Plasma Renin Concentration Research Articles

Peperomia pellucida (L.) Kunth as an angiotensin-converting enzyme inhibitor in two-kidney, one-clip Goldblatt hypertensive rats

BackgroudPeperomia pellucida (L.) Kunth has been used widely to treat headache, kidney disease, fever, and hypertension. Previous in vitro studies discovered that the flavonoid-rich extract of this plant has potential hypotensive effects, specifically angiotensin-converting enzyme (ACE)-inhibitory activity. However, there is insufficient scientific evidence to validate the result in vivo.PurposeThis study investigated the dose dependencies of the effects of the ethyl acetate fraction of the ethanolic extract of this plant on blood pressure and biomarkers associated with the renin–angiotensin–aldosterone systems (RAAS), such as angiotensin II (AII) and the plasma renin concentration (PRC).Study designIn total, 30 two-kidney, one-clip (2K1C) hypertensive model rats were divided into five groups (n = 6 each): model group, captopril 25 mg/kg BW group, and three different ethyl acetate groups (25, 50, and 100 mg/kg BW). Another six rats comprised the sham group.MethodsRenal hypertensive rats (RHRs) were generated using stainless steel modification clips. Drugs were administered via oral gavage for 2 consecutive weeks. Blood pressure was measured weekly prior to treatment. Blood samples were collected before treatment and after the last dose to measure AII and PRC. The left kidney was isolated for histopathological examination.ResultsBlood pressure, AII levels, and PRC were elevated after 6 weeks in RHRs. Treatment with captopril and the ethyl acetate fraction of P. pellucida (L.) Kunth decreased blood pressure, AII levels, and PRC. The ethyl acetate fraction at a dose of 50 mg/kg BW had similar ACE-inhibitory effects as captopril. Histopathological examination disclosed coagulative necrosis in clipped kidneys. Impairment was alleviated in a dose-dependent manner by P. pellucida (L.) Kunth, similarly as observed in the captopril group.ConclusionP. pellucida (L.) Kunth targets the renin–angiotensin–aldosterone system, which might explain its antihypertensive effects.

Renin Kinetics Are Superior to Lactate Kinetics for Predicting In-Hospital Mortality in Hypotensive Critically Ill Patients.

Whole blood lactate concentration is widely used in shock states to assess perfusion. We aimed to determine if the change in plasma renin concentration over time would be superior to the change in lactate concentration for predicting in-hospital mortality in hypotensive patients on vasopressors. Prospective, observational cohort study. Tertiary academic ICU. Adult patients on vasopressors for greater than 6 hours to maintain a mean arterial pressure greater than or equal to 65 mm Hg during January 2020. Plasma renin concentrations were measured at enrollment and at 24, 48, and 72 hours. Whole blood lactate measurements were performed according to normal standard of care. Logistic regression was performed to evaluate whether the change in renin or lactate concentration could predict in-hospital mortality. Generalized estimating equations were used to analyze the association between renin and lactate concentration and in-hospital mortality. The area under the receiver operating characteristics curve was performed to measure the discriminative ability of initial and peak renin and lactate concentration to predict mortality. The association between renin and lactate concentration above the upper limit of normal at each timepoint with in-hospital mortality was also examined. The study included 197 renin and 148 lactate samples obtained from 53 patients. The slope of the natural log (ln) of renin concentration was independently associated with mortality (adjusted odds ratio, 10.35; 95% CI, 1.40-76.34; p = 0.022), but the slope of ln-lactate concentration was not (adjusted odds ratio, 4.78; 95% CI, 0.03-772.64; p = 0.55). The generalized estimating equation models found that both ln-renin (adjusted odds ratio, 1.18; 95% CI, 1.02-1.37; p = 0.025) and ln-lactate (adjusted odds ratio, 2.38; 95% CI, 1.05-5.37; p = 0.037) were associated with mortality. Area under the receiver operating characteristics curve analysis demonstrated that initial renin could predict in-hospital mortality with fair discrimination (area under the receiver operating characteristics curve, 0.682; 95% CI, 0.503-0.836; p = 0.05), but initial lactate could not (area under the receiver operating characteristics curve, 0.615; 95% CI, 0.413-0.803; p = 0.27). Peak renin (area under the receiver operating characteristics curve, 0.728; 95% CI, 0.547-0.888; p = 0.01) and peak lactate (area under the receiver operating characteristics curve, 0.746; 95% CI, 0.584-0.876; p = 0.01) demonstrated moderate discrimination. There was no significant difference in discriminative ability between initial or peak renin and lactate concentration. At each study time point, a higher proportion of renin values exceeded the threshold of normal (40 pg/mL) in nonsurvivors than in survivors, but this association was not significant for lactate. Although there was no significant difference in the performance of renin and lactate when examining the absolute values of each laboratory, a positive rate of change in renin concentration, but not lactate concentration, over 72 hours was associated with in-hospital mortality. For each one-unit increase in the slope of ln-renin, the odds of mortality increased 10-fold. Renin levels greater than 40 pg/mL, but not lactate levels greater than 2 mmol/L, were associated with in-hospital mortality. These findings suggest that plasma renin kinetics may be superior to lactate kinetics in predicting mortality of hypotensive, critically ill patients.

Mildly Increased Renin Expression in the Absence of Kidney Injury in the Murine Transverse Aortic Constriction Model.

Cardiorenal syndrome type 2 is characterized by kidney failure as a consequence of heart failure that affects >50% of heart failure patients. Murine transverse aortic constriction (TAC) is a heart failure model, where pressure overload is induced on the heart without any systemic hypertension or its consequences. Whether renal function is altered in this model is debated, and if so, at which time post-TAC renal dysfunction starts to contribute to worsening of cardiac function. We therefore studied the effects of progressive heart failure development on kidney function in the absence of chronically elevated systemic blood pressure and renal perfusion pressure. C57BL/6J mice (N = 129) were exposed to TAC using a minimally invasive technique and followed from 3 to 70 days post-TAC. Cardiac function was determined with 3D ultrasound and showed a gradual decrease in stroke volume over time. Renal renin expression and plasma renin concentration increased with progressive heart failure, suggesting hypoperfusion of the kidney. In addition, plasma urea concentration, a surrogate marker for renal dysfunction, was increased post-TAC. However, no structural abnormalities in the kidney, nor albuminuria were present at any time-point post-TAC. Progressive heart failure is associated with increased renin expression, but only mildly affected renal function without inducing structural injury. In combination, these data suggest that heart failure alone does not contribute to kidney dysfunction in mice.

Preoperative Renin Status Indicate the Clinical Outcome of Aldosterone-Producing Adenoma

Primary aldosteronism is widely recognized as renin-independent hypersecretion of aldosterone and aldosterone-producing adenoma(APA) represents the typical clinical subtype. Plasma renin below detection levels was considered as an important indicator for PA, and the suppressed renin level after confirmatory tests was considered to be a prerequisite when interpreting the results of confirmatory tests, before making the diagnosis of PA. Strictly, there is no specific definition of suppressed renin level in patients with PA. Clinically, the renin level of patients with APA varied greatly within the low to normal range. However, the clinical characteristics and outcomes in patients with APA having different renin status remain unclear. This retrospective study included 274 patients with APA who underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Patients were classified into the following 2 groups: low renin and non-low renin groups measured at 8.2 mU/L, according to the widely used criteria(defined as plasma renin activity<1ng/ml/h≈PRC 8.2 mU/L). Only patients with two consecutive PRC less than 8.2 mU/L could be classified into the low renin group. For the screening test and the confirmatory tests, antihypertensive medication was withheld or changed according to the guideline. Chemiluminescence immunoassays showed the range of the plasma renin concentration as 0.4–41.5mU/L. Non-low renin APA patients (n=26) had higher presurgical SBP(p=0.028), DBP(p=0.001) and PRC post confirmatory tests(p<0.001), compared with low renin APA patients(n=248). There was no significant difference in baseline PAC(p=0.507) and serum potassium(p=0.348) between the two groups. Intriguingly, non-low renin APA patients had higher PAC(p<0.001) and PRC(p<0.001) and lower serum potassium(p<0.001) at follow-up. For non-low renin APA patients, the rate of complete clinical success after surgery was 42.3%, 25% lower than that of low renin APA patients. APA patients with PRC<0.5mU/L had the highest rate of complete clinical success(75%), followed by PRC 0.5~8.2 mU/L(65%) and 8.2~20 mU/L(50%), with the lowest rate in patients with PRC>20 mU/L(33%). Multivariable logistic regression showed that the presence of baseline PRC>8.2 mU/L was a strong independent predictor for the lack of complete clinical success[OR 3.7(1.5–8.9),p=0.004]. Plasma renin concentration is closely related to the clinical outcome of APA patients postoperatively. APA patients with higher baseline renin status are at high likelihood of persistent hypertension after surgery, in whom strengthened monitoring of blood pressure is necessary.

Prospective Screening for Primary Aldosteronism in Patients With Suspected Obstructive Sleep Apnea.

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THE EFFECT OF AGE, BMI, AND SEX ON ALDOSTERONE, RENIN AND THE ALDOSTERONE-TO-RENIN RATIO IN ESSENTIAL HYPERTENSIVES

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 investigation is to identify the impact of age, body mass index (BMI) and sex on renin, aldosterone, and the ARR, when measured under strictly standardised conditions. Design and method: We measured plasma aldosterone, plasma renin concentration and the ARR in 190 essential hypertensive patients (120 males, 70 females). All measurements were taken in the supine position at 9am. A low sodium diet (55mmol/day) was in place for no less than two weeks prior to screening. In those who were receiving antihypertensive medications, all medications were discontinued at least 2 week before testing. Results: Renin and aldosterone were significantly higher in men, and remained so when controlling for BMI and age. However, the ARR was not significantly affected by sex. Aldosterone was not significantly influenced by age but renin correlated inversely with age, with and without controlling for BMI (r = -0.285, p &lt; 0.001). The ARR was positively correlated with age (r = 0.236, p &lt; 0.001), with and without controlling for BMI. Subgroup analysis demonstrated a significant effect on the ARR in males only, with and without controlling for BMI (p &lt; 0.001 and p0.004, respectively). Although renin and aldosterone individually were not significantly influenced by BMI, the ARR showed a positive correlation (p = 0.022). However, this effect was not seen when age was controlled for nor was it seen in the subgroup analysis of males and females (p = 0.125, p = 0.515, p = 0.207, respectively) Conclusions: Under strictly standardized conditions, advanced age is associated with an increased ARR in male essential hypertensives. BMI when controlling for age does not influence the ARR. The impact of sex on the ARR appears negligible.

DEVELOPING A MOST EQUIVALENT ALDOSTERONE MEASUREMENT TO LC-MS/MS BY A NOVEL HIGH-QUANTITATIVE NONCOMPETITIVE CHEMILUMINESCENCE IMMUNOASSAY

Objective: Measurement of plasma aldosterone and renin concentration, or activity, is useful for selecting antihypertensive agents and detecting hyperaldosteronism in hypertensive patients. However, it takes several days to get results even if measured by inaccurate radioimmunoassay, or we must accept high-cost LC/MS, and development of a more rapid and accurate substitute has been long hoped. We have developed a novel, fully-automated, high-quantitative noncompetitive chemiluminescence immunoassay (NC-CLEIA) for detecting aldosterone in serum and plasma, and its performance is evaluated as compared to LC/MS measurement. Design and method: Recently a unique anti-metatype antibody, which recognizes the immunocomplex of aldosterone and its monoclonal antibody, was established. Using this antibody for sensing permitted the construction of non-competitive assay for the detection of aldosterone. The reaction protocol of novel aldosterone assay is the following. In the 1st reaction, aldosterone in patient's sample is captured on anti-body coated magnetic particles. Alkaline phosphatase-conjugated anti-metatype antibody is added and incubated as 2nd reaction following a wash. Then substrate solution is added after washing immunocomplex. The resulting reaction signals are proportional to the amount of aldosterone in the sample allowing quantitative determination of in serum or plasma sample. The overall reaction is completed within 30 min. Results: Limit of blank (LoB), limit of detection (LoD) and limit of quantitation (LoQ) of our NC-CLEIA aldosterone assay were 0.09 ng/dL, 0.21 ng/dL and 0.57 ng/dL, respectively. NC-CLEIA aldosterone measurements were linearly well correlated with LC/MS aldosterone measurements (N = 130, y = 1.027x - 0.23 ng/dL, Spearman's p = 0.996, p &lt; 0.0001). Bland-Altman plot analysis between NC-CLEIA and LC-MS/MS of aldosterone revealed a bias of 0.40 ng/dL with the limits of agreement of -4.60 and 5.41 ng/dL with 95% confidence interval. Conclusions: Our novel NC-CLEIA aldosterone assay was well-correlated and had only a very low bias with LC-MS/MS method and also was able to accurately quantify low level samples even in essential hypertension patients. This assay may be useful for the routine analysis of aldosterone and for the screening and diagnosis of PA from large number of hypertensive patients.

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.

Aldosterone-producing adenoma associated with non-suppressed renin: a case series.

Although the aldosterone/renin ratio (ARR) is the preferred screening test for primary aldosteronism (PA), patients with non-suppressed renin and a falsely negative ARR on non-interfering medications have occasionally been reported. This report describes the clinical characteristics and outcomes of seven patients with proven aldosterone-producing adenoma (APA) and non-suppressed renin.Chart review of seven PA patients with an APA and a non-suppressed plasma renin concentration (PRC > 8.4 mU/L) was undertaken to collect data on anthropometric and biochemical characteristics, diagnostic evaluation and postsurgical outcomes.Seven patients (two women and five men) with a proven APA had median (range) PRC, plasma aldosterone and ARR of 20 (9-43) mU/L, 750 (270-1940) pmol/L and 45 (8-62, normal <70), respectively, on non-interfering medications. Six patients had two consecutive ARR measurements and in five of them both were normal. Renal artery stenosis was carefully excluded in all patients. Further evaluation for PA was pursued because of high clinical suspicion (either hypokalaemia and/or a known adrenal mass lesion on imaging). All underwent adrenal vein sampling confirming unilateral PA which was managed by unilateral adrenalectomy. Postsurgical follow-up data either confirmed or were highly suggestive of cure of PA.Strict control of factors known to influence the ARR is crucial to avoid false-negative results. Other causes that could explain a non-suppressed renin should be excluded. In patients with a consistently non-suppressed renin further diagnostic workup for PA should be considered if clinical suspicion remains high.

Therapeutic Assessment of Combination Therapy with a Neprilysin Inhibitor and Angiotensin Type 1 Receptor Antagonist on Angiotensin II-Induced Atherosclerosis, Abdominal Aortic Aneurysms, and Hypertension.

Combined neprilysin (NEP) inhibition (sacubitril) and angiotensin type 1 receptor (AT1R) antagonism (valsartan) is used in the treatment of congestive heart failure and is gaining interest for other angiotensin II (AngII)-related cardiovascular diseases. In addition to heart failure, AngII promotes hypertension, atherosclerosis, and abdominal aortic aneurysms (AAAs). Similarly, NEP substrates or products have broad effects on the cardiovascular system. In this study, we examined NEP inhibition (with sacubitril) and AT1R antagonism (with valsartan) alone or in combination on AngII-induced hypertension, atherosclerosis, or AAAs in male low-density lipoprotein receptor–deficient mice. Preliminary studies assessed drug delivery via osmotic minipumps for simultaneous release of sacubitril and/or valsartan with AngII over 28 days. Mice were infused with AngII (1000 ng/kg per minute) in the absence (vehicle) or presence of sacubitril (1, 6, or 9 mg/kg per day), valsartan (0.3, 0.5, 1, 6, or 20 mg/kg per day), or the combination thereof (1 and 0.3, or 9 or 0.5 mg/kg per day of sacubitril and valsartan, respectively). Plasma AngII and renin concentrations increased 4-fold at higher valsartan doses, indicative of removal of AngII negative feedback on renin. Sacubitril doubled plasma AngII concentrations at lower doses (1 mg/kg per day). Valsartan dose-dependently decreased systolic blood pressure, aortic atherosclerosis, and AAAs of AngII-infused mice, whereas sacubitril had no effect on atherosclerosis or AAAs but reduced blood pressure of AngII-infused mice. Combination therapy with sacubitril and valsartan did not provide additive benefits. These results suggest limited effects of combination therapy with NEP inhibition and AT1R antagonism against AngII-induced hypertension, atherosclerosis, or AAAs.SIGNIFICANCE STATEMENTThe combination of valsartan (angiotensin type 1 receptor antagonist) and sacubitril (neprilysin inhibitor) did not provide benefit above valsartan alone on AngII-induced hypertension, atherosclerosis, or abdominal aortic aneurysms in low-density lipoprotein receptor–deficient male mice. These results do not support this drug combination in therapy of these AngII-induced cardiovascular diseases.

Effect of Electroacupuncture on Stress-induced High Blood Pressure via Autonomic Nervous System in Normotensive Young Adults

Acupuncture, which is widely used as a complementary and alternative medicine, has been expected to be beneficial for the treatment of hypertension. However, the antihypertensive effect of acupuncture is still under debate. In the present study, the blood pressure induced by handgrip stress were evaluated using power spectral frequency analysis and hormone examination. This study, which recruited 6 normotensive participants, was designed as a randomized crossover trial of two interventions; electroacupuncture and sham-electroacupuncture. Intervention was delivered as 5 sessions over 2 consecutive weeks. The first electroacupuncture immediately before handgrip exercise did not affect the rates of increase in blood pressure and heart rate. Also, neither increase in LF/HF ratio, as sympathetic nerve activity, nor decrease in HF value, as parasympathetic nerve activity, by handgrip stress was significantly inhibited by a single intervention of electroacupuncture. In addition, 5 repeated electroacupuncture sessions did not attenuate the elevation of blood pressure after handgrip stress, and did not suppress the increase in LF/HF ratio and decrease in HF value. Also, electroacupuncture did not influence the changes in plasma concentrations of renin, aldosterone, norepinephrine, and epinephrine after handgrip stress. No difference was observed in the rate of change in each parameter after handgrip stress between the electroacupuncture treatment group and the sham-electroacupuncture group. The present study did not show any suppressive effect on stress-induced response of blood pressure as well as sympathetic nerve activity. The obtained findings showed no beneficial effects of acupuncture on hypertension as a standalone therapy, consistent with suggestions by previous systematic reviews and meta-analyses. Research with larger sample sizes or higher-quality randomized controlled trials are expected, and a conclusion on the utility of acupuncture treatment for hypertension should be carefully made.

Normotensive presentation in primary aldosteronism: A report of two cases

Normotensive patients with primary aldosteronism (PA) are relatively rare. Herein, we report two patients with normotensive PA and present a literature review to improve an understanding of the disease. Patient 1, a 56-year-old man, presented with recurrent hypokalemia that lasted for more than 2 years. Patient 2 was a 33-year-old man who presented with sexual dysfunction and was diagnosed with a prolactinoma combined with adrenal insufficiency and hypogonadism. Neither of these patients had hypertension that was detectable on repeated manual measurements. In both patients, a typical biological profile of PA was demonstrated that included hypokalemia with kaliuresis, elevated plasma aldosterone concentration (PAC), suppressed plasma renin concentration, and a high aldosterone-to-renin ratio. Both patients did not have sufficiently suppressed PAC on the saline infusion test, confirming the diagnosis of PA. Computed tomography of the adrenal gland and adrenal venous sampling suggested an aldosteronoma, which was confirmed by lateralized hypersecretion of aldosterone. After removal of the benign adenoma, the biochemical abnormalities were corrected. As hypertension is not necessarily a sign of PA, we propose that all patients with hypokalemia should be screened for PA in order to prevent cardiovascular complications while balancing economics and effectiveness.

Relationship between Soluble (Pro)Renin Receptor and Renin Activity in Patients with Severe Heart Failure

The (pro)renin receptor ((P)RR), which evokes renin activity with prorenin, is secreted extracellularly as soluble (P)RR (s(P)RR) and may participate in tissue renin-angiotensin system (RAS) activity in severe heart failure (HF) patients. The aim of this study was to determine whether s(P)RR is an adequate marker in severe HF patients treated with RAS inhibitors, beta-blockers, and tolvaptan. We enrolled 11 patients with severe HF between May 2013 and June 2014. First of all, furosemide of all patients was changed to tolvaptan with hydrochlorothiazide and then the treatment had been changed according to the patient’s condition. After 1, 3, 6, and 12 months, the variance of s(P)RR, plasma renin activity (PRA), plasma renin concentration (PRC), brain natriuretic peptide (BNP) and their association was investigated. Furosemide was restarted in five patients and two patients suffered cardiac death. PRA/PRC and s(P)RR were unchanged (PRA: 10.7 ± 13.9 to 12.8 ± 8.5 ng/mL/h; PRC: 347.1 ± 577.5 to 148.3 ± 123.8 pg/mL; s(P)RR: 28.2 ± 19.3 to 33.4 ± 22.4 ng/mL) and had no significant correlations (PRA and s(P)RR: p = 0.36; PRC and s(P)RR: p = 0.35). There was a significant positive correlation with a high correlation coefficient (CC) between PRA and PRC (p < 0.0001, CC = 0.76), and a negative correlation with weak CC between BNP and s(P)RR (p = 0.01, CC = −0.45). In conclusion, s(P)RR was always high and had no correlations with disease state and PRA/PRC in severe HF patients.

Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients.

Rationale: The renin-angiotensin-aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiotensin II might be disturbed, leading to increased renin concentrations. Cardiac surgery and the use of cardiopulmonary bypass both induce inflammatory response and cardiovascular instability, which can contribute to acute kidney injury (AKI).Objectives: To investigate whether renin concentrations are associated with hypotension and AKI.Methods: This is a single-center, prospective, observational study among patients undergoing cardiac surgery.Measurements and Main Results: The primary endpoint was the occurrence of AKI within 72 hours after cardiac surgery. A total of 197 patients were available for the primary analysis. The median renin serum concentration was 40.2 μU/ml (quartile 1 [Q1]-Q3, 9.3-144.4) at baseline and 51.3 μU/ml (Q1-Q3, 19.1-167.0) 4 hours after cardiac surgery, whereas the difference between postoperation and preoperation concentrations (Δ-renin) was 3.7 μU/ml (Q1-Q3, -22.7 to 50.9). Patients with an elevated Δ-renin developed an AKI significantly more often (43% vs. 12.2%; P < 0.001). High Δ-renin after cardiac surgery was associated with a significantly lower mean arterial pressure, longer time on vasopressors, and longer length of ICU and hospital stay. The area under the curve (AUC) of Δ-renin for the prediction of AKI (AUC, 0.817; 95% confidence interval, 0.747-0.887) was significantly greater compared with the AUC of the postoperative renin concentrations (AUC, 0.702; 95% CI, 0.610-0.793; P = 0.007).Conclusions: Elevated renin concentrations were associated with cardiovascular instability and increased AKI after cardiac surgery. Elevated renin concentrations could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention that could improve their outcomes.

Interrelationship between renin-angiotensin-aldosterone system and oxidative stress in chronic heart failure patients with or without renal impairment

We investigated oxidative stress and RAAS biomarkers, as well as their association, in chronic heart failure (CHF) patients on optimized medical therapy, stratified by disease severity or by renal function. Since vitamin D has been shown to attenuate RAAS activation and oxidative stress, we further evaluated the relationship between vitamin D, RAAS and oxidative stress in CHF patients with or without renal impairment. Sixty CHF outpatients were included and stratified by disease severity or by renal function. We quantified urinary hydrogen peroxide, plasma and urinary isoprostanes, plasma total antioxidant status, urinary angiotensinogen (intrarenal RAAS activation biomarker) and plasma angiotensinogen, plasma renin and aldosterone concentration, serum angiotensin-converting enzyme (ACE) activity, plasma angiotensin peptides, and serum total 25-hydroxyvitamin D (S-total 25(OH)D). Severe CHF patients had higher urinary isoprostanes (p = 0.002) and lower S-total 25(OH)D (p = 0.006) compared to mild-to-moderate patients, but no differences were observed for other redox or RAAS biomarkers. Patients with impaired renal function (iRF) had higher urinary angiotensinogen (p = 0.003) and lower S-total 25(OH)D (p = 0.028) compared to those with normal renal function (nRF), while no differences were observed for the remaining RAAS and redox parameters. Several positive correlations between oxidative stress and RAAS biomarkers were detected in iRF patients, while in patients with nRF these correlations were primarily inverse. In CHF-iRF patients, S-25(OD)D was inversely associated with urinary isoprostanes, which in turn were positively associated with plasma angiotensinogen and serum ACE. In conclusion, CHF patients with renal function impairment have increased intrarenal RAAS activation and lower vitamin D values and might benefit from the combination of RAAS blockers with vitamin D and/or antioxidants.

A drug-induced hypotensive challenge to verify catheter-based radiofrequency renal denervation in an obese hypertensive swine model

ObjectiveSham-controlled trials provided proof-of-principle for the blood pressure-lowering effect of catheter-based renal denervation (RDN). However, indicators for the immediate assessment of treatment success are lacking. This study sought to investigate the impact of RDN on renal renin arteriovenous difference (renal renin AV-Δ) following a hypotensive challenge (HC).MethodsTwelve hypertensive Ossabaw swine underwent either combined surgical and chemical (n = 3) or catheter-based RDN (n = 9). A telemetry monitor was implanted to acquire hemodynamic data continuously. Before and after RDN, a sodium nitroprusside-induced HC was performed. Renal renin AV-Δ was calculated as the difference of plasma renin concentrations drawn from the renal artery and vein.ResultsIn total, complete renal renin AV data were obtained in eight animals at baseline and six animals at baseline and 3 months of follow-up. Baseline renal renin AV-Δ correlated inversely with change in 24-h minimum systolic (− 0.764, p = 0.02), diastolic (r = − 0.679, p = 0.04), and mean (r = − 0.663, p = 0.05) blood pressure. In the animals with complete renin secretion data at baseline and follow-up, the HC increased renal renin AV-Δ at baseline, while this effect was attenuated following RDN (0.55 ± 0.34 pg/ml versus − 0.10 ± 0.16 pg/ml, p = 0.003). Renin urinary excretion remained unchanged throughout the study (baseline 0.286 ± 0.187 pg/ml versus termination 0.305 ± 0.072 pg/ml, p = 0.789).ConclusionRenin secretion induced by HC was attenuated following RDN and may serve as an indicator for patient selection and guide successful RDN procedures.

The Renal Extraction and the Natriuretic Action of GLP-1 in Humans Depend on Interaction With the GLP-1 Receptor.

The natriuretic effect of glucagon-like peptide-1 (GLP-1) in humans is independent of changes in renal plasma flow (RPF) and glomerular filtration rate (GFR) but may involve suppression of angiotensin II (ANG II) and a significant (~45%) renal extraction of GLP-1. The current study was designed to investigate the consequences for the renal extraction and the natriuretic effect of blocking GLP-1 receptors with the specific GLP-1 receptor antagonist, Exendin 9-39 (Ex 9-39). Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study where GLP-1 or vehicle was infused (1). In the present new experiments, participants were examined during a 3-hour infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-hour infusion of Ex 9-39 (900 pmol/kg/min). Timed urine collections were conducted throughout the experiments. Renal extraction of GLP-1 as well as RPF and GFR were measured via Fick's principle after catheterization of a renal vein. Arterial plasma renin, ANG II, and aldosterone concentrations were measured. Co-infusion of Ex 9-39 significantly reduced renal extraction of GLP-1 to ~25% compared with GLP-1 infusion alone (~45%). Urinary sodium excretions remained at baseline levels during co-infusion of Ex 9-39 as well as vehicle. By contrast, GLP-1 infusion alone resulted in a 2-fold increase in natriuresis. Ex 9-39 abolished the GLP-1-induced decrease in arterial ANG II concentrations. RPF and GFR remained unchanged during all experiments. Renal extraction of GLP-1 and its effect on natriuresis are both dependent on GLP-1 receptor activation in healthy humans.

Prorenin and active renin levels in paediatrics: a bioanalytical review.

As part of the extended renin-angiotensin-aldosterone system, active renin and its precursor prorenin have been an area of research interest for decades. Although several studies showed a correlation with disease, other studies found no significant association, e.g. attributed to limited sample size or pharmacological effects of antihypertensive drugs. Since the measurement of both proteins has typically been carried out in adult populations, the data in paediatrics is limited. This review aimed to collate the current data on plasma renin and prorenin levels in children and compare the levels of healthy vs. the diseased state. A literature search using Medline resulted in 213 publications of which 15 studies were classified as relevant. In the extant studies in the literature, an age-dependent decline of renin plasma concentration was observed in newborns compared to adolescents. For children with cardiovascular disease, five studies were identified that provide limited insight into the pathophysiological regulation of renin. In general, sample handling is still a crucial step, which might particularly affect measured active renin concentrations due to conformational changes of its precursor prorenin. A reliable assessment for prorenin levels in the maturating population is yet not possible due to the low number of available publications. Three different approaches to quantify prorenin were found and raise the question on the comparability of these methods. The review emphazised several weaknesses and highlights the need for an accurate procedure to determine levels of active renin as well as prorenin in its closed and open form.