Primary aldosteronism, characterized by the dysregulated production of aldosterone from 1 or both adrenal glands, is the most common endocrine cause of hypertension. It confers a high risk of cardiovascular, renal, and metabolic complications that can be ameliorated with targeted medical therapy or surgery. Diagnosis can be achieved with a positive screening test (elevated aldosterone to renin ratio) followed by confirmatory testing (saline, captopril, fludrocortisone, or oral salt challenges) and subtyping (adrenal imaging and adrenal vein sampling). However, the diagnostic pathway may be complicated by interfering medications, intraindividual variations, and concurrent autonomous cortisol secretion. Furthermore, once diagnosed, careful follow-up is needed to ensure that treatment targets are reached and adverse effects, or even recurrence, are promptly addressed. These challenges will be illustrated in a series of case studies drawn from our endocrine hypertension clinic. We will offer guidance on strategies to facilitate an accurate and timely diagnosis of primary aldosteronism together with a discussion of treatment targets which should be achieved for optimal patient outcomes.

The systematic use of confirmatory tests in the diagnosis of primary aldosteronism (PA) increases costs, risks and complexity to the diagnostic work-up. In light of this, some authors proposed aldosterone-to-renin (ARR) cut-offs and/or integrated flow-charts to avoid this step. Patients with resistant hypertension (RH), however, are characterized by a dysregulated renin-angiotensin-aldosterone system, even in the absence of PA. Thus, it is unclear whether these strategies might be applied with the same diagnostic reliability in the setting of RH.
We enrolled 129 consecutive patients diagnosed with RH and no other causes of secondary hypertension. All patients underwent full biochemical assessment for PA, encompassing both basal measurements and a saline infusion test.
34/129 patients (26.4%) were diagnosed with PA. ARR alone provided a moderate-to-high accuracy in predicting the diagnosis of PA (AUC=0.908). Among normokalemic patients, the ARR value that maximized the diagnostic accuracy, as identified by the Youden index, was equal to 41.8 (ng/dL)/(ng/mL/h), and was characterized by a sensitivity and a specificity of 100% and 67%, respectively (AUC=0.882); an ARR > 179.6 (ng/dL)/(ng/mL/h) provided a 100% specificity for the diagnosis of PA, but was associated with a very low sensitivity of 20%. Among hypokalemic patients, the ARR value that maximized the diagnostic accuracy, as identified by the Youden index, was equal to 49.2 (ng/dL)/(ng/mL/h), and was characterized by a sensitivity and a specificity of 100% and 83%, respectively (AUC=0.941); an ARR > 104.0 (ng/dL)/(ng/mL/h) provided a 100% specificity for the diagnosis of PA, with a sensitivity of 64%.
Among normokalemic patients, there was a wide overlap in ARR values between those with PA and those with essential RH; the possibility to skip a confirmatory test should thus be considered with caution in this setting. A better discriminating ability could be seen in the presence of hypokalemia; in this case, ARR alone may be sufficient to skip confirmatory tests in a suitable percentage of patients.

Aldosterone-to-renin ratio is the most reliable screening method of primary aldosteronism and has been widely used in clinical practice, but the index is influenced by many factors, some of which cause it false-negative, consequently leading to primary aldosteronism underdiagnosed. We report a rare case of a 27-year-old woman complaining of elevated arterial blood pressure and spontaneous hypokalemia but whose aldosterone-to-renin ratio were negative consecutively. She also had symptoms of polydipsia and polyuria for more than 20 years, with the volume of water intake and urine output up to 17 liters per day. Confirmatory tests of saline infusion test and captopril challenge test could not suppress plasma aldosterone concentration to the cutoff value. Abdominal contrast-enhanced CT suggested an adenoma on the right adrenal gland. After excluding other known causes of hypertension with hypokalemia, the patient was ultimately diagnosed with aldosterone-producing adenoma complicated with primary polydipsia. Complete clinical remission was achieved after unilateral adrenalectomy. The histopathology showed typical features of adrenocortical adenoma which was positive for CYP11B2 by immunohistochemistry, and next-generation sequencing results of tumor tissues revealed a missense mutation of the KCNJ5 gene [chr11:128781619, c.451 (exon 2) G>A]. All these findings supported the diagnosis of aldosterone-producing adenoma. This study has shown that negative aldosterone-to-renin ratio screening result cannot simply exclude primary aldosteronism. Comprehensive patient\'s evaluation should be taken to avoid missed diagnosis in clinical work, especially for those who have potentially curative surgery.

Primary aldosteronism (PA) is a potentially curable form of secondary hypertension caused by excessive renin-independent aldosterone secretion, leading to increased target organ damage and cardiovascular morbidity and mortality. The diagnosis of PA requires measuring renin and aldosterone to calculate the aldosterone-to-renin ratio, followed by confirmatory tests to demonstrate renin-independent aldosterone secretion and/or PA subtype differentiation. Various antihypertensive drug classes interfere with the renin-angiotensin-aldosterone axis and hence evaluation for PA should ideally be performed off-drugs. This is, however, often precluded by the risks related to suboptimal control of blood pressure and serum potassium level in the evaluation period. In the present review, we summarized the evidence regarding the effect of various antihypertensive drug classes on biochemical testing for PA, and critically appraised the issue whether and which antihypertensive medications should be withdrawn or, conversely, might be continued in patients evaluated for PA. The least interfering drugs are calcium antagonists, alpha-blockers, hydralazine, and possibly moxonidine. If necessary, the testing may also be attempted during treatment with beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers but renin and aldosterone measurements must be interpreted in the context of known effects of these drugs on these parameters. Views are evolving on the feasibility of testing during treatment with mineralocorticoid receptor antagonists, as these drugs are now increasingly considered acceptable in specific patient subsets, particularly in those with severe hypokalemia and/or poor blood pressure control on alternative treatment.

BACKGROUND: Plasma aldosterone-to-renin ratio (ARR) is popularly used for screening primary aldosteronism (PA). Some medications, including diuretics, are known to have an effect on ARR and cause false-negative and false-positive results in PA screening. Currently, there are no studies on the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors, which are known to have diuretic effects, on ARR. We aimed to investigate the effects of SGLT2 inhibitors on ARR.
METHODS: We employed a retrospective design; the study was conducted from April 2016 to December 2018 and carried out in three hospitals. Forty patients with diabetes and hypertension were administered SGLT2 inhibitors. ARR was evaluated before 2 to 6 months after the administration of SGLT2 inhibitors to determine their effects on ARR.
RESULTS: No significant changes in the levels of ARR (90.9 ± 51.6 vs. 81.4 ± 62.9) were found. Body mass index, diastolic blood pressure, heart rate, fasting plasma glucose, and hemoglobin A1c were significantly decreased by SGLT2 inhibitors. Serum creatinine was significantly increased.
CONCLUSIONS: SGLT2 inhibitor administration yielded minimal effects on ARR and did not increase false-negative results in PA screening in patients with diabetes and hypertension more than 2 months after administration.

BACKGROUND: Satisfactory tools to preclude low-risk patients from intensive diagnostic testing for primary aldosteronism (PA) are lacking. Therefore, we aimed to develop a decision tool to determine which patients with difficult-to-control hypertension have a low probability of PA, thereby limiting the exposure to invasive testing while at the same time increasing the efficiency of testing in the remaining patients.
METHODS: Data from consecutive patients with difficult-to-control hypertension, analysed through a standardized diagnostic protocol between January 2010 and October 2017 (n = 824), were included in this cross-sectional study. PA was diagnosed by a combined approach: 1) elevated aldosterone-to-renin ratio (> 5.0 pmol/fmol/s), confirmed with 2) non-suppressible aldosterone after standardized saline infusion (≥280 pmol/L). Multivariable logistic regression analyses including seven pre-specified clinical variables (age, systolic blood pressure, serum potassium, potassium supplementation, serum sodium, eGFR and HbA1c) was performed. After correction for optimism, test reliability, discriminative performance and test characteristics were determined.
RESULTS: PA was diagnosed in 40 (4.9%) of 824 patients. Predicted probabilities of PA agreed well with observed frequencies and the c-statistic was 0.77 (95% confidence interval (95%CI) 0.70-0.83). Predicted probability cut-off values of 1.0-2.5% prevented unnecessary testing in 8-32% of the patients with difficult-to-control hypertension, carrying sensitivities of 0.98 (95%CI 0.96-0.99) and 0.92 (0.83-0.97), and negative predictive values of 0.99 (0.98-1.00) and 0.99 (0.97-0.99).
CONCLUSIONS: With a decision tool, based on seven easy-to-measure clinical variables, patients with a low probability of PA can be reliably selected and a considerable proportion of patients with difficult-to-control hypertension can be spared intensive diagnostic testing.

Primary aldosteronism (PA) is common with an estimated prevalence rate of 10% in subjects with essential hypertension and higher in those with resistant hypertension. As well as contributing to hypertension, aldosterone has detrimental effects on the heart, vasculature and kidneys as well as adverse metabolic effects leading to an excess of cardiovascular morbidity. Therefore, recognition and appropriate treatment of PA is of increasing importance. However, the diagnosis of PA and determination of subtype can be problematic. The purpose of this review is to provide an overview of the evidence supporting this increased prevalence of PA, explore the metabolic and cardiovascular consequences of aldosterone excess and discuss optimal diagnostic and therapeutic strategies of PA.

The current clinical investigation for primary aldosteronism (PA) diagnosis requires complex expensive tests from the initial suspicion to the final subtype classification, including invasive approaches; therefore, appropriate markers for subtype definition are greatly desirable. The present study performs a metabolomics analysis to further examine specific molecular signatures of PA urines EXPERIMENTAL DESIGN: The study considered PA subtype and gender-related differences using two orthogonal advanced UHPLC-MS metabolomics approaches. Patients with essential hypertension (n = 36) and PA (n = 50) who were referred to the outpatient hypertension clinic and matched healthy subjects (n = 10) are investigated.
Statistically significant changes (p < 0.05 ANOVA, Fc > 1.5) of metabolites involved in central carbon, energy, and nitrogen metabolism are identified, especially purine and pyrimidine nucleosides and precursors, and free amino acids. PLS-DA interpretation provides strong evidence of a disease-specific metabolic pattern with dAMP, diiodothyronine, and 5-methoxytryptophan as leading factors, and a sex-specific metabolic pattern associated with orotidine 5-phosphate, N-acetylalanine, hydroxyproline, and cysteine. The results are verified using an independent sample set, which confirms the identification of specific signatures.
Metabolomics is used to identify low molecular weight molecular markers of PA, which paves the way for follow-up validation studies in larger cohorts.

UNASSIGNED: The aim of the study was to evaluate clinical and biochemical differences between patients with low-renin and high-renin primary arterial hypertension (AH), mainly in reference to serum lipids, and to identify factors determining lipid concentrations.
UNASSIGNED: In untreated patients with AH stage 1 we measured plasma renin activity (PRA) and subdivided the group into low-renin (PRA < 0.65 ng/mL/h) and high-renin (PRA ⩾ 0.65 ng/mL/h) AH. We compared office and 24-h ambulatory blood pressure, serum aldosterone, lipids and selected biochemical parameters between subgroups. Factors determining lipid concentration in both subgroups were assessed in regression analysis.
UNASSIGNED: Patients with high-renin hypertension ( N = 58) were characterized by higher heart rate ( p = 0.04), lower serum sodium ( p < 0.01) and aldosterone-to-renin ratio ( p < 0.01), and significantly higher serum aldosterone ( p = 0.03), albumin ( p < 0.01), total protein ( p < 0.01), total cholesterol ( p = 0.01) and low-density lipoprotein cholesterol (LDL-C) ( p = 0.04) than low-renin subjects ( N = 39). In univariate linear regression, only PRA in the low-renin group was in a positive relationship with LDL-C ( R2 = 0.15, β = 1.53 and p = 0.013); this association remained significant after adjustment for age, sex, and serum albumin and aldosterone concentrations.
UNASSIGNED: Higher serum levels of total and LDL-C characterized high-renin subjects, but the association between LDL-C level and PRA existed only in low-renin primary AH.

The biological diagnosis of primary aldosteronism (PA) is a real challenge in clinical laboratories. First, PA is a major cause of secondary hypertension, and more widespread screening is currently recommended. In addition, the recent development of automated and mass spectrometry tests has made it necessary to determine the most appropriate cutoff values in clinical studies. New French and international guidelines will play an important role in the standardization of PA diagnosis. The first diagnostic step is to measure the aldosterone to renin ratio (ARR), which is widely considered the best screening test. The preanalytical phase is crucial to properly interpret the ARR, and rigorous testing conditions must be observed to improve the diagnostic efficiency. The choice of the most appropriate cutoff value for ARR is a real concern in laboratories due to variability between methods. The second step of PA diagnosis aims to rule out false-positive ARRs using one or more dynamic confirmatory tests based on aldosterone suppression. Finally, the third step involves adrenal venous sampling to distinguish between unilateral and bilateral disease.