 2 weeks (n = 6–7 per group). Before and after 2 weeks of siRNA, blood pressure responses to intravenous bolus injections of angiotensin II (0.05; 0.5 and 5 mg/kg) and noradrenalin (0.1; 1.0 and 10 mg/kg) were recorded via radiotelemetry in anaesthetised rats. Results: Baseline mean arterial pressure (MAP; 136 ± 3 mmHg) was lowered by 19 ± 1 mmHg by AGT siRNA in combination with a low-salt diet. Acute pressor responses to angiotensin II and noradrenalin were identical before and after siRNA. Fludrocortisone restored MAP to baseline levels (137 ± 3 mmHg), as did replacing the low-salt diet with a high-salt diet (139 ± 4 mmHg). Midodrine had no effect. Under low salt conditions, siRNA virtually abolished plasma AGT by 99.2 ± 0.1% to 6 ± 1 nM, and increased active plasma renin concentrations. AGT was not altered by midodrine, only marginally raised by high sodium intake, but increased to 20 ± 5% of pre-siRNA treatment levels by fludrocortisone, paralleled by near-elimination of plasma renin levels by 98 ± 1% to 2.1 ± 0.9 ng angiotensin I/mL/h. Conclusions: The efficacy of angiotensin II and noradrenaline to raise blood pressure is not affected by RNAi-mediated AGT suppression. Increased sodium intake or fludrocortisone may represent chronic, less invasive alternatives for controlling blood pressure during AGT depletion, of which the latter seems to be facilitated by amplification of AGT production.

Novel chemiluminescent immunoassay to measure plasma aldosterone and plasma active renin concentrations for the diagnosis of primary aldosteronism

Determination of plasma aldosterone concentrations (PAC) and plasma active renin concentrations (ARC) is essential for the diagnosis of primary aldosteronism (PA). In Japan, although PAC and ARC are measured by radioimmunoassay and immunoradiometric assay, respectively, non-radioisotopic methods with better detection sensitivity, measurement accuracy, and technical simplicity are needed. We developed two-site sandwich chemiluminescent enzyme immunoassays (CLEIAs) to measure both PAC and ARC using monoclonal antibodies immobilized onto ferrite particles. The results of both assays are obtained simultaneously from a single plasma sample within 30 min using a fully automated system. The novel CLEIAs were validated using plasma samples from patients with PA (n = 52) and essential hypertension (n = 23). The PAC determined by the CLEIA was significantly correlated with that measured by liquid chromatography/mass spectrometry or conventional radioimmunoassay. The ARC determined by the CLEIA was significantly correlated with that measured by immunoradiometric assay. The limits of detection of the CLEIAs for PAC and ARC were 0.1 ng/dl and 0.04 pg/ml, respectively, which were better than those of conventional methods (PAC: 2.5 ng/dl; ARC: 5 pg/ml). The PAC and PAC/ARC ratio (ARR) were significantly higher, and the ARC significantly lower, in patients with PA than in those with essential hypertension. An ARR cut-off of 1.31 ng/dl per pg/ml showed a sensitivity of 96.2% and specificity of 78.3% for PA screening. The newly developed CLEIAs for measuring PAC and ARC could provide a clinically powerful alternative to conventional methods used for hypertension screening in clinical practice.

Effect of sample delivery conditions on Renin-Angiotensin-Aldosterone System (RAAS) assay

Renin-Angiotensin-Aldosterone System (RAAS) measurements are influenced by several factors. We investigated the effect of sample delivery conditions on RAAS measurements including sample storage temperature and time. Blood samples were collected from thirty participants using enzyme inhibitor tubes and serum separation gel evacuated tubes. Plasma and serum from fresh blood samples without further storage (as baseline), and from blood samples that were stored at either 0 °C, 4 °C, or 25 °C for 3 h, 6 h and 24 h, respectively, were extracted and stored at −30 °C for batch measurements using radioimmunoassay. Concentrations of Aldosterone (Ald) decreased following delivery temperature and time, and were significantly different when samples were set aside at 0 °C for 24 h (p < .01), 4 °C for 6 h (p < .01), and 25 °C for 3 h (p < .05). However, levels of Angiotensin (Ang I) increased following delivery temperature and time, and were significantly different when samples were set aside at 0 °C and 4 °C for 6 h (p < .05) and at 25 °C for 3 h (p < .001). However, no changes were observed for the concentrations of plasma renin activity (PRA) and Ang II, except for Ang II which increased significantly when samples were set aside at 25 °C for 24 h (p < .001). Our results indicate that samples used for RAAS measurement should be placed at a low temperature and analyzed as soon as possible after collection.

P3568The relationship between plasma renin and aldosterone levels and the reduction of blood pressure with spironolactone in patients with resistant hypertension

Abstract The group of patients with resistant hypertension (RH) is not homogeneous on concentration of renin and aldosterone (AS). A lot of studies have shown that spironolactone (SP) was by far the most effective blood pressure-lowering treatment for patients with RH. However, it has been unknown whether SP would be the most effective in patients with different plasma renin profile. The aim was to determine whether plasma renin and AS predict the most effective treatment of SP. Methods 79 patients with RH were included in the study (a mean of 3.4±1.4 drugs per patient including diuretic, ACE-I or an ARB). The plasma AS and active renin concentration (ARC), the plasma aldosterone-to-renin ratio (ARR) were estimated at baseline. After chemical evaluation patients started on SP treatment with a mid-dose 25 mg daily (range 12.5–50 mg). At baseline and after 12 weeks of therapy patients underwent clinic and 24-hour BP measurement, also hematocrit, potassium (K), serum creatinine (C), eGFR were checked. Results In patients with RH the ARC varied widely and they were divided into low 46%, normal 29% and high renin 25% subgroups. All groups of patients had similar AS levels. Patients with high renin hypertension (HRH) had significantly worse renal function than patients with low renin (LRH) or normal renin hypertension (NRH), also hematocrit were significantly higher in HRH patients than in patients with LRH and NRH. At baseline in patients with RH was an excellent correlation between ARC and eGFR (P&lt;0.001). After SP in whole group, the change from baseline in the clinic BP was −13.4/−6.8 mm Hg (P&lt;0.0001 for both) and in 24-hour BP was −10.6/−6.1 mm Hg (P&lt;0.001 for both), but patients with HRH showed less efficacy than patients with LRH and NRH (−5.4/−3.1 mm Hg; P&lt;0.05 for both) and in 24-hour BP was −4.8/−2.9 mm Hg (P&lt;0.05 for both). Moreover, in HRH patients the hematocrit and C levels increased significantly after the start of SP (P&lt;0.001; P&lt;0.0001 respectively). By regression analysis in whole group patients RH ARC and AS levels were not associated with the changes in BP, only eGFR was significantly associated with BP change for DBP (0.391, P&lt;0.05); in patients with LRH and NRH was a mild relation between the change for SBP and ARR (P&lt;0.05 for both), but not for HRH patients. Conclusion SP showed additional antihypertensive effect in the whole group of patients with RH, but in patients with HRH was less effective than in patients with LRH and NRH and lead to the worsening of renal function. In the whole group of patients with RH plasma renin and aldosterone levels were not associated with BP response to SP, but the change in DBP was correlated with baseline eGFR. Only in patients with LRH and NRH was a mild association between BP response to SP and ARR. So, we can't treat all RH patients with the help of one universal algorytm and treatment should be tailored to each patient according to neurohumoral profile and renal function.

Abstract P2031: Control Of Antihypertensive Effect Of Small Interfering RNA Targeting Angiotensinogen

A single dose of small interfering ribonucleic acids (siRNA) targeting angiotensinogen (AGT) provides a strong and sustained antihypertensive effect, lasting weeks to months in preclinical models. It is not known whether conventional vasopressors are effective to reverse RNAi-mediated blood pressure lowering. Here, we investigated whether conventional vasopressors can elevate arterial pressure under conditions of AGT depletion. Spontaneously hypertensive rats on a low-salt diet (&lt;0.03% NaCl) were treated for 4 weeks with siRNA (10 mg/kg fortnightly; s.c.), supplemented with fludrocortisone (6 mg/kg/day; s.c.), midodrine (4 mg/kg/day; s.c.) or a high-salt diet (4% NaCl) during the final 2 weeks (all groups n=6-7). Before and after 2 weeks of siRNA, blood pressure responses to intravenous bolus injections of angiotensin II (0.05; 0.5 and 5 μg/kg) and noradrenalin (0.1; 1.0 and 10 μg/kg) were examined in anesthetized rats, via radiotelemetry. Baseline mean arterial pressure (MAP; 136±3 mmHg) was lowered by 19±1 mmHg by AGT siRNA combined with a low-salt diet. Acute pressor responses to angiotensin II and noradrenalin were identical before and after siRNA. Fludrocortisone restored MAP to baseline levels (137±3 mmHg), as did replacing the low-salt diet with a high-salt diet (139±4 mmHg). Midodrine had no effect. Under low salt conditions, siRNA virtually abolished plasma AGT by 99.2±0.1% to 6±1 nM, and increased active plasma renin concentrations. AGT was not altered by midodrine, only marginally increased by high sodium intake, but increased to 20±5% of pre-siRNA treatment levels by fludrocortisone, paralleled by near-elimination of plasma renin levels by 97.6±0.9% to 2.1±0.9 ng angiotensin I/mL.h. Collectively, these data indicate that the efficacy of angiotensin II and noradrenaline to raise blood pressure is not affected by RNAi-mediated AGT suppression. Increased sodium intake or fludrocortisone may represent chronic, less invasive alternatives for controlling blood pressure during AGT depletion, of which the latter seems to be facilitated by amplification of AGT production.

The state of renin-aldosterone system in patients with resistant arterial hypertension

Purpose. The understanding of pathophysiology and clinical characteristics of resistant hypertension (RH) remains elusive. The aim of this work was to study the relationships between clinical course of RH and levels of renin and aldosterone (AS). Materials and methods. A total of 47 patients with true RH were included in the study. The control group included 50 patients with controlled arterial hypertension (CAH). All patients underwent general clinical examination, calculation of body mass index (BMI), office blood pressure measurement, determination of plasma potassium, AS and active renin concentrations (ARC), assessment of plasma aldosterone-to-renin ratio, urinary albumin excretion, albumin-creatinine ratio (ACR), uric acid, serum creatinine, calculation of glomerular filtration rate (GFR) by Cockcroft–Gault formula, echocardiography. Results. AS and ARC levels were significantly higher (AS 145.21 ± 11.90 ng/ml and 122.04 ± 8.60 ng/ml, P < 0.001; ARC 18.21 ± 3.50 ng/ml and 14.40 ± 2.20 ng/ml, P < 0.05) in patients with RH compared to those with CAH, respectively. At the same time, among patients with RH, only 38 % had a normal ARC; increased ARC was in 27 % and reduced ARC was in 35 % of patients. Among patients with CAH, 78 % had a normal ARC; increased ARC was in 7 % and reduced ARC was in 15 % of patients. In patients with CAH, there was negative correlation between AS and ARC levels (r = -0.38, P < 0.05), at the same time in patients with RH, no correlation was found between AS and ARC levels. However, in patients with RH, there were negative correlations between AS, ARC and GFR (r = -0.36, P < 0.05; r = -0.32, P < 0.05, respectively); positive – ARC and left ventricular mass index (r = 0.43, P < 0.05); AS and ACR (r = 0.76, Р < 0.01); AS and left ventricular end-diastolic volume (r = 0.38, P < 0.05). Moreover, significant correlations were found between ARC and BMI (r = 0.59, P < 0.001), AS and BMI (r = 0.42, P < 0.05). Conclusions. The results indicate that in patients with RH, higher renin and AS levels are mediated by overweight as well as renin and AS have a different influence on target organs in RH. Furthermore, stimulation of AS production occurs regardless of the renin-angiotensin system and angiotensin II effects. The group of patients with RH is not homogeneous according to renin concentration and “low-renin” and “high-renin” hypertension are more frequently registered among them. It seems that pathophysiologic mechanisms are different in each case and need to be identified for the selection of antihypertensive agents to treat patients successfully.

Responses of the renin-angiotensin-aldosterone system in pregnant chronic kidney disease patients with and without superimposed pre-eclampsia.

BackgroundWomen with chronic kidney disease (CKD) are at increased risk of superimposed pre-eclampsia (SPE). Accurate identification of SPE is challenging. We hypothesized that specific components of the renin–angiotensin–aldosterone system (RAAS) would discriminate between CKD and SPE. The aim of the study was to establish differences in circulating and intrarenal RAAS in women with CKD with and without SPE and compare these to normotensive controls (NCs) and women with pre-eclampsia (PE).MethodsWhite European NC women (n = 20), women with PE (n = 9), normotensive CKD without SPE (n = 8) and with SPE (n = 11) were recruited in the third trimester. Plasma renin, plasma and urine total angiotensinogen (AGT) concentrations were quantified by enzyme-linked immunosorbent assay, urinary tetrahydroaldosterone (TH-aldo) concentration by gas chromatography-mass spectrometry and placental growth factor (PlGF) by immunoassay.ResultsUrinary TH-aldo:creatinine ratios were lower in women with PE or SPE compared with NC or women with CKD (P < 0.05 for all). The same group differences were observed for plasma active renin and PlGF concentrations (P < 0.05 for all). Urine total AGT was higher in women with PE compared with NC (P < 0.05) and urine TH-aldo:urine AGT was lower (P < 0.05). However, women with SPE had lower urinary AGT concentrations compared with women with PE (P < 0.05). No differences in plasma total AGT were observed between groups.ConclusionsWomen with SPE have a lower urinary TH-aldo:creatinine ratio, lower plasma active renin and lower PlGF concentrations than women with CKD, comparable to women with PE without pre-existing disease, suggestive of similar pathophysiology. These data suggest disruption of the RAAS pathway in SPE similar to PE. Exploration of the predictive value of RAAS components for adverse pregnancy events in women with CKD is required.

Effects of mineralocorticoid and AT-1 receptor antagonism on the aldosterone-renin ratio (ARR) in primary aldosteronism patients (EMIRA Study): rationale and design.

Current guidelines recommend withdrawal of treatments that affect the aldosterone/renin ratio (ARR) when screening for primary aldosteronism (PA). However, abandonment of mineralocorticoid-receptor antagonist (MRA) and/or blockers of the renin-angiotensin system can deteriorate control of blood pressure (BP) and hypokalemia. Thus, in consecutive patients with an unambiguous diagnosis of PA in washout from confounding treatments and subtyped by AVS, we will compare within-patient plasma aldosterone and active renin concentration, and the ARR values, measured at baseline, and after a 1-month treatment with MRA alone and combined with an AT-1 receptor blocker (ARB). Patients on a regular salt intake will be treated with canrenone (50-100 mg orally) for 1 month, after which olmesartan (10 or 20 mg orally) will be added for another month with up-titration of both treatments over the first 2 weeks to control BP and hypokalemia, while background therapy will be maintained. The biochemical variables and the ARR will be assessed in an identical manner at baseline values and after each month of treatment. With a sample size of 40 patients, the study will have a 95% power to show a clinically significant 20% change in the ARR at a 5% α value using a two-sided paired t test. Hence, this study will allow us to determine if an MRA alone, or added to an ARB at doses that control BP and hypokalemia, affects or not the ARR, thus allowing to establish if these agents can be administered or must be forbidden during the screening of PA.

Cure With Cryoablation of Arterial Hypertension Due to a Renin-Producing Tumor

We herein report on a 20 years old woman with stage I hypertension, who was found to carry a renin-producing tumor (RPT). Due to her young age, the patient underwent screening measurement of plasma renin and aldosterone, abdominal computed tomography (CT) angiography, and selective renal vein renin assessment to identify secondary hypertension. The patient was screened for secondary causes of hypertension and was diagnosed with secondary aldosteronism. Therefore, she underwent an abdominal computed tomography (CT) angiography that was reported as unremarkable. Selective renal vein renin studies showed overproduction of renin in the right kidney and a re-evaluation of her CT allowed detection of an 8-mm mass in her right kidney, suggesting the presence of a RPT. Considering the technical difficulty of renal sparing surgery a CT-guided cryoablation was undertaken, which provided long-term cure of arterial hypertension and normalization of plasma active renin concentration. RPTs usually present with a clinical phenotype featuring stage III and/or malignant hypertension and are held to be exceptionally rare. This case is unique in that it presented with stage I hypertension and a mild clinical phenotype. Moreover, to our knowledge this is the first case of RPTs shown to be safely treated with CT-guided cryoablation and found to be cured at long-term.

PP.23.04] RESPONSES OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM TO PLASMA VOLUME DEPLETION IN PRE-ECLAMPSIA &amp; SUPERIMPOSED PRE-ECLAMPSIA

Objective: Women with chronic kidney disease (CKD) are at increased risk of superimposed pre-eclampsia (SPE) and associated adverse pregnancy outcomes. Diagnosis of SPE using blood pressure and proteinuria is of limited use because these may develop in women with CKD even without the condition. Inaccurate diagnosis may result in unnecessary iatrogenic preterm delivery. Plasma and urinary aldosterone concentrations are elevated in patients with CKD, but suppressed in established pre-eclampsia (PE). The aim of the study was to determine plasma active renin, total plasma and urinary angiotensinogen (AGT) and aldosterone availability in women with CKD with and without SPE compared with normotensive controls (NC) and those with PE without CKD. Design and method: NC women (n = 19), women with PE (n = 14), CKD without SPE (n = 6) and with SPE (n = 11) were recruited from two tertiary antenatal clinics (mean ± SD 38 ± 3 weeks). Active renin and total AGT concentrations were measured by ELISA; urinary tetrahydroaldosterone was measured by gas chromatography-mass spectrometry; creatinine was measured using a standard clinical laboratory assay for normalisation. Results: Aldosterone and plasma active renin (Kruskal Wallis, both P < 0.05) were significantly different between groups. Aldosterone: creatinine ratios were significantly lower in both PE and SPE compared to the NC and women with CKD (median [IQR], PE: 6.5 [3, 14.4]; SPE: 10.8 [5.4, 16.4]; NC: 13.8 [9.1, 29.8]; CKD: 24.2 [16.3, 37.9] μg/mmol creatinine; P < 0.05 for all). Plasma active renin concentrations were also lower in PE, SPE and CKD women compared to NC women (PE: 5.3 [9.7, 21.8]; SPE: 3.4 [2.4, 12]; CKD: 3.9 [3.2, 6.2]; NC: 5.3 [0.2, 8.7] pg/ml; P < 0.05 for all). No differences in either plasma or urinary total AGT were observed between the groups. Conclusions: Women with SPE have lower urinary aldosterone and plasma active renin than women with CKD in keeping with women with PE without pre-existing kidney disease, suggestive of similar pathophysiology. Further exploration of the predictive value of low urinary aldosterone and plasma renin for adverse pregnancy events in women with CKD and its role in cases of diagnostic uncertainty is required.

Dose-effect relationship of perindopril 10, 14 and 20 mg assessed by urine and plasma AcSDKP levels in mildly sodium-depleted healthy volunteers

BackgroundWe describe a pharmacodynamic study of the dose-effect relationship of perindopril arginine at 10, 14, and 20mg with in vivo angiotensin-converting enzyme (ACE) activity, assessed by urine and plasma AcSDKP levels, as well as the effect on plasma active renin concentrations and blood pressure. MethodsThis randomized, double-blind, four-period, crossover study involved single-dose administration of perindopril arginine (10, 14, and 20mg or placebo) to 32 healthy male normotensive mildly sodium-depleted volunteers. Blood and urine were collected over 48h for AcSDKP, ACE activity, and plasma active renin measurements. ResultsThere were dose-related increases in urinary AcSDKP excretion and plasma AcSDKP concentration after administration of perindopril, with significant between-period differences (estimate of the median difference in urinary excretion over 48h of AcSDKP, 49.1 [95% CI: 15.3–82.0] nmol for 14 versus 10mg, and 73.2 [95% CI: 44.9–106.3] nmol for 20 versus 14mg). Consequently, a dose-dependent increase in plasma active renin concentration was observed. Even though each dose of perindopril 10 to 20mg was associated with a significant 24-h ambulatory blood pressure reduction versus placebo, no dose-dependency was detected in these normotensive subjects. ConclusionsAdministration of perindopril arginine 10, 14, or 20mg to mildly sodium-depleted healthy volunteers is associated with a dose-dependent inhibition of in vivo ACE activity with significant between-dose differences. This effect was associated with a dose-dependent increase in plasma active renin concentration, indicating a dose-dependent blockade of the renin angiotensin system.