Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021.

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

Increased Dosage of MRA Improves BP and Urinary Albumin Excretion in Primary Aldosteronism With Suppressed Plasma Renin.

PURPOSE: Excessive aldosterone secretion causes a high risk of cardio-cerebrovascular events. Mineralocorticoid receptor antagonist (MRA) is 1 of the treatment strategies for primary aldosteronism (PA). However, current MRA treatment is insufficient because MRA-treated patients with suppressed plasma renin activity (PRA) < 1 ng/mL/h still had a higher risk of cardiovascular disease than those with unsuppressed PRA. This is a prospective interventional study to determine the effects of an increase in MRA dosage on blood pressure (BP) control and urinary albumin excretion (UAE) in MRA-treated PA patients. METHODS: Thirty-four PA patients were recruited, and 24 patients (6 male, 18 female) completed this study. Serum potassium concentration was assessed every two months to adjust the dosage of MRA safely for 6 months. The primary outcomes were the changes in BP and UAE between baseline and 6 months. RESULTS: Systolic BP (SBP) and log10UAE decreased significantly as the daily dose of MRA increased. Diastolic BP (DBP) tended to decrease. We divided the PA patients into two groups (baseline PRA < 1 ng/mL/h and baseline PRA ≥ 1 ng/mL/h) according to PRA. In the group with baseline PRA < 1 ng/mL/h but not that with baseline PRA ≥ 1 ng/mL/h, SBP, DBP and log10UAE after 6 months were significantly lower than those at baseline. CONCLUSIONS: The increase in MRA dosage improved BP and UAE in PA patients with suppressed PRA.

γENaC/CD9 in urinary extracellular vesicles as a potential biomarker of MR activity.

Primary aldosteronism (PA) is caused by autonomous overproduction of aldosterone, which induces organ damage directly via activation of the mineralocorticoid receptor (MR); however, no specific or sensitive biomarkers are able to reflect MR activity. Recently, it is found that urinary extracellular vesicles (uEVs) are secreted by multiple cell types in the kidney and are an enriched source of kidney-specific proteins. Here, we evaluate sodium transporters in uEVs as candidates of biomarkers of MR activity in the clinical setting. Sixteen patients were examined to determine their plasma aldosterone concentration (PAC) and renin activity, and their morning urine was collected. The protein levels of two sodium transporters in uEVs, γ-epithelial sodium channel (γENaC) and thiazide-sensitive sodium chloride cotransporter (NCC), were quantified by Western blot analysis, and their clinical correlation with PAC was determined. Consequently, we found PAC was significantly correlated with the γENaC protein level adjusted by the CD9 protein level in uEVs (correlation coefficient = 0.71). PAC was also correlated with the NCC protein level adjusted by the CD9 protein level in uEVs (correlation coefficient = 0.61). In two PA patients, treatment with an MR antagonist or adrenalectomy reduced γENaC/CD9 in uEVs. In conclusion, γENaC/CD9 in uEVs is a valuable biomarker of MR activity in PA patients and may be a useful biomarker for other MR-associated diseases.

Diabetes Mellitus Itself Increases Cardio-Cerebrovascular Risk and Renal Complications in Primary Aldosteronism.

CONTEXT: The prevalence of diabetes mellitus (DM) in patients with primary aldosteronism (PA) is higher than in those with essential hypertension and the general population. Although DM is a common major risk factor for cardio-cerebrovascular (CCV) diseases and renal complications, details of its effects in PA have not been demonstrated. OBJECTIVE: The aim of this study was to determine the effects of coexistent DM on the risk of CCV events and progression of renal complications in PA patients. DESIGN: A multi-institutional, cross-sectional study was conducted. PATIENTS AND METHODS: PA patients experienced between January 2006 and October 2016 and with available data of CCV events and DM were enrolled from the Japan PA registry of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Diseases Study (n = 2524). CCV events and renal complications were compared between a DM group and a non-DM group by logistic and liner-regression analysis. RESULTS: DM significantly increased the odds ratio (OR) of CCV events (OR 1.59, 95% CI: 1.05-2.41) and that of proteinuria (OR 2.25, 95% CI: 1.59-3.16). DM correlated significantly with declines in estimated glomerular filtration rate (ß = .05, P = .02). CONCLUSIONS: This the first report to demonstrate the presence of DM as an independent risk factor for CCV events and renal complications, even in PA patients. Management of DM should be considered in addition to the specific treatment of PA.

Basal Plasma Aldosterone Concentration Predicts Therapeutic Outcomes in Primary Aldosteronism.

PURPOSE: Normal basal plasma aldosterone concentration (PAC) reflects mild aldosterone excess compared to high basal PAC. We previously reported lower risk for cardiovascular and cerebrovascular events in patients with primary aldosteronism (PA) and normal basal PAC (nPA) than in those with high basal PAC (hPA). However, the differences in therapeutic outcomes between nPA and hPA are unclear. The aim of this multi-institutional, retrospective cohort study was to determine the clinical significance of nPA to therapeutic outcomes, including adrenalectomy (ADX) and treatment with mineralocorticoid receptor antagonists (MRAs). METHODS: A total of 1146 patients with PA who were diagnosed and underwent adrenal venous sampling (AVS) between January 2006 and October 2016 were enrolled. The clinical parameters at baseline and after ADX or treatment with MRA were compared between the nPA and hPA groups. RESULTS: Significantly higher rates of absent clinical success (36.6 vs. 21.9%, P = 0.01) and absent biochemical success (26.4 vs. 5.2%, P < 0.01) were found for the nPA group than for the hPA group, respectively. Logistic regression analysis identified baseline PAC as a significant independent predictor of absent clinical success of ADX and MRAs. CONCLUSIONS: Plasma aldosterone concentration at baseline was a significant and independent predictor of absent clinical success of ADX and MRA. Mineralocorticoid receptor antagonist treatment appeared to be a better therapeutic choice than ADX in the nPA group.

The number of positive confirmatory tests is associated with the clinical presentation and incidence of cardiovascular and cerebrovascular events in primary aldosteronism.

Primary aldosteronism (PA) is a major cause of secondary hypertension and presents a higher risk for cardio-cerebrovascular (CCV) events compared with essential hypertension. To diagnose PA after a positive screening test, at least one of three available confirmatory tests [the saline infusion test (SIT), the captopril challenge test (CCT) or the furosemide upright test (FUT)] should be performed. The aim of our study was to investigate the relationship between the number of positive confirmatory tests using SIT and CCT and the clinical presentation and prevalence of CCV events in 398 PA patients. The number of PA patients doubled when PA diagnosis was defined by positive results on either the SIT or CCT confirmatory tests (single positive) compared to positive results on both the SIT and CCT confirmatory tests (double positive). We also found a more typical clinical presentation of PA, such as the use of more antihypertensive drugs to control blood pressure and a higher incidence of hypokalemia, in PA patients with double positive confirmatory tests than in those with a single positive confirmatory test. The incidence of CCV events in PA patients with double positive confirmatory tests was significantly higher than that in those with a single positive confirmatory test. Our results demonstrated that the number of PA patients was doubled by the use of PA diagnostic criteria using a single positive confirmatory test compared to the use of double positive confirmatory tests. PA patients with double positive confirmatory tests were associated with a more typical clinical presentation and a higher incidence of CCV events than those with a single positive confirmatory test.

Clinical Characteristics of Acromegalic Patients With Paradoxical GH Response to Oral Glucose Load.

CONTEXT: A paradoxical GH response to oral glucose (OG) is often found in acromegaly. However, the clinical characteristics of patients with acromegaly and a paradoxical GH response to OG (OG responders) remain unclear. OBJECTIVE: The aim of the present study was to define the clinical characteristics of OG responders with acromegaly. DESIGN: Retrospective study. SETTING: Hospitalized care at Osaka University Hospital. PATIENTS AND METHODS: Of 63 patients with acromegaly admitted to our hospital from January 2006 to January 2017, 19 were classified as OG responders and 44 as nonresponders. The clinical characteristics of these groups were compared. RESULTS: Before surgery, OG responders had substantially greater IGF-1 SD scores than nonresponders (P < 0.05), although no difference was found in basal GH levels between the two groups (P = 0.46). Regarding glucose metabolism, 120-minute plasma glucose and immunoreactive insulin after OG administration and hemoglobin A1c were significantly greater in OG responders than in nonresponders (P < 0.01, P < 0.05, P < 0.05, respectively). GH levels during octreotide or bromocriptine testing were decreased more significantly in OG responders than in nonresponders (P < 0.05, P < 0.05, respectively). The proportion of pituitary tumors with hypointensity on T2-weighted MRI was significantly greater in OG responders than in nonresponders (P < 0.05). The difference in IGF-1 and parameters of glucose metabolism described disappeared between the two groups after surgery. CONCLUSIONS: The paradoxical GH response reflected the clinical characteristics, especially IGF-I level, glucose metabolism, and drug efficacy in acromegaly. A paradoxical GH response, in addition to the nadir GH levels, to OG load is potentially useful for evaluation of the clinical characteristics of acromegaly.