Aumento de la lipocalina orosomucoide-1 (ORM1) en sujetos con hiperaldosteronismo primario / Increase of lipocalin ORM1 in primary aldosteronism

El hiperaldosteronismo primario (HAP) es la causa más común de hipertensión arterial secundaria. A pesar de la prevalencia del HAP (6-10%) y sus consecuencias, los mecanismos que median los efectos deletéreos renales y extrarenales originados por la aldosterona más allá de la hipertensión arterial (ej. inflamación renal, alteraciones cardiacas y disfunción vascular), siguen siendo poco conocidos. Estudios previos sugieren que el exceso de aldosterona aumentaría proteínas sensibles a la activación del receptor de mineralocorticoides (MR), como las lipocalinas LCN2 (NGAL) y ORM1. OBJETIVO: Determinar la concentración de las lipocalinas ORM1, NGAL y NGAL-MMP9 en sujetos HAP. SUJETOS Y MÉTODOS: Estudio de cohorte transversal en sujetos adultos (similares en sexo, edad e IMC) separados en controles normotensos (CTL), hipertensos esenciales (HE) y con screening positivo de HAP (aldosterona ≥9 ng/dL y ARP < 1 ng/mL*h acorde a las guías internacionales de HAP). Se determinó la presión arterial sistólica (PAS) y diastólica (PAD), aldosterona plasmática, actividad renina plasmática (ARP) y la relación aldosterona / actividad de renina plasmática (ARR). Se determinó la concentración de NGAL, NGAL-MMP9 y ORM1 en suero por ELISA. RESULTADOS: Detectamos mayores niveles de ORM1 en sujetos HAP. No se detectaron diferencias en NGAL ni NGAL-MMP9 entre los grupos. Detectamos una asociación positiva de ORM1 con ARP (rho= -0,407, p=0,012) y con ARR (rho= 0,380 p= 0,021). CONCLUSIÓN: La mayor concentración de ORM1 en sujetos HAP y las asociaciones de ORM1 con aldosterona, ARP y ARR, proponen a esta proteína como un potencial biomarcador de HAP y de utilidad en el desarrollo de algoritmos diagnósticos de HAP.

Primary hyperaldosteronism (PA) is the most common cause of secondary hypertension. Despite the prevalence of PA (6-10%) and its consequences, the mechanisms that mediate the deleterious renal and extrarenal effects caused by aldosterone beyond arterial hypertension (eg renal inflammation, cardiac alterations and vascular dysfunction), remain barely known. Previous studies suggest that excess aldosterone would increase proteins sensitive to activation of the mineralocorticoid receptor (MR), such as lipocalins LCN2 (NGAL) and ORM1. AIM: To determine the concentration of the lipocalins ORM1, NGAL and NGAL-MMP9 in PA subjects. SUBJECTS AND METHODS: Cross-sectional study in adult subjects (similar in sex, age and BMI) grouped as normotensive controls (CTL), essential hypertensive (HE) and subjects with positive PA screening (aldosterone ≥ 9 ng/dL and PRA <1 ng/mL*h, according to international PA guidelines). Systolic (SBP) and diastolic (DBP) blood pressure, plasma aldosterone, plasma renin activity (PRA), and plasma aldosterone renin ratio (ARR) were determined. The concentration of NGAL, NGAL-MMP9 and ORM1 in serum was determined by ELISA. RESULTS: We detected higher levels Recibido: 03-09-2021 of ORM1 in PA subjects. No differences in NGAL or NGAL-MMP9 were detected between the groups. We detected a positive association of ORM1 with ARP (rho = -0.407, p < 0.05) and with ARR (rho = 0.380 p <0.05). CONCLUSION: The high levels of ORM1 in PA subjects and the associations of ORM1 with aldosterone, ARP and ARR, suggest ORM1 is a potential biomarker of PA, and useful in the development of a diagnostic algorithm for PA.

Hiperaldosteronismo primario en una población de pacientes hipertensos / Primary hyperaldosteronism in a population of hypertensive patients

El diagnóstico de hiperaldosteronismo primario (HPAP) aumentó en los últimos años y algunos autores lo consideran la principal causa de hipertensión arterial secundaria. Estudiamos la prevalencia de HPAP en el total de pacientes hipertensos atendidos en la Unidad de Hipertensión Arterial, en el período comprendido entre julio 1999 a julio 2017. Se incluyeron 2500 pacientes y en 79 se diagnosticó HPAP (3.2%). El HPAP fue más frecuente en mujeres (55.7%), observándose un incremento en la edad geriátrica con relación a estudios previos (27.8%). El diagnóstico se sospechó ante la presencia de kaliuria inapropiada y alcalosis metabólica, acompañada de un cociente aldosterona/actividad de renina plasmática superior a 30 (ng/dl)/(ng/ ml/h). Tras su confirmación se realizaron estudios de imagen para determinar la etiología. Se detectaron así 29 casos (36.8%) de adenomas productores de aldosterona y 5 de hiperplasia bilateral suprarrenal con nódulos. La tomografía computarizada identificó el 100% de los adenomas y de las hiperplasias con nódulos corticales bilaterales. El tratamiento con suprarrenalectomía y/o antialdosterónicos resultó eficaz en el control de la presión arterial en el 69.9% de los casos. Se comentan aspectos particulares de esta serie, como la remisión de la insuficiencia renal, la elevada presencia de litiasis urinaria hipercalciúrica y la detección de un carcinoma de mama tras dosis prolongadas de espironolactona.

The diagnosis of primary hyperaldosteronism (PHPA) has progressively increased over the last years and some authors consider it as the main cause of secondary hypertension. We studied the prevalence of PHPA in hypertensive patients followed at the Hypertension Unit from July 1999 to July 2017. A total of 2500 patients were included and diagnosis of PHPA was done in 79 of them (3.2%). It was more frequent in women (55.7%) with an increased incidence in the elderly, as compared to previous studies (27.8%). Initial diagnosis was suspected upon the presence of inappropriate kaliuria and metabolic alkalosis, associated to an aldosterone/plasma renin activity ratio > 30 (ng/dl)/(ng/ml/h). After confirmation of the presence of PA, imaging techniques to determine the etiology were performed. In this way, 29 cases (36.8%) of aldosterone-producing adenoma and 5 cases of bilateral adrenal hyperplasia with nodules were identified. Computed tomography identified the adenomas and hyperplasias with bilateral cortical nodules in all patients. Adrenalectomy and/o r antialdosteronics were efficient in controlling blood pressure in 69.9% of cases. Of note in this series was the remission of stage 3 chronic renal failure in two cases, the high prevalence of hypercalciuric urinary lithiasis and a case of breast carcinoma after prolonged treatment with spironolactone.

Diagnosis and management of primary aldosteronism

ABSTRACT Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a "gold standard" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment.

Pseudohipoaldosteronismo y aparente exceso de mineralocorticoides: cara y ceca en dos pacientes pediátricos / Pseudohypoaldosteronism and apparent mineralocorticoid excess: two faces, two pediatric patients

Los síndromes endocrinológicos con hipofunción o hiperfunción con niveles paradójicos de dosajes hormonales han sido bien caracterizados en los últimos años del siglo XX, a partir del desarrollo de técnicas genéticas y moleculares. Presentamos dos pacientes con pseudohipoaldosteronismo y aparente exceso de mineralocorticoides como síndromes en espejo, con la intención de alertar al médico clínico respecto de su consideración como entidad diagnóstica en niños con alteraciones hidroelectrolíticas. (AU)

Endocrinological syndromes with underactive or overactive hormonal levels with paradoxical dosages have been well characterized over the years of the twentieth century, from the development of genetic and molecular techniques. We present two patients with pseudohypoaldosteronism and apparent mineralocorticoid excess as mirror syndromes, with the aim to alert the clinician regarding their consideration as a diagnostic entity in children with fluid and electrolyte disturbances. (AU)

Aldosterona e IL-17 en la génesis de la hipertensión arterial mineralocorticoídea, un estudio ex vivo / Aldosterone and il-17 in the genesis of mineralocorticoid arterial hypertension: an ex vivo study

Background: Treatment of dendritic cells (DC) with aldosterone induces the secretion of IL-6 and TGF-beta. The polarization of naïve T cells to helper 17 T lymphocytes with DCs pre-incubated with aldosterone, has been described in vivo, generating an IL-17 hyper-secreting phenotype, a cytokine associated with cardiac and renal fibrosis. There are mineralocorticoid receptors (MR) in immune cells and their activation may determine the inflammatory (M1) or adaptive (M2) macrophage phenotype. Aldosterone levels could regulate immunogenic gene expression in these cells, modulating the liberation of specific cytokines. Aim: To assess in humans the association of aldosterone levels and IL-17 with inflammatory markers in peripheral blood mononuclear cells (PBMC). Material and Methods: In blood samples of 176 participants aged 18 to 67 years (61 percent women) with a body mass index of 27.1 +/- 4.8 kg/m2, aldosterone, plasma renin activity (ARP), cortisol, C reactive protein, andIL-17 were measured. mRNA was isolated from PBMCs to measure the expression of MR RAC-1, HO-1, TLR-4, CD-14, NGAL and IL-17 by real time polymerase chain reaction. Results: Aldosterone correlated positively with ARP and the expression of CD-14 in PBMCs. Plasma levels of IL-17 were positively associated with the expression of MR, Rac1a and NGAL. Conclusions: Aldosterone and IL-17 levels were associated with inflammatory activation markers in PBMC, which could activate MRand promote a subclinical inflammatory status inducing hypertension.

Screening for primary aldosteronism in an argentinian population: a multicenter prospective study

Objectives Primary aldosteronism (PA) is characterized by the autonomous overproduction of aldosterone. Its prevalence has increased since the use of the aldosterone (ALD)/plasma renin activity (PRA) ratio (ARR). The objective of this study is to determine ARR and ARC (ALD/plasma renin concentration ratio) cut-off values (COV) and their diagnostic concordance (DC%) in the screening for PA in an Argentinian population.Design multicenter prospective study.Subjects and methods We studied 353 subjects (104 controls and 249 hypertensive patients). Serum aldosterone, PRA and ARR were determined. In 220 randomly selected subjects, 160 hypertensive patients and 60 controls, plasma renin concentration (PRC) was simultaneously measured and ARC was determined.Results According to the 95th percentile of controls, we determined a COV of 36 for ARR and 2.39 for ARC, with ALD ≥ 15 ng/dL. In 31/249 hypertensive patients, ARR was ≥ 36. PA diagnosis was established in 8/31 patients (23/31 patients did not complete confirmatory tests). DC% between ARR and ARC was calculated. A significant correlation between ARR and ARC (r = 0.742; p < 0.0001) was found only with PRA > 0.3 ng/mL/h and PRC > 5 pg/mL. DC% for ARR and ARC above or below 36 and 2.39 was 79.1%, respectively.Conclusion This first Argentinian multicenter study determined a COV of 36 for ARR and 2.39 for ARC. Applying an ARR ≥ 36 in the hypertensive group, we confirmed PA in a higher percentage of patients than the previously reported one in our population. As for ARC, further studies are needed for its clinical application, since DC% is acceptable only for medium range renin values.

Changes in cardiac aldosterone and its synthase in rats with chronic heart failure: an intervention study of long-term treatment with recombinant human brain natriuretic peptide

The physiological mechanisms involved in isoproterenol (ISO)-induced chronic heart failure (CHF) are not fully understood. In this study, we investigated local changes in cardiac aldosterone and its synthase in rats with ISO-induced CHF, and evaluated the effects of treatment with recombinant human brain natriuretic peptide (rhBNP). Sprague-Dawley rats were divided into 4 different groups. Fifty rats received subcutaneous ISO injections to induce CHF and the control group (n=10) received equal volumes of saline. After establishing the rat model, 9 CHF rats received no further treatment, rats in the low-dose group (n=8) received 22.5 μg/kg rhBNP and those in the high-dose group (n=8) received 45 μg/kg rhBNP daily for 1 month. Cardiac function was assessed by echocardiographic and hemodynamic analysis. Collagen volume fraction (CVF) was determined. Plasma and myocardial aldosterone concentrations were determined using radioimmunoassay. Myocardial aldosterone synthase (CYP11B2) was detected by quantitative real-time PCR. Cardiac function was significantly lower in the CHF group than in the control group (P<0.01), whereas CVF, plasma and myocardial aldosterone, and CYP11B2 transcription were significantly higher than in the control group (P<0.05). Low and high doses of rhBNP significantly improved hemodynamics (P<0.01) and cardiac function (P<0.05) and reduced CVF, plasma and myocardial aldosterone, and CYP11B2 transcription (P<0.05). There were no significant differences between the rhBNP dose groups (P>0.05). Elevated cardiac aldosterone and upregulation of aldosterone synthase expression were detected in rats with ISO-induced CHF. Administration of rhBNP improved hemodynamics and ventricular remodeling and reduced myocardial fibrosis, possibly by downregulating CYP11B2 transcription and reducing myocardial aldosterone synthesis.

Adrenal Cortical Scintigraphy for Lateralization of Bilateral Adrenal Nodules in Primary Aldosteronism

No abstract available.

Aldosterone secretion in patients with septic shock: a prospective study / Secreção de aldosterona em pacientes com choque séptico: estudo prospectivo

OBJECTIVE: To assess serum levels of the main factors that regulate the activation of the zona glomerulosa and aldosterone production in patients with septic shock, as well as their response to a high-dose (250 µg) adrenocorticotropic hormone (ACTH) stimulation test. SUBJECTS AND METHODS: In 27 patients with septic shock, baseline levels of aldosterone, cortisol, ACTH, renin, sodium, potassium, and lactate were measured, followed by a cortrosyn test. RESULTS: Renin correlated with baseline aldosterone and its variation after cortrosyn stimulation. Baseline cortisol and its variation did not correlate with ACTH. Only three patients had concomitant dysfunction of aldosterone and cortisol secretion. CONCLUSIONS: Activation of the zona glomerulosa and zona fasciculata are independent. Aldosterone secretion is dependent on the integrity of the renin-angiotensin-aldosterone system, whereas cortisol secretion does not appear to depend predominantly on the hypothalamic-pituitary-adrenal axis. These results suggest that activation of the adrenal gland in critically ill patients occurs by multiple mechanisms.

OBJETIVO: Avaliar os níveis séricos dos principais fatores que regulam a ativação da zona glomerulosa e a produção de aldosterona em pacientes com choque séptico, assim como sua resposta ao teste de cortrosina em alta dose (250 µg). SUJEITOS E MÉTODOS: Em 27 portadores de choque séptico, foram aferidos níveis basais de aldosterona, cortisol, ACTH, renina, sódio, potássio e lactato, bem como realizado teste de cortrosina. RESULTADOS: Renina se correlacionou com níveis basais de aldosterona e sua variação após teste de cortrosina. Cortisol basal e sua variação não se correlacionaram com ACTH. Apenas três pacientes apresentaram disfunção concomitante da secreção de aldosterona e cortisol. CONCLUSÕES: Ativação das zonas fasciculada e glomerulosa são independentes. Secreção de aldosterona é dependente da integridade do sistema renina-angiotensina-aldosterona, enquanto secreção de cortisol não parece predominantemente dependente do eixo hipotálamo-hipófise-adrenal. Esses resultados sugerem que a ativação da adrenal em pacientes críticos ocorre por múltiplos mecanismos.

Additional antihypertensive effect of magnesium supplementation with an angiotensin II receptor blocker in hypomagnesemic rats

BACKGROUND/AIMS: Magnesium (Mg) is an essential element for vascular function and blood pressure regulation. Several studies have demonstrated that Mg concentration is inversely associated with blood pressure, and that Mg supplementation attenuates hypertension. The purpose of this study was to evaluate the effect of dietary Mg supplementation on the blood pressure effects of an angiotensin II receptor blocker (ARB) in hypomagnesemic rats. METHODS: Fifty male Sprague-Dawley rats were randomly divided into Mg-deficient (n = 30), normal diet plus Mg (n = 10), and control groups (n = 10). Mg-free, high-Mg, and normal-Mg diets were respectively fed to the rats. After 14 weeks, 10 of the 30 Mg-deficient rats were treated with Mg, 10 Mg-deficient rats received an ARB, and 10 Mg-deficient rats received an ARB plus Mg for 4 weeks. RESULTS: Systolic blood pressure was significantly higher in the Mg-deficient rats than in the control rats at week 14. Hypomagnesemic rats exhibited decreased systolic blood pressure after treatment with Mg, and systolic blood pressure showed a greater decrease after ARB treatment. Treatment with the ARB/Mg combination resulted in the greatest decrease in systolic blood pressure. Mg deficiency did not affect the serum angiotensin II level, but did increase the serum aldosterone concentration. Concomitant Mg/ARB supplementation significantly decreased the elevated serum aldosterone level in hypomagnesemic rats. Kidney tissues of the hypomagnesemic rats revealed mild to moderate inflammatory infiltrates. Mg and/or ARB treatment did not reverse the inflammatory reaction in the kidneys of hypomagnesemic rats. CONCLUSIONS: Concurrent dietary Mg supplementation can enhance ARB-induced blood pressure reduction in rats with hypomagnesemic hypertension.

Leptina e aldosterona na atividade simpática na hipertensão resistente, com ou sem Diabetes Tipo 2 / Leptin and aldosterone in sympathetic activity in resistant hypertension with or without type 2 diabetes

FUNDAMENTO: A descoberta da leptina como um estimulador da atividade simpática trouxe uma nova perspectiva para os mecanismos fisiopatológicos da obesidade-hipertensão. OBJETIVO: Avaliamos a relação entre a atividade simpática aumentada e as concentrações plasmáticas de leptina e aldosterona em Hipertensos Resistentes (HR), comparando os grupos com e sem Diabetes Tipo 2 (DT2). MÉTODOS: Vinte e cinco pacientes HR foram avaliados por eletrocardiografia ambulatorial para análise da Variabilidade da Frequência Cardíaca (VFC) nos domínios do tempo e frequência, os quais foram estratificados em dois períodos: 24 horas e período Diurno (D), compreendendo as medidas entre 14 e 18h (domínio do tempo) e uma hora às 15h (domínio da frequência). RESULTADOS: O grupo DT2 (n = 10) apresentou maiores concentrações de aldosterona e leptina que o grupo não DT2 (n = 15) (26,0 ± 11,5 vs. 16,9 ± 7,0 ng/dL - p = 0,021; 81,368.7 ± 47,086.1 vs. 41,228.1 ± 24,523.1 pg/mL - p = 0,048, respectivamente). Houve correlação entre aldosterona e VFC no domínio da frequência em ambos os grupos. Não-DT2 apresentaram a aldosterona correlacionada com D baixa frequência em unidades normalizadas (BFnu) (r = 0,6 [0,12 - 0,85] p = 0,018) e D alta frequência em unidades normalizadas (AFnu) (r = -0,6 [-0,85 - -0,12] p = 0,018). No grupo com diabetes, a aldosterona correlacionou-se com DBFnu (r = 0,72 [0,16 - 0,93] p = 0,019) e DAFnu (r = -0,72 [-0,93 - -0,16] p = 0,019). Apesar da importância da leptina na atividade simpática aumentada na hipertensão, não houve correlação com VFC. CONCLUSÃO: A aldosterona parece estimular a atividade simpática em HR com ou sem DT2. Essa informação combinada com a eficácia clínica dos bloqueadores de receptor mineralocorticoide em HR pode reforçar a aldosterona como alvo terapêutico relevantes em HR. (Arq Bras Cardiol. 2012; [online].ahead print, PP.0-0).

BACKGROUND: The finding of adipocyte-derived hormone leptin as an overstimulator of sympathetic activity brought a new perspective to the pathophysiological mechanisms of obesity-hypertension. OBJECTIVES: As aldosterone also increases sympathetic activity, we aimed to assess the relationship between sympathetic overactivity and plasma leptin and aldosterone levels in resistant hypertension (RHTN), comparing the groups with and without T2D. METHODS: Twenty-five RHTN patients underwent ambulatory electrocardiography to analyze heart rate variability (HRV) in time and frequency domains, which were stratified into two periods: 24 hours and daytime (DT), comprising the records between 2:00 p.m to 6:00 p.m (time domain) and one hour at 3:00 p.m (frequency domain). RESULTS: T2D group (n=10) had higher serum aldosterone and plasma leptin levels than the non-T2D (n=15) (26.0±11.5 vs. 16.9±7.0 ng/dL - p=0.021; 81.368.7±47.086.1 vs 41.228.1±24.523.1 pg/mL - p=0.048, respectively). Both groups had aldosterone correlated with HRV in frequency domain. Non-T2D had aldosterone correlated with DT low frequency in normalized units (LF nu) (r=0.6 [0.12-0.85] p=0.018) and DT high frequency in normalized units (HF nu) (r=-0.6 [-0.85- -0.12] p=0.018). Type-2-diabetes group had aldosterone correlated with DT LF nu (r=0.72 [0.16-0.93] p=0.019) and DT HF nu (r=-0.72 [-0.93- -0.16] p=0.019). However, despite of the importance of leptin in sympathetic overactivity in hypertension, leptin did not correlate with HRV. CONCLUSION: Aldosterone seems to overdrive sympathetic activity in RHTN with and without T2D. This information combined with the clinical efficacy of mineralocorticoid receptor blocker in RHTN may reinforce that aldosterone is a major player to be a therapeutic target in RHTN. (Arq Bras Cardiol. 2012; [online].ahead print, PP.0-0).

Utilidad de la relación aldosterona y actividad renina plasmática en el diagnóstico de hiperaldosteronismo primario / Aldosterone/renin ratio in the diagnosis of primary aldosteronism

El hiperaldosteronismo primario (HP) es la forma más común de hipertensión arterial (HTA) secundaria. Recientemente varios estudios sugieren que la prevalencia de esta enfermedad varía entre 5% y 15% entre la población hipertensa, y 20% para hipertensión arterial refractaria. El objetivo de este estudio fue, ante la gran variabilidad de prevalencias sobre HP según las publicaciones internacionales y pocos datos en la Argentina, aportar la prevalencia de HP en un hospital general del interior del país, relacionándolo con el grado de HTA y presencia de normokalemia. En este estudio transversal se realizó dosaje de A/ARP en 123 pacientes hipertensos, suspendiendo toda medicación que interfiriera en los dosajes hormonales; se utilizó como método confirmatorio el test de solución salina (SS) para el diagnóstico de HP y la tomografía computarizada (TC) de abdomen para el diagnóstico etiológico del HP. Se detectó una relación A/ARP elevada en 20 (16.4%) pacientes. En 18 se realizó el test de SS, confirmando el diagnóstico de aldosteronismo en 8 (6.5% del total). En la TC, dos presentaron adenomas, y seis glándulas suprarrenales normales. Todos los pacientes con HP pertenecían al grupo II y III de HTA según el VI Joint National Committee (VI JNC) y el 50% fue normokalémico. Encontramos una prevalencia de 6.5% de HP, asociado a grado II y III de hipertensión, y valores de potasio normal en la mitad de los pacientes.

Primary aldosteronism (PA) is a possible cause of endocrine hypertension. Recent studies have suggested a prevalence ranging between 5% and 15% of all hypertensive patients, and 20% in patients with refractory hypertension.The objective of this transversal study was to establish the prevalence of PA in a hypertensive population using the aldosterone / plasma renin ratio (ARR) as a screening method, considering that the prevalence rates for PA among hypertensive people present a wide range and that there are only few reports in Argentina. This ratio was then related with the degree of hypertension and with the presence or absence of hypokalemia. Serum aldosterone and plasma renin activity levels were measured in 123 hypertensive patients after discontinuing all medications that could interfere with the hormonal tests. Patients with an aldosterone/plasma renin activity ratio > 25 were submitted to the saline suppression test (SST) to confirm the diagnosis of PA, followed by computed tomography (CT) of the abdomen. Twenty patients presented an ARR > 25 (16.4%). Eighteen were submitted to the SST, eight had a diagnosis of PA confirmed with positive SST (6.5%). Of 8 patients who underwent an abdominal CT, two showed adenoma, and six normal adrenal anatomy. All the eight patients with a PA diagnosis belonged to group II and III of hypertension according to Joint National Committee VI (JNC VI), and only 4 (50%) were normokalemic. We found a 6.5% prevalence of PA, associated with grade II and III hypertension, and normal potassium values in half of the patients with PA.

A comparison between sphygmomanometer-based and ambulatory blood pressure monitoring in acute salt loading and depletion protocol

INTRODUCTION: Ambulatory blood pressure monitors have been used in salt loading and depletion protocols. However, the agreement between measurements made using ambulatory blood pressure monitors and those made with the sphygmomanometer has not been evaluated. OBJECTIVE: The objective of this study was to compare the concordance of the two methods of blood pressure measurements in protocols of acute salt loading and depletion. METHOD: Systolic blood pressure was measured using a sphygmomanometer at the completion of salt infusion (2 L NaCl 0.9 percent, 4 h) and salt depletion (furosemide, 120mg/day, p.o.) in 18 volunteers. Using the Pearson correlation coefficient (ρ), these readings were compared with the mean systolic blood pressure measured using the ambulatory blood pressure monitoring device during the following periods: 4 h of saline infusion and 12 h of salt depletion; 4 h of saline infusion and the last 6 h of salt depletion; 12 h of salt loading and the last 6 h of depletion; 12 h of salt loading and 12 h of depletion. Salt sensitivity was defined by a difference in the systolic blood pressure between salt loading and salt depletion greater than 10 mmHg when measured with the sphygmomanometer, and the Kappa analysis of concordance (K) was used with a significance level of P<0.05. RESULTS: Only the blood pressure readings obtained using the ambulatory blood pressure device during 4 h of intravenous NaCl and during 12 h of salt depletion showed a high correlation with the variation in the systolic blood pressure measured by the sphygmomanometer, with a full agreement with the salt sensitivity classification (p = 0.71; P = 0.001 and K=1). CONCLUSION: In acute salt loading and depletion protocols, an ambulatory blood pressure monitoring device should be used to record the blood pressure during the 4-h interval of salt infusion and 12-h interval of salt depletion.

Role of 11â-hydroxysteroid dehydrogenase 2 renal activity in potassium homeostasis in rats with chronic renal failure

Aldosterone concentrations vary in advanced chronic renal failure (CRF). The isozyme 11â-hydroxysteroid dehydrogenase 2 (11â-HSD2), which confers aldosterone specificity for mineralocorticoid receptors in distal tubules and collecting ducts, has been reported to be decreased or normal in patients with renal diseases. Our objective was to determine the role of aldosterone and 11â-HSD2 renal microsome activity, normalized for glomerular filtration rate (GFR), in maintaining K+ homeostasis in 5/6 nephrectomized rats. Male Wistar rats weighing 180-220 g at the beginning of the study were used. Rats with experimental CRF obtained by 5/6 nephrectomy (N = 9) and sham rats (N = 10) were maintained for 4 months. Systolic blood pressure and plasma creatinine (Pcr) concentration were measured at the end of the experiment. Sodium and potassium excretion and GFR were evaluated before and after spironolactone administration (10 mg·kg-1·day-1 for 7 days) and 11â-HSD2 activity on renal microsomes was determined. Systolic blood pressure (means ± SEM; Sham = 105 ± 8 and CRF = 149 ± 10 mmHg) and Pcr (Sham = 0.42 ± 0.03 and CRF = 2.53 ± 0.26 mg/dL) were higher (P < 0.05) while GFR (Sham = 1.46 ± 0.26 and CRF = 0.61 ± 0.06 mL/min) was lower (P < 0.05) in CRF, and plasma aldosterone (Pald) was the same in the two groups. Urinary sodium and potassium excretion was similar in the two groups under basal conditions but, after spironolactone treatment, only potassium excretion was decreased in CRF rats (sham = 0.95 ± 0.090 (before) vs 0.89 ± 0.09 µEq/min (after) and CRF = 1.05 ± 0.05 (before) vs 0.37 ± 0.07 µEq/min (after); P < 0.05). 11â-HSD2 activity on renal microsomes was lower in CRF rats (sham = 0.807 ± 0.09 and CRF = 0.217 ± 0.07 nmol·min-1·mg protein-1; P < 0.05), although when normalized for mL GFR it was similar in both groups. We conclude that K+ homeostasis is ...

Genetic Analyses of the Chimeric CYP11B1/CYP11B2 Gene in a Korean Family with Glucocorticoid-Remediable Aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.

Predictors of Resolution of Hypertension after Adrenalectomy in Patients with Aldosterone-producing Adenoma

Primary aldosteronism (PA) is a frequent cause of secondary hypertension and is amenable to surgical intervention when it is caused by aldosterone-producing adenoma (APA). Many patients, however, continue to require antihypertensive medications to control their blood pressure after adrenalectomy. The aim of this study was to determine the preoperative factors that predict clinical outcomes after adrenalectomy in patients with APA. We studied 27 patients (mean age 45+/-4 yr) who had APA and underwent unilateral adrenalectomy between December 1995 and September 2008 at our institution. Clinical and biochemical data were evaluated at baseline and after a mean follow-up of 51.8+/-47.0 months (range, 6-159). At the end of the follow-up, 16 patients (59.3%) were considered to experience "complete resolution" without postoperative medications, whereas 7 patients (25.9%) "improved" with medications and 4 patients (14.8%) were "uncontrolled." Three factors (< or =2 antihypertensive medications [P=0.007], duration of hypertension <6 yr [P=0.002], and serum aldosterone <350 pg/mL [P<0.001]) were the predictive for complete resolution in univariate analysis. Multivariate regression analysis showed that serum aldosterone level (<350 pg/mL) was the single most important factor that predicted complete resolution after surgery (P<0.001). The best preoperative clinical factor that predicted resolution of postoperative hypertension after adrenalectomy is serum aldosterone level (<350 pg/mL).

Hyponatremia and brain injury: absence of alterations of serum brain natriuretic peptide and vasopressin / Hiponatremia e traumatismo cranioencefálico: ausência de alteração sanguínea do peptídeo natriurético cerebral e hormônio antidiurético

OBJECTIVE: To study any possible relation between hyponatremia following brain injury and the presence of cerebral salt-wasting syndrome (CSWS) or the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and if vasopressin, brain natriuretic peptide (BNP) and aldosterone have a role in its mechanism. METHOD: Patients with brain injury admitted to the intensive care unit were included and had their BNP, aldosterone and vasopressin levels dosed on day 7. RESULTS: Twenty six adult patients were included in the study. Nine (34.6 percent) had hyponatremia and presented with a negative water balance and higher values of urinary sodium, serum potassium and diuresis than patients with normonatremia. The serum levels of BNP, aldosterone, and vasopressin were normal and no relation was observed between plasma sodium and BNP, aldosterone or vasopressin. CONCLUSION: The most likely cause of hyponatremia was CSWS and there was no correlation between BNP, aldosterone and vasopressin with serum sodium level.

OBJETIVO: Estudar a possível relação entre a hiponatremia seguindo traumatismo cranioencefálico e a presença da síndrome cerebral perdedora de sal (SCPS) ou a síndrome da secreção inapropriada do hormônio antidiurético (SSIHAD), e se a vasopressina, peptídeo natriurético cerebral (BNP) e aldosterona têm um papel nesse mecanismo. MÉTODO: Foram incluídos pacientes com traumatismo cranioencefálico admitidos na unidade de terapia intensiva e foram dosados no sétimo dia seguindo o trauma, BNP, aldosterona e vasopressina. RESULTADOS: Vinte e seis pacientes foram incluídos no estudo. Nove (34,6 por cento) tiveram hiponatremia e apresentaram um balanço hídrico mais negativo e altos valores de sódio urinário, potássio sérico e diurese quando comparados com o grupo que apresentou normonatremia. Os níveis séricos de BNP, aldosterona e vasopressina foram normais e não foi observada relação entre o sódio sérico e BNP, aldosterona e vasopressina. CONCLUSÃO: A causa mais provável da hiponatremia foi a SCPS e não houve correlação entre BNP, aldosterona e vasopressina com o nível sérico de sódio.

A pilot study on hypothalamo-pituitary-adrenocortical axis in primary hyperparathyroidism.

Background & objectives: Parathormone (PTH) and calcium, both have been shown to stimulate adrenal steroidogenesis in animal models and in vitro experiments. This is attributed to structural similarity between 15-25 amino acid region of the parathyroid hormone (PTH) and 1-11 amino acid region of adrenocorticotropin (ACTH). However, there are no in vivo human data regarding the effect of PTHcalcium axis on adrenocortical function. Materials: Ten patients with primary hyperparathyroidism underwent evaluation for cortisol dynamics including 0800 h and 2000 h plasma cortisol on day 1, cortisol response to insulin induced hypoglycaemia (IIH) on day 2, and 1 mg overnight dexamethasone suppression test (ONDST) on day 4. Serum aldosterone was also measured at 0800 h in fasting state on salt ad libitum for three days. These parameters were repeated 3 months after curative parathyroidectomy. Results: Basal plasma cortisol level at 0800 h and 2000 h were within upper normal range and loss of circadian rhythm in cortisol secretion was observed in half and forty per cent of patients had nonsuppressibility with ONDST. The defined peak cortisol response to insulin induced hypoglycaemia (>550 nmol/l) was achieved in all and nearly one third of patients had exaggerated response (>2000 nmol/l). After curative parathyroidectomy, the abnormalities in circadian rhythm and non-suppressibility with ONDST continued to prevail in 40 per cent of patients. The peak cortisol response to IIH showed a decrement but remained higher than normal. No correlation was observed between circulating parathyroid hormone and calcium with cortisol levels. Serum aldosterone was in upper normal range pre - and postoperatively, though it decreased postoperatively, but it could not attain a statistical significance (p = 0.5). Interpretation & conclusion: Abnormalities in hypothalamo-pituitary-adrenocortical axis in primary hyperparathyroidism do occur, however these are inconsistent and do not recover in majority of patients even after 3 months of curative parathyroidectomy.

Prevalência do hiperaldosteronismo primário em uma liga de hipertensão arterial sistêmica / Prevalencia del hiperaldosteronismo primario en una liga de hipertensión arterial sistémica / Prevalence of primary hyperaldosteronism in a systemic arterial hypertension league

FUNDAMENTO: Até recentemente, o hiperaldosteronismo primário era considerado uma causa rara de hipertensão secundária. Porém, ao longo dos últimos anos, muitos estudos têm sugerido que essa doença pode afetar até 20 por cento dos hipertensos. OBJETIVO: Determinar a prevalência do hiperaldosteronismo primário em pacientes hipertensos em tratamento na liga de hipertensão de um hospital universitário. MÉTODOS: Foram realizadas dosagens de aldosterona sérica e atividade plasmática da renina em 105 pacientes, em vigência do tratamento anti-hipertensivo usual, excetuando-se aqueles em uso de beta-bloqueadores e espironolactona, em jejum e após repouso na posição deitada por 20 minutos. Aqueles com relação aldosterona/atividade plasmática da renina maior que 25 foram submetidos ao teste de supressão com sobrecarga salina endovenosa e, após a confirmação da autonomia da secreção de aldosterona, foi realizada tomografia computadorizada das adrenais. Os resultados são apresentados como porcentagens, médias e desvios-padrão. RESULTADOS: Dos 105 pacientes, 6,54 por cento eram hipertensos refratários. Nove apresentaram relação aldosterona/atividade plasmática da renina > 25 (8,5 por cento do total). Destes, oito foram submetidos ao teste de supressão e um (hipertenso refratário) teve o diagnóstico confirmado de hiperaldosteronismo primário (0,96 por cento do total). Foi realizada tomografia computadorizada de adrenais, sendo considerada normal. CONCLUSÃO: A prevalência do hiperaldosteronismo primário na amostra estudada foi de 0,96 por cento do total. No entanto, quando avaliados apenas os portadores de hipertensão refratária, a prevalência foi de 14,3 por cento.

BACKGROUND: Until recently, primary hyperaldosteronism was considered a rare cause of secondary hypertension. However, in recent years, many studies have suggested that this disease can affect up to 20 percent of hypertensive individuals. OBJECTIVE: To determine the prevalence of primary hyperaldosteronism in hypertensive patients treated at the hypertension league of a university hospital. METHODS: Serum aldosterone and plasma renin activity levels were measured in 105 patients while they were undergoing standard antihypertensive treatment, with the exception of those using betablockers and spironolactone, in fasting condition and after rest in the supine position for 20 minutes. Those with an aldosterone/plasma renin activity ratio > 25 were submitted to the saline suppression test and, after the confirmation of the autonomy of aldosterone secretion, a computed tomography of the adrenals was performed. The results are presented as percentages and means and standard deviations. RESULTS: Of the 105 patients, 6.54 percent presented refractory hypertension. Nine presented an aldosterone/plasma renin activity ratio > 25 (8.5 percent of the total). Of these, 08 were submitted to the saline suppression test and 01 (with refractory hypertension) had the diagnosis of primary hyperaldosteronism confirmed (0.96 percent of the total). A computed tomography of the adrenals was performed, which showed normal results. CONCLUSION: The prevalence of primary hyperaldosteronism in the studied sample was 0.96 percent of the total. However, when only the patients with refractory hypertension were evaluated, the prevalence was 14.3 percent.

FUNDAMENTO: Hasta recientemente, se consideraba el hiperaldosteronismo primario como una causa rara de hipertensión secundaria. Sin embargo, a lo largo de los últimos años, muchos estudios han sugerido que esa enfermedad puede afectar hasta el 20 por ciento de los hipertensos. OBJETIVO: Determinar la prevalencia del Hiperaldosteronismo Primario en pacientes hipertensos en tratamiento en la Liga de Hipertensión de un Hospital Universitario. MÉTODOS: Se realizaron dosificaciones de aldosterona sérica y actividad plasmática de la renina en 105 pacientes, en vigencia del tratamiento antihipertensivo usual, excepto aquellos en uso de betabloqueantes y espironolactona, en ayuno y tras guardar reposo en posición acostada por 20 minutos. Aquellos con relación aldosterona/actividad plasmática de la renina mayor que 25 se sometieron a prueba de supresión con sobrecarga salina endovenosa y, luego de la confirmación de la autonomía de la secreción de aldosterona, se realizó tomografía computarizada de las adrenales. Los resultados se presentan como porcentajes, promedios y desviaciones estándar. RESULTADOS: De los 105 pacientes, el 6,54 por ciento eran hipertensos refractarios. Nueve presentaron relación aldosterona/actividad plasmática de la renina > 25 (8,5 por ciento del total). De estos, ocho se sometieron al examen de supresión y uno (hipertenso refractario) tuvo el diagnóstico confirmado de Hiperaldosteronismo Primario (el 0,96 por ciento del total). Se realizó una tomografía computarizada de adrenales, que estaba normal. CONCLUSIÓN: La prevalencia del Hiperaldosteronismo Primario en la muestra estudiada fue del 0,96 por ciento del total. Sin embargo, cuando se evaluaron sólo los portadores de hipertensión refractaria, la prevalencia fue del 14,3 por ciento.