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1.
Eur J Endocrinol ; 183(6): R185-R196, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33077688

RESUMO

Primary aldosteronism is common and contributes to adverse cardiovascular, kidney, and metabolic outcomes. When instituted early and effectively, targeted therapies can mitigate these adverse outcomes. Surgical adrenalectomy is among the most effective treatments because it has the potential to cure, or attenuate the severity of, pathologic aldosterone excess, resulting in a host of biochemical and clinical changes that improve health outcomes. Herein, we review the role of surgical adrenalectomy in primary aldosteronism while emphasizing the physiologic ramifications of surgical intervention, and compare these to other targeted medical therapies for primary aldosteronism. We specifically review the role of curative adrenalectomy for unilateral primary aldosteronism, the role of non-curative adrenalectomy for bilateral primary aldosteronism, and how these interventions influence biochemical and clinical outcomes in relation to medical therapies for primary aldosteronism.


Assuntos
Adrenalectomia/tendências , Aldosterona/sangue , Hiperaldosteronismo/sangue , Hiperaldosteronismo/cirurgia , Adrenalectomia/métodos , Doenças do Sistema Endócrino/sangue , Doenças do Sistema Endócrino/cirurgia , Cardiopatias/sangue , Cardiopatias/prevenção & controle , Humanos , Nefropatias/sangue , Nefropatias/prevenção & controle
2.
Eur J Endocrinol ; 183(6): 657-667, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33112264

RESUMO

Objective: Adrenal venous sampling (AVS) is the gold standard to discriminate patients with unilateral primary aldosteronism (UPA) from bilateral disease (BPA). AVS is technically demanding and in cases of unsuccessful cannulation of adrenal veins, the results may not always be interpreted. The aim of our study was to develop diagnostic models to distinguish UPA from BPA, in cases of unilateral successful AVS and the presence of contralateral suppression of aldosterone secretion. Design: Retrospective evaluation of 158 patients referred to a tertiary hypertension unit who underwent AVS. We randomly assigned 110 patients to a training cohort and 48 patients to a validation cohort to develop and test the diagnostic models. Methods: Supervised machine learning algorithms and regression models were used to develop and validate two prediction models and a simple 19-point score system to stratify patients according to their subtype diagnosis. Results: Aldosterone levels at screening and after confirmatory testing, lowest potassium, ipsilateral and contralateral imaging findings at CT scanning, and contralateral ratio at AVS, were associated with a diagnosis of UPA and were included in the diagnostic models. Machine learning algorithms correctly classified the majority of patients both at training and validation (accuracy: 82.9-95.7%). The score system displayed a sensitivity/specificity of 95.2/96.9%, with an AUC of 0.971. A flow-chart integrating our score correctly managed all patients except 3 (98.1% accuracy), avoiding the potential repetition of 77.2% of AVS procedures. Conclusions: Our score could be integrated in clinical practice and guide surgical decision-making in patients with unilateral successful AVS and contralateral suppression.


Assuntos
Glândulas Suprarrenais/irrigação sanguínea , Aldosterona/sangue , Coleta de Amostras Sanguíneas/estatística & dados numéricos , Hiperaldosteronismo/diagnóstico , Adulto , Coleta de Amostras Sanguíneas/métodos , Diagnóstico Diferencial , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Análise de Regressão , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Veias
4.
PLoS One ; 15(8): e0237364, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764816

RESUMO

OBJECTIVES: Uromodulin has been associated with arterial hypertension in genome-wide association studies, but data from clinical and preclinical studies are inconsistent. We here analyzed the association of serum uromodulin (sUmod) with arterial hypertension and vasoactive hormones in a population-based study. METHODS: In 1108 participants of the KORA F4 study aged 62-81 years, sUmod was measured and the association of sUmod with arterial hypertension was assessed using logistic regression models. The associations of sUmod with renin and aldosterone and with the vasoconstrictive prohormone C-terminal pro-endothelin-1 (CT-proET-1) were analyzed in 1079 participants and in 618 participants, respectively, using linear regression models. RESULTS: After multivariable adjustment including sex, age, eGFR, BMI, fasting glucose, current smoking, previous stroke and myocardial infarction, sUmod was inversely associated with arterial hypertension (OR 0.78; 95% CI 0.68-0.91; p = 0.001). SUmod was not significantly associated with renin and aldosterone after adjustment for sex, age and eGFR. However, sUmod was inversely associated with CT-proET-1 (ß -0.19 ± 0.04; p < 0.001) after adjustment for sex, age, eGFR, BMI, arterial hypertension, fasting glucose, current smoking, previous stroke and myocardial infarction. The association with CT-proET-1 was stronger in participants with hypertension (ß -0.22 ± 0.04) than in normotensive participants (ß -0.13 ± 0.06; p for interaction hypertension = 0.003 in the model adjusted for hypertension). CONCLUSIONS: SUmod was inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1, suggesting direct or indirect effects of sUmod on blood pressure regulation.


Assuntos
Endotelina-1/sangue , Hipertensão/sangue , Fragmentos de Peptídeos/sangue , Uromodulina/sangue , Idoso , Aldosterona/sangue , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Renina/sangue
5.
Medicine (Baltimore) ; 99(29): e20826, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702825

RESUMO

RATIONALE: The typical clinical presentations of patients with primary aldosteronism (PA) include generalized weakness, fatigue, high blood pressure, and potassium deficiency. However, normotensive PA is rare. Therefore, an atypical presentation of normal blood pressure is a challenge for the diagnosis and treatment of PA. PATIENT CONCERNS: A 43-year-old, thin, and tall woman (body mass index, 18.6 kg/m) with generalized weakness for 1 day presented to our emergency department, where hypokalemia was a significant finding. The initial diagnosis was anorexia nervosa with the evidence of renal potassium wasting with low urinary sodium and chloride levels, metabolic alkalosis, normal blood pressure, and low body mass index. However, neither vomiting features nor other specific induced vomiting features were noted. DIAGNOSES: The laboratory examination revealed high plasma aldosterone level, low plasma renin activity, and extremely high aldosterone-to-renin ratio indicating the diagnosis of PA, confirmed via adrenal computed tomography. INTERVENTIONS: Surgical adrenalectomy was performed. Pathological diagnosis was a benign cortical adenoma. OUTCOMES: Patient's serum potassium level and hormonal status became normalized after surgical removal of adrenal adenoma. She fully recovered without any further sequelae. LESSONS: It is too early to rule out PA based on the presence of normal blood pressure in a patient with metabolic alkalosis and renal wasting hypokalemia. Moreover, PA should be considered in a normotensive patient with an unknown hypokalemic etiology to avoid delayed diagnosis and treatment.


Assuntos
Anorexia Nervosa/diagnóstico , Hiperaldosteronismo/diagnóstico por imagem , Hipopotassemia/diagnóstico , Adenoma/cirurgia , Adrenalectomia/métodos , Adulto , Aldosterona/sangue , Alcalose/etiologia , Anorexia Nervosa/psicologia , Pressão Sanguínea/fisiologia , Diagnóstico Diferencial , Serviço Hospitalar de Emergência , Feminino , Humanos , Hiperaldosteronismo/sangue , Hiperaldosteronismo/patologia , Hiperaldosteronismo/cirurgia , Hipopotassemia/etiologia , Debilidade Muscular/etiologia , Renina/sangue , Sódio/urina , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
6.
Eur J Endocrinol ; 183(4): 399-409, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698132

RESUMO

Context: Unilateral aldosteronomas should suppress renin and contralateral aldosterone secretion. Complete aldosterone suppression in contralateral adrenal vein sample (AVS) could predict surgical outcomes. Objectives: To retrospectively evaluate the prevalence of basal contralateral suppression using Aldosterone (A)contralateral(CL)/Aperipheral(P) as compared to (A/Cortisol(C)CL)/(A/C)P ratio in primary aldosteronism (PA) patients studied in two Canadian centers. To determine the best cut-off to predict clinical and biochemical surgical cure. To compare the accuracy of ACL/AP to the basal and post-ACTH lateralization index (LI) in predicting surgical cure. Methods: In total, 330 patients with PA and successful AVS were included; 124 lateralizing patients underwent surgery. Clinical and biochemical cure at 3 and 12 months were evaluated using the PASO criteria. Results: Using ACL/AP and (A/C)CL/(A/C)P at the cut-off of 1, the prevalence of contralateral suppression was 6 and 45%, respectively. Using ROC curves, the ACL/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)CL/(A/C)P is associated with biochemical cure only. The cut-offs for ACL/AP offering the best sensitivity (Se) and specificity (Sp) for clinical and biochemical cures at 12 months are 2.15 (Se: 63% and Sp: 71%) and 6.15 (Se: 84% and Sp: 77%), respectively. Basal LI and post-ACTH LI are associated with clinical cure but only the post-ACTH LI is associated with biochemical cure. Conclusions: In lateralized PA, basal contralateral suppression defined by ACL/AP is rare and incomplete compared to the (A/C)CL/(A/C)P ratio and is associated with clinical and biochemical postoperative outcome, but with modest accuracy.


Assuntos
Neoplasias das Glândulas Suprarrenais/sangue , Glândulas Suprarrenais/metabolismo , Adenoma Adrenocortical/sangue , Aldosterona/sangue , Coleta de Amostras Sanguíneas/métodos , Hiperaldosteronismo/sangue , Hiperaldosteronismo/epidemiologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Glândulas Suprarrenais/patologia , Adrenalectomia/estatística & dados numéricos , Adenoma Adrenocortical/diagnóstico , Adenoma Adrenocortical/epidemiologia , Adenoma Adrenocortical/cirurgia , Adulto , Aldosterona/análise , Canadá/epidemiologia , Estudos de Coortes , Técnicas de Diagnóstico Endócrino , Regulação para Baixo , Feminino , Humanos , Hidrocortisona , Hiperaldosteronismo/patologia , Hiperaldosteronismo/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
7.
Anesthesiology ; 133(2): 439-457, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32501957

RESUMO

The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.


Assuntos
Estado Terminal/terapia , Hipoaldosteronismo/sangue , Hipoaldosteronismo/terapia , Mineralocorticoides/sangue , Aldosterona/sangue , Aldosterona/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Glucocorticoides/sangue , Glucocorticoides/uso terapêutico , Humanos , Mineralocorticoides/uso terapêutico
8.
Anaesth Crit Care Pain Med ; 39(4): 453-455, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32565254

RESUMO

The pathophysiology of acute kidney injury (AKI) in COVID-19 patients is still poorly understood. SARS-CoV-2 has been suggested to modulate the renin-angiotensin-aldosterone system (RAAS). In this series of COVID-19 critically ill patients, we report evidence of activation of the RAAS in COVID-19 patients with AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Betacoronavirus , Infecções por Coronavirus/metabolismo , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina/fisiologia , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/terapia , Idoso , Aldosterona/sangue , Infecções por Coronavirus/complicações , Creatinina/sangue , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações
10.
Eur J Endocrinol ; 183(2): 191-201, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32460235

RESUMO

Objective: Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has become state of the art for the quantitative analysis of steroid hormones. Although method comparisons show that aldosterone measurement using LC-MS/MS yields considerably lower levels than immunoassays (IAs), method-specific cutoff values for primary aldosteronism (PA) are largely missing. Objective of this study was to analyze the diagnostic accuracy of proposed LC-MS/MS-specific cutoff values for the saline infusion test (SIT). Design and methods: From 2016 to 2019, 104 consecutive patients suspected of PA underwent the SIT and captopril challenge test in the tertiary medical center at the University Hospital of Leipzig, Germany. Patients with positive case confirmation underwent adrenal imaging and adrenal venous sampling for subtype classification. Results: Overall, proposed assay-specific PACLC-MS/MS cutoff values for the SIT achieved higher diagnostic accuracy than established PACIA values with a sensitivity and specificity of 87.5% (95% CI: 71.0-96.5) and 97% (95% CI: 89.6-99.6) for a cutoff of 120 pmol/L and 93.8% (95% CI: 79.2-99.2) and 92.5% (95% CI: 83.4-97.5) for a cutoff of 94 pmol/L. The most accurate post-SIT PACLC-MS/MS cutoff value in this study was 83 pmol/L, yielding a sensitivity and specificity of 96.9% (95% CI: 83.8-99.9) and 92.5% (95% CI: 83.4-97.5), respectively. Conclusions: The present data confirm the need for the implication of lower method-specific aldosterone cutoff values for the diagnosis of PA with LC-MS/MS based aldosterone measurement.


Assuntos
Aldosterona/sangue , Hiperaldosteronismo/sangue , Hiperaldosteronismo/diagnóstico , Solução Salina/farmacologia , Glândulas Suprarrenais/diagnóstico por imagem , Adulto , Idoso , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Valores de Referência , Reprodutibilidade dos Testes , Solução Salina/administração & dosagem , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem , Adulto Jovem
11.
Am J Cardiol ; 127: 9-15, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32418719

RESUMO

Recent experimental studies have suggested that galectin-3 has an interaction with aldosterone, and modifies its adverse effects. We therefore aimed to elucidate whether the relationship between plasma aldosterone concentrations (PACs) and long-term fatal cardiovascular (CV) events would depend on plasma galectin-3 levels. A total of 2,457 patients (median age: 63.5 [interquartile range (IQR) = 56.3 to 70.6] years, 30.1% women) from the LUdwigshafen RIsk and Cardiovascular Health study, with a median follow-up of 9.9 (IQR = 8.5 to 10.7) years, were included. We tested the interaction between aldosterone and galectin-3 for CV-mortality using a multivariate Cox proportional hazard model, reporting hazard ratios (HRs) with 95% confidence intervals (95%CIs). Adjustments for multiple CV risk factors as well as medication use were included. Mean PAC was 79.0 (IQR = 48.0 to 124.0) pg/ml and there were 558 (16.8%) CV deaths. There was a significant interaction between PAC and galectin-3 (p = 0.021). When stratifying patients by the median galectin-3, there was a significant association between aldosterone and CV-mortality for those above (HR per 1 standard deviation = 1.14; 95%CI [1.01 to 1.30], p = 0.023), but not below the cut-off value (HR per 1 standard deviation = 1.00; 95%CI [0.87 to 1.15], p = 0.185). In conclusion, the current study demonstrates for the first time a modifying effect of galectin-3 on the association between aldosterone and CV-mortality risk in humans. These findings indicate that galectin-3 is an intermediate between aldosterone and adverse outcomes.


Assuntos
Aldosterona/sangue , Doenças Cardiovasculares/sangue , Angiografia Coronária/métodos , Galectina 3/sangue , Medição de Risco/métodos , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendências
12.
Nat Commun ; 11(1): 2673, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471973

RESUMO

Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, ClinicalTrial.gov: NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1st day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes.


Assuntos
Aldosterona/sangue , Aprepitanto/farmacologia , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Adolescente , Córtex Suprarrenal/metabolismo , Glândulas Suprarrenais/metabolismo , Adulto , Aldosterona/metabolismo , Células Cultivadas , Humanos , Hipoglicemia/sangue , Masculino , Metoclopramida , Mineralocorticoides/biossíntese , Placebos/administração & dosagem , Estudo de Prova de Conceito , Estudos Prospectivos , Transaminases/sangue , Adulto Jovem
13.
Am J Respir Crit Care Med ; 202(5): 700-707, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32396775

RESUMO

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.


Assuntos
Aldosterona/sangue , Ácido Ascórbico/sangue , Hidrocortisona/farmacocinética , Choque Séptico/tratamento farmacológico , Idoso , Anti-Inflamatórios/farmacocinética , Austrália/epidemiologia , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Choque Séptico/sangue , Choque Séptico/mortalidade , Taxa de Sobrevida/tendências , Resultado do Tratamento
14.
Am J Cardiol ; 125(12): 1794-1800, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32307090

RESUMO

Experimental studies support a link between activation of the renin-angiotensin-aldosterone system and cardiovascular disease (CVD). The relationship with subclinical atherosclerosis is uncertain. Among 1,699 individuals without prevalent CVD from the Multiethnic Study of Atherosclerosis, we measured plasma renin activity (PRA) and aldosterone. Using multivariable logistic regression with restricted cubic splines, we assessed continuous log-transformed PRA and aldosterone associations with the ankle-brachial index (ABI) and coronary artery calcium (CAC) scores (Agatston) with adjustment for cardiovascular disease (CVD) risk factors, kidney function, and inflammatory biomarkers. In fully adjusted models mutually adjusting for PRA and aldosterone, higher PRA was associated with an ABI <1.0 (p overall <0.001, p nonlinear = 0.02) and CAC Agatston score >300 (p overall = 0.02, p nonlinear = 0.22), while aldosterone was not associated with either outcome. For example, compared to the 10th percentile (0.16 ng/ml/hr) of PRA, the 90th percentile (2.68 ng/ml/hr) had 3.6 times (OR 3.62; 95% CI: 2.13 to 6.13) and 1.7 times higher odds (odds ratio 1.67; 95% confidence interval: 1.13 to 2.48) of ABI <1.0 and CAC >300, respectively. These associations persisted after adjustment for levels of C-reactive protein, Interleukin-6, and Tumor Necrosis Factor-alpha. There were no significant differences in these associations by race/ethnicity or antihypertensive medication status. In conclusion, in a multiethnic cohort of community-living adults without prevalent clinical CVD, PRA was associated with greater burden of subclinical peripheral artery and coronary artery disease. These findings provide additional evidence that PRA may have deleterious effects on cardiovascular health through an atherosclerotic pathway.


Assuntos
Aterosclerose/sangue , Doença da Artéria Coronariana/sangue , Doenças Vasculares Periféricas/sangue , Renina/sangue , Aldosterona/sangue , Índice Tornozelo-Braço , Biomarcadores/sangue , Feminino , Humanos , Inflamação/sangue , Testes de Função Renal , Masculino , Fatores de Risco , Calcificação Vascular/sangue
15.
Am J Physiol Renal Physiol ; 318(5): F1113-F1121, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32174140

RESUMO

Ubiquitination of the epithelial Na+ channel (ENaC) in epithelial cells may influence trafficking and hormonal regulation of the channels. We assessed ENaC ubiquitination (ub-ENaC) in mouse and rat kidneys using affinity beads to capture ubiquitinated proteins from tissue homogenates and Western blot analysis with anti-ENaC antibodies. Ub-αENaC was observed primarily as a series of proteins of apparent molecular mass of 40-70 kDa, consistent with the addition of variable numbers of ubiquitin molecules primarily to the NH2-terminal cleaved fragment (~30 kDa) of the subunit. No significant Ub-ßENaC was detected, indicating that ubiquitination of this subunit is minimal. For γENaC, the protein eluted from the affinity beads had the same apparent molecular mass as the cleaved COOH-terminal fragment of the subunit (~65 kDa). This suggests that the ubiquitinated NH2 terminus remains attached to the COOH-terminal moiety during isolation through disulfide bonds. Consistent with this, under nonreducing conditions, eluates contained material with increased molecular mass (90-150 kDa). In mice with a Liddle syndrome mutation (ß566X) deleting a putative binding site for the ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-2, the amount of ub-γENaC was reduced as expected. To assess aldosterone dependence of ubiquitination, we fed rats either control or low-Na+ diets for 7 days before kidney harvest. Na+ depletion increased the amounts of ub-αENaC and ub-γENaC by three- to fivefold, probably reflecting increased amounts of fully cleaved ENaC. We conclude that ubiquitination occurs after complete proteolytic processing of the subunits, contributing to retrieval and/or disposal of channels expressed at the cell surface. Diminished ubiquitination does not appear to be a major factor in aldosterone-dependent ENaC upregulation.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Rim/metabolismo , Síndrome de Liddle/metabolismo , Ubiquitinação , Aldosterona/sangue , Animais , Modelos Animais de Doenças , Canais Epiteliais de Sódio/genética , Feminino , Síndrome de Liddle/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Proteólise , Ratos Sprague-Dawley
16.
Am Heart J ; 222: 199-207, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32105986

RESUMO

BACKGROUND: The effect of the renin angiotensin system on blood pressure (BP) values in young adults from the general population is not well studied. We investigated the relationship between the aldosterone-to-renin ratio (ARR) and various BP indices in this population. METHODS: We assembled a population-based sample of adults aged 25-41 years. Conventional and 24-hour BP recordings were obtained in all patients. Direct renin concentration and plasma aldosterone concentration were measured. Multivariable regression models were constructed to assess the relationships of ARR with BP and hypertension. RESULTS: We included 1,353 individuals (mean age 37 years, 56% women). The median (interquartile range) ARR, direct renin concentration, and plasma aldosterone concentration were 13.8 (8.7-22.9), 7.2 ng/L (4.4-11.0) and 94 ng/L (68-134). All BP indices were higher across sex-specific ARR quartiles. Per 1-unit increase in log-transformed ARR, the multivariable-adjusted ß-coefficients (95% CI) for conventional, 24-hour, daytime, and nighttime systolic BP were 1.68 (0.87-2.48), P < .0001; 2.40 (1.68-3.12), P < .0001; 2.23 (1.48-2.99), P < .0001; and 2.80 (2.03-3.58), P < .0001, respectively. Per 1-unit increase in log-transformed ARR, the multivariable-adjusted odds ratio (95% CI) for conventional, 24-hour, sustained and masked hypertension was 1.70 (1.17-2.28), P = .0004; 1.29 (1.06-1.56), P = .01; 1.82 (1.33-2.49), P = .002; and 1.14 (0.94-1.38), P = .20, respectively. CONCLUSIONS: In young adults, ARR was strongly associated with conventional and ambulatory BP. Our data suggest that an aldosterone-driven phenomenon occurs very early in the development of hypertension.


Assuntos
Aldosterona/sangue , Pressão Sanguínea/fisiologia , Hipertensão/sangue , Vigilância da População/métodos , Sistema Renina-Angiotensina/fisiologia , Renina/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Masculino , Morbidade/tendências , Prognóstico , Suíça/epidemiologia
17.
Clin Chem ; 66(3): 483-492, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068832

RESUMO

BACKGROUND: Many medications (including most antihypertensives) and physiological factors affect the aldosterone/renin ratio (ARR) when screening for primary aldosteronism (PA). We sought to validate a novel equilibrium angiotensin II (eqAngII) assay and compare correlations between the aldosterone/angiotensin II ratio (AA2R) and the current ARR under conditions affecting the renin-angiotensin system. METHODS: Among 78 patients recruited, PA was excluded in 22 and confirmed in 56 by fludrocortisone suppression testing (FST). Peripheral levels of eqAngII, plasma renin activity (PRA) and direct renin concentration (DRC) were measured. RESULTS: EqAngII showed good consistency with DRC and PRA independent of PA diagnosis, posture, and fludrocortisone administration. EqAngII showed close (P < 0.01) correlations with DRC (r = 0.691) and PRA (r = 0.754) during FST. DRC and PRA were below their assays' functional sensitivity in 43.9% and 15.1%, respectively, of the total 312 samples compared with only 7.4% for eqAngII (P < 0.01). Bland-Altman analysis revealed an overestimation of PRA and DRC compared with eqAngII in a subset of samples with low renin levels. The AA2R showed not only consistent changes with the ARR but also close (P < 0.01) correlations with the ARR, whether renin was measured by DRC (r = 0.878) or PRA (r = 0.880). CONCLUSIONS: Dynamic changes of eqAngII and the AA2R show good consistency and close correlations with renin and the ARR. The eqAngII assay shows better sensitivity than DRC and PRA assays, especially at low concentrations. Whether the AA2R can reduce the impact of some factors that influence the diagnostic power of the ARR warrants further study.


Assuntos
Angiotensina II/sangue , Hiperaldosteronismo/diagnóstico , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Idoso , Aldosterona/sangue , Cromatografia Líquida de Alta Pressão , Feminino , Fludrocortisona/química , Humanos , Imunoensaio , Masculino , Pessoa de Meia-Idade , Radioimunoensaio , Renina/sangue , Adulto Jovem
18.
Best Pract Res Clin Endocrinol Metab ; 34(2): 101375, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32007424

RESUMO

Primary aldosteronism (PA) is the most common form of secondary hypertension affecting 5%-10% of patients with arterial hypertension. In PA, high blood pressure is associated with high aldosterone and low renin levels, and often hypokalemia. In a majority of cases, autonomous aldosterone production by the adrenal gland is caused by an aldosterone producing adenoma (APA) or bilateral adrenal hyperplasia (BAH). During the last ten years, a better knowledge of the pathophysiology of PA came from the discovery of somatic and germline mutations in different genes in both sporadic and familial forms of the disease. Those genes code for ion channels and pumps, as well as proteins involved in adrenal cortex development and function. Targeted next generation sequencing following immunohistochemistry guided detection of aldosterone synthase expression allows detection of somatic mutations in up to 90% of APA, while whole exome sequencing has discovered the genetic causes of four different familial forms of PA. The identification, in BAH, of somatic mutations in aldosterone producing cell clusters open new perspectives in our understanding of the bilateral form of the disease and the development of new therapeutic approaches.


Assuntos
Estudos de Associação Genética , Hiperaldosteronismo/genética , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Aldosterona/sangue , Estudos de Associação Genética/métodos , Estudos de Associação Genética/tendências , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/terapia , Hipertensão/genética
19.
J Chromatogr A ; 1609: 460456, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31471132

RESUMO

Accurate quantitation of aldosterone is critical for the clinical detection of hypertension. However, no reference intervals for aldosterone in healthy volunteers and patients with hypertension have yet been established using highly sensitive methods with a wide linear range based on low plasma volumes. We developed a modified ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantitation of aldosterone and established reference intervals for healthy volunteers and patients with hypertension. We measured aldosterone by UPLC-MS/MS in human plasma samples (90 µL). We established a reference range for aldosterone based on blood collected midmorning from 888 patients with hypertension and 258 seated, normotensive subjects. The linear range was 10-5000 pg/mL (r2 > 0.995), with a limit of quantification of 10 pg/mL. Similar results were obtained using different collection tubes, including EDTA plasma, sodium citrate plasma, and serum, respectively. Based on a comparison of results from UPLC-MS/MS and enzyme-linked immunosorbent assay, we derived the equation: UPLC-MS/MS = 0.8444 × ELISA + 1.162. Aldosterone concentrations in normotensive subjects ranged from 12.76 to 196.21 pg/mL, with no effect of age or sex on the reference interval. Aldosterone levels were significantly higher in patients with hypertension versus healthy controls (median: 71.05 versus 52.54 pg/mL, P < 0.0001), and patients with secondary hypertension versus primary hypertension (median: 67.25 versus 46.70 pg/mL, P = 0.0128) which were age- and sex-matched. Reference intervals for aldosterone in healthy individuals and patients with hypertension were established based on an improved UPLC-MS/MS method with higher sensitivity, a wider linear range, and lower plasma volume.


Assuntos
Aldosterona/sangue , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaio de Imunoadsorção Enzimática , Feminino , Voluntários Saudáveis , Humanos , Hipertensão/sangue , Masculino , Pessoa de Meia-Idade , Controle de Qualidade , Valores de Referência , Reprodutibilidade dos Testes , Adulto Jovem
20.
Urology ; 135: e1, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31604068

RESUMO

A 29-year-old female was referred to the urology clinic because of an incidentally found left renal mass discovered during workup for secondary erythrocytosis. Since 12 years of age, she has had headaches and poorly controlled hypertension refractory to trimodal antihypertensive therapy. Laboratory workup revealed markedly elevated aldosterone and renin levels. Computed tomography demonstrated a 3 cm left renal mass. The patient was admitted for intravenous blood pressure control. After partial nephrectomy, aldosterone and renin levels normalized. The patient was weaned off of blood pressure medications. Pathology was consistent with a juxtaglomerular cell tumor secreting renin (ie, reninoma).


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/etiologia , Sistema Justaglomerular/patologia , Neoplasias Renais/complicações , Adulto , Aldosterona/sangue , Anti-Hipertensivos/uso terapêutico , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Sistema Justaglomerular/diagnóstico por imagem , Sistema Justaglomerular/metabolismo , Neoplasias Renais/diagnóstico , Neoplasias Renais/cirurgia , Nefrectomia , Renina/sangue , Renina/metabolismo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
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