Plasma Aldosterone Concentration Research Articles

Mineralocorticoid receptor antagonist treatment improved arterial stiffness in patients with primary aldosteronism: a cohort study compared with adrenalectomy.

Elevated arterial stiffness in patients with primary aldosteronism (PA) can be reversed after adrenalectomy; however, the effect of medical treatment with mineralocorticoid receptor antagonist (MRAs) is unknown. The aim of this study was to evaluate the effect of MRAs and compare both treatment strategies on arterial stiffness in PA patients. Prospective cohort study. We prospectively enrolled PA patients from 2006 to 2019 who received either adrenalectomy or MRA treatment (spironolactone). We compared their baseline and 1-year post-treatment biochemistry characteristics and arterial pulse wave velocity (PWV) to verify the effects of treatment and related determinant factors. A total 459 PA patients were enrolled. After 1:1 propensity score matching for age, sex and blood pressure (BP), each group had 176 patients. The major determinant factors of baseline PWV were age and baseline BP. The adrenalectomy group had greater improvements in BP, serum potassium level, plasma aldosterone concentration, and aldosterone-to-renin ratio. The MRA group had a significant improvement in PWV after 1 year of treatment (1706.2 ± 340.05 to 1613.6 ± 349.51 cm/s, p < 0.001). There were no significant differences in post-treatment PWV (p = 0.173) and improvement in PWV (p = 0.579) between the adrenalectomy and MRA groups. The determinant factors for an improvement in PWV after treatment were hypertension duration, baseline PWV, and the decrease in BP. The PA patients who received medical treatment with MRAs had a significant improvement in arterial stiffness. There was no significant difference in the improvement in arterial stiffness between the two treatment strategies.

PS-BPR01-6: A CASE SERIES OF UNILATERAL PRIMARY ALDOSTERONISM TREATED BY RADIOFREQUENCY ABLATION

Background: In primary aldosteronism (PA), early and appropriate management based on its subtype is crucial to abolish an enhanced cardiovascular risk. Mineralocorticoid receptor antagonists (MRAs) are the mainstay of PA treatment, while a unilateral adrenalectomy (ADX) has been considered as the gold standard intervention for unilateral PA, mainly caused by an aldosterone-producing adenoma. The laparoscopic ADX is a less-invasive procedure than open surgery, whereas the procedure harbors a perioperative risk associated with general anesthesia. Herein, we report 3 PA cases where we employed radiofrequency ablation (RFA) as an alternate therapy for their aldosterone-producing tumors. In those cases, RFA successfully and safely led to remission of PA with more reduced physical burden, compared with the laparoscopic ADX. Case presentation: We performed RFA in 3 unilateral PA cases with aldosterone-producing tumors; Case 1, a 46-year-old man with a right adrenal tumor (14 mm); Case 2, a 65-year-old man with a right adrenal tumor (15 mm); Case 3, a 47-year-old man with a left adrenal tumor (19 mm). At baseline, their blood pressure levels were 124/87, 118/79 and 142/88 mmHg under 1, 2 and 2 antihypertensive agents, respectively. Plasma aldosterone concentrations and renin activity levels were as follows; 29.70, 25.7 and 48.6 ng/dL and 0.5, &lt; 0.2 and &lt; 0.2 ng/mL/hr, respectively. In all cases, we confirmed the presence and localization of PA with confirmatory tests and segmental adrenal venous sampling. Before the RFA procedure, we initiated and titrated MRAs to sufficiently block effects of hyperaldosteronism. Percutaneous RFA was guided by computed tomography under intravenous anesthesia without intubation. Complete tumor ablation was achieved within 1 hour, confirmed by enhanced adrenal imaging. No major complication was observed, and physical activity was almost recovered on the same day. Three months after RFA, all 3 patients showed normotension without any antihypertensives. For biochemical parameters, plasma aldosterone levels decreased to 2.47, &lt; 0.40 and 1.41 ng/dL in Case 1, 2 and 3, respectively, followed by mild restoration of plasma renin activity (1.4, 0.5 and &lt; 0.2 ng/mL/hr, respectively). Conclusion: This case series demonstrates that RFA is an alternate treatment for unilateral PA. Based on accurate localization of hyperaldosteronism, RFA could cause necrosis of only an adrenal-producing tumor and spare an ipsilateral adjacent adrenal gland, resulting in remission of PA with minimal physical burden.

PS-BPC02-2: CLINICAL IMPACTS OF ENDOTHELIUM-DEPENDENT FLOW-MEDIATED VASODILATION ASSESSMENT ON PRIMARY ALDOSTERONISM

Objective: Primary aldosteronism (PA) is defined as autonomous aldosterone production from the adrenal glands and represents the most common and treatable cause of hypertension. Also, it is well known that the incidence of cardiovascular morbidity is higher among patients with PA than among those with essential hypertension (EH). Histologically, PA is divided into two major subtypes, aldosterone-producing adenoma (APA) and bilateral idiopathic hyperplasia (IHA). However, the nature of vascular function in PA patients remains to be determined. The aim of this study was to determine the vascular function and investigate the implications of vascular function assessments in the patients with PA. Design and Method: All patients were diagnosed with PA according to the guidelines of the Japan Endocrine Society. Flow-mediated dilation (FMD), as an index of endothelial function, and cardio-ankle vascular index (CAVI), as an index of arterial stiffness, were retrospectively compared between 42 patients with APA, 37 patients with IHA, and 42 patients with EH. These values were also compared with background factors, KCNJ5 mutation and clinical outcome in terms of blood pressure reduction after adrenalectomy in the APA group. Results: No differences were found among the three groups (APA, IHA and EH) with regard to age, sex, duration of hypertension, body mass index, blood pressure, renal function and hemoglobin A1c. FMD was significantly lower in the APA group (4.8 ± 2.1%) and IHA group (4.1 ± 1.9%) than in the EH group (5.7 ± 2.1%). CAVI did not differ significantly among APA, IHA and EH groups (7.9 ± 1.3, 7.8 ± 1.0, 7.8 ± 1.1, respectively). Although no significant correlations were seen between FMD and background factors (i.e. age, body mass index, renal function, glucose and lipid metabolic parameters, and hormonal data) in the IHA group, FMD correlated negatively with BMI and plasma aldosterone concentration in the APA group (rs = -0.313, rs = -0.342, respectively). No significant difference in FMD (4.8 ± 1.4%, 4.5 ± 2.1%, respectively) or CAVI (8.1 ± 1.8, 8.0 ± 1.1, respectively) was seen between the KCNJ5-mutant group and the wild-type group. A cut-off FMD of 4.3% was selected for complete clinical success after adrenalectomy, offering 78% sensitivity and 80% specificity. Conclusions: Patients with PA displayed impaired endothelial function. Complete clinical success after adrenalectomy was associated with preserved endothelial function. This study provides a better understanding of FMD assessment in patients with PA.

PS-R07-9: A CASE OF ADRENAL VEIN SAMPLING IN PRIMARY ALDOSTERONISM WITH DISCREPANT RESULTS OF ALDOSTERONE-OVERSECRETION-LATERALITY UNDER BASAL CONDITIONS AND COSYNTROPIN STIMULATION

Background: Adrenal venous sampling (AVS) is regarded as the gold standard for diagnosis of primary aldosteronism (PA) subtypes before surgery. Cosyntropin stimulation during AVS improves the success rate of bilaterally selective catheterization and outcome prediction for PA. However, in some cases cosyntropin stimulation may obscure the judgement of laterality of aldosterone oversecretion. Case presentation: A 66-year-old Japanese man was referred to our hospital for evaluation and management of hypertension and hypokalemia. His home blood pressure was 160/80 mmHg and poorly controlled with a calcium channel blocker, and a serum potassium level was 3.3 mEq/L under oral potassium administration. Plasma aldosterone concentration (PAC) was 249 pg/mL. Abdominal computed tomography scan revealed a 7 mm nodule on the left adrenal gland. Both captopril challenge test and saline infusion test revealed positive test results, which confirmed a diagnosis of PA. The AVS was performed both under basal conditions and during cosyntropin stimulation, which revealed discrepant results of laterality (Table 1). Since the absolute value of aldosterone secretion was significantly higher on the right adrenal gland, suggesting autonomous secretion from the right, AVS was performed again. The second procedure showed unilaterality in the right under basal AVS and bilaterality during cosyntropin stimulation (Table 2). Similarly, aldosterone levels were clearly higher on the right side, leading to the diagnosis of microadenoma of the right adrenal gland, and a laparoscopic right adrenalectomy was performed. Histopathology of the removed right adrenal gland revealed a diagnosis of a 2 mm adenoma. After adrenalectomy, his blood pressure control and hypokalemia improved. Conclusions: Cosyntropin stimulation during AVS is believed to increase the local diagnostic value of aldosterone oversecretion, but in rare cases, as in this case, basal and cosyntropin-stimulated AVS results yielded contrary findings. Cosyntropin-stimulated AVS should be interpreted with caution.

PS-C21-9: REVISITING ORAL SALT LOADING TEST: A NEW CHEMILUMINESCENT IMMUNOASSAY OF 24-HOUR URINE ALDOSTERONE MEASUREMENT

Primary aldosteronism (PA) is widely recognized as the most frequent cause of secondary hypertension, and its prevalence ranges from 5% to 10% in hypertensive patients. The number of patients diagnosed with PA has increased due to more frequent screening in JAPAN. PA is diagnosed by a screening test, followed by a confirmatory or exclusionary test and a subtype test using computed tomography and adrenal vein sampling. Measuring of the urinary aldosterone concentration is important in oral sodium loading test (OSLT), one of the confirmatory tests. Therefore, an accurate aldosterone measurement method is required for clinical practice. Since April 2021, the plasma aldosterone concentration has been measured by chemiluminescent enzyme immunoassay (CLEIA) in Japan. In the present study, we developed a new CLEIA using a two step sandwich method to measure the 24 hour urine aldosterone level. We collected urine samples and measured 24 hour urine aldosterone levels employing radioimmunoassay (RIA), CLEIA, and liquid chromatography tandem mass spectrometry (LC MS/MS). The results showed that the 24-hour urine aldosterone levels measured using CLEIA and LC MS/MS were significantly correlated. The 24 hour urine aldosterone levels measured using CLEIA and RIA were also significantly correlated. However, the aldosterone level measured by CLEIA was lower than that measured by RIA (slope, 0.729; intercept, 120.9). In Japan, a new guideline for primary aldosteronism has been announced, with changes in the aldosterone measurement method, and the cutoff values for oral sodium loading test (OSLT) were changed. Therefore, we examined the cut off value of the 24 hour urine aldosterone level after the OSLT. Receiver operating characteristic analysis revealed a cut off value for primary aldosteronism of 3 mcg/day.

PS-C26-8: UNIQUE PROPERTIES OF DEPRESSOR, RENAL, AND ALDOSTERONE RESPONSES TO ALISKIREN THERAPY IN HYPERTENSIVE PATIENTS WITH NEPHROPATHY

Objective: Blood pressure (BP) control using renin-angiotensin system (RAS) inhibitor as a first choice is recommended in hypertension accompanied by chronic kidney disease (CKD), and RAS localized in the kidney is known to exist independent of circulating RAS. Aliskiren, direct renin inhibitor (DRI), is most excellent in kidney tissue migration among RAS inhibitors despite it has been reported to cause aldosterone breakthrough like angiotensin II receptor blocker (ARB) in essential hypertension. Therefore, DRI-induced antihypertensive, renoprotective and aldosterone-suppressing effects were investigated as compared to those of ARB in hypertensive CKD patients. Design and method: 168 hypertensive patients with CKD (stage G1–4) were employed in this study. Home BP in the morning, estimated glomerular filtration rate (eGFR), urinary protein/creatinine ratio (UPCR), urinary liver-type fatty-acid-binding protein (U-LFABP) as an indicator of tubular dysfunction, plasma and urinary aldosterone concentration (PAC and UAC) were measured before and 0.5 to 5 years after administration of ARB or DRI and assessed retrospectively. Aldosterone breakthrough was defined as any increase in PAC from the baseline level following treatment with a RAS inhibitor. Results: In ARB-treated group, BP and UPCR decreased significantly at 6 months, but sufficient declines were not observed 1st year onward. In DRI-treated group, a significant reduction in BP was sustained until 3 years and BP unchanged decreasing tendency even 4 years later, meanwhile UPCR decreased significantly for 2 years and was below the pretreatment value 3 years after. ARB raised BP and UPCR again in patients with CKD G3–4 prior to those with CKD G1–2, however, DRI expressed no difference between stages. Although PAC diminished up to 6 months in ARB group and 1 year in DRI group, it turned up 1 year and 2 years after, respectively. PAC-ascensive rate and maximum elevation in PAC were higher and greater in ARB group than in DRI group (48.7 vs 22.6%, 56.1 vs 29.3pg/ml). All significant differences in rising PAC cases disappeared by 5 years, whereas in non-rising PAC cases, only DRI reduced U-LFABP without deterioration in eGFR and UAC further lowered while PAC was maintained. Conclusions: In comparison with ARB, aliskiren prolongs hypotensive and proteinuria-lowering effects with retained eGFR regardless of CKD severity possibly via improvement of tubular disorders and less PAC reascent in hypertensive nephropathy. Aliskiren given to CKD patients might elicit mild and delayed aldosterone breakthrough rather than ARB due to a direct action against aldosterone derived from the kidney.

PS-R04-10: MALIGNANT HYPERTENSION AFTER COVD-19 VACCINE INJECTION

Case; 40 y/o male. Clinical course; The patient was transferred to our university hospital because of DOE and severe headache. He had been well and had no history of hypertension or obesity. He had experienced the COVID-19 vaccine injection two week before this visit. After the injection he had been experienced high fever and general fatigue as well as 7 kg of weight loss. On examnation, it was found that he had severe hypertension (190/110 mmHg) and hypertensive optic fundi. On chest X-ray, cardiomegaly and bilateral lung infiltrations was evident and biochemical data indicated renal dysfunction (serum creatinine 2.35 mg/dl), high levels of plasma renin activity (39.1 ng/ml/hour normal; 0.6–3.9) and aldosterone concentration (176 pg/ml normal; 4.0–82.1), and inflammatory changes (CRP = 23 mg/dl). We also found that increased levels of LDH and decreased levels of hemoglobin which indicated hemolytic anemia and thrombotic microangiopathy. After the control of high blood pressure by intravenous administration of Calcium channel blockades, We performed renal biopsy, which had a finding of diffuse findings of onion skin lesion and global glomerular sclerosis compatible with the diagnosis of malignant hypertension. Any secondary etiologies including renal artery disease or collagen disease had not been identified. Seven days after the admission, we started hemodialysis for this patient because of the renal failure was not resolved. We also had startred ACE inhibitors. We stopped the diuretics and minimized the ultrafiltration. Twenty-five days after the admission the patients was withdrawn from dialysis with the urine volume around 2000 ml/day and the serum creatinine concentration 5.29 mg/dl. He was discharged without any aid of dialysis and with small number of anti-hypertensives. Four months after the discharge, his serum creatinine concentration was 3.36 mg/dl and his blood pressure was 139/85 mmHg with the ACE inhibitor and calcium channel blockades. Conclusions; The case suggested that the malignant hypertension might be triggered by COVID-19 vaccine injection, which is of clinical importance.

PS-BPC01-2: PREDICTORS AND EFFECTS OF COMORBID ATRIAL FIBRILLATION IN HYPERTENSIVE PATIENTS DUE TO PRIMARY ALDOSTERONISM

Objective: The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than those with essential hypertension. This study sought to determine independent predictors of comorbid AF and cardiovascular events in PA patients after PA treatment. Design and method: This nationwide registration study included PA patients more than 20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3,654 patients with PA were included at the time of analysis. Results: Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent determinants for AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P &lt; 0.001). Multivariate Cox analyses demonstrated AF in addition to duration of hypertension, older age, male sex, hypokalemia and surgery as independent prognostic factors for cardiovascular events (hazard ratio [HR] 1.866, 95% confidence interval [CI] 1.024–3.401, P &lt; 0.05; HR 1.022, 95%CI 1.006–1.039, P &lt; 0.01; HR 1.424, 95%CI 1.043–1.943, P &lt; 0.05; HR 1.027, 95%CI 1.012–1.042, P = 3.2 × 10–4; HR 1.726, 95%CI 1.226–2.430, P &lt; 0.005; HR 1.458, 95%CI 1.041–2.041, P &lt; 0.05, respectively). After PA treatment, incidence of cardiovascular events did not differ significantly between PA patients with AF and essential hypertension patients with AF from the Fushimi registry during follow up after adjusting age, sex and prevalence of hypertension. Conclusion: Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension.

PS-BPR03-11: A CASE OF MALIGNANT PHASE HYPERTENSION ASSOCIATED WITH PRIMARY ALDOSTERONISM

Background: Primary aldosteronism is associated with low plasma renin levels, while malignant phase hypertension is generally associated with raised renin activity. Therefore, these two conditions are at opposite ends of the renin spectrum, so in theory their co-existence would be unusual. Case presentation: We present a case of a 41-year-old male with uncontrolled hypertension on multiple antihypertensive drugs. He discontinued these drugs for three days, thereafter he admitted to our hospital with congestive heart failure and acute ischemic stroke. He manifested malignant phase hypertension (blood pressure 216/130 mmHg; Keith-Wagener IV) accompanying renal dysfunction (serum creatinine 2.4 mg/dL), high plasma aldosterone concentration (PAC, 221 pg/mL) and mildly elevated plasma renin activity (PRA, 3.0 ng/mL/hr). A computed tomography did not reveal the presence of adrenal mass. After the treatment for congestive heart failure, the reassessment for endocrine causes of hypertension showed high level of PAC (468 pg/mL) and low level of PRA (0.2 ng/mL/hr), resulting in a high PAC/PRA ratio under the treatment with angiotensin-converting enzyme inhibitor. Adrenal venous sampling (AVS) confirmed the excessive aldosterone secretion from bilateral adrenal glands. Given these findings, we diagnosed him with idiopathic aldosteronism. After an addition of the mineralocorticoid receptor antagonist, he could keep his blood pressure under control. Conclusions: PRA in patients with primary aldosteronism could be increased under the conditions in which renin release from the kidney is overstimulated by glomerular ischemia, leading to an incorrect diagnosis of primary aldosteronism. Repeated endocrine assessment including the measurement of PRA and PAC should be considered to reveal the cause of malignant phase hypertension.

JS-NG-10: A RARE CAUSE OF TREATMENT-RESISTANT HYPERTENSION

Objective: To present an educational case report. Design and method: In a 22-year old female arterial hypertension was diagnosed and she was treated to blood pressure target values with a combination of candesartan and lercanidipine. At the age of 27 years she planned a pregnancy, therefore antihypertensive treatment was switched to alpha-methyl-dopa and metoprolol. Blood pressure control was no longer achieved, the patient was symptomatic, mostly headaches. A diagnostic work-up for secondary causes of hypertension was performed. Results: There were no signs of kidney disease, renal artery stenosis was ruled out by color-coded duplex-ultrasound, plasma metanephrines were normal, sleep apnea syndrome and hypercortisolism were clinically very unlikely and not formally ruled out. No signs of hypertensive end-organ damage (left ventricular hypertrophy, microalbuminuria, carotid artery alterations) were detected. The only pathologic finding confirmed was a marked secondary hyperaldosteronism. Plasma renin concentration was 230 pg/ml, plasma aldosterone concentration 508 pg/ml, along with low normal serum potassium (3.5 to 4 mmol/l). Addition of nifedipine and low-dose HCT did not achieve blood pressure control, daytime ABPM mean was 144/102 mmHg, nighttime ABPM mean 127/86 mmHg. Because of suspected missed renal artery stenosis (fibromuscular dysplasia) an MR-angiography of the renal arteries was performed revealing normal renal arteries and normal adrenal glands but a left kidney tumor - not observed in the previous ultrasound examination but confirmed with contrast-enhanced ultrasound. Surgical removal of the tumor was performed. The histology was suggestive for a juxtaglomerular cell tumor (reninoma). After surgery, plasma aldosterone normalized to 57 pg/ml and plasma renin concentrations were low (3.4 pg/ml). Within 3 months after surgery, all antihypertensive medication could be discontinued and home blood pressure measurements averaged 119/78 mmHg. Soon thereafter the patient became pregnant and delivered a healthy girl. There were no pregnancy related complications and the patient remained normotensive. A juxtaglomerular cell tumor represents a rare curable cause of hypertension. The first report dates for 1967, until 2019 only about 100 cases were reported in the literature. It may be suspected that the diagnosis juxtaglomerular cell tumors is missed in many cases since these tumors are not easy to detect in standard diagnostic workup of hypertension and many antihypertensive drugs interfere with plasma renin concentrations.

Biochemical Evaluation by Confirmatory Tests after Unilateral Adrenalectomy for Primary Aldosteronism.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. Unilateral PA can be cured using unilateral adrenalectomy (Adx). PA surgery outcome (PASO) criteria, which include clinical and biochemical outcomes, have been proposed to evaluate PA cure after Adx. However, clinical outcomes are often inconsistent with biochemical outcomes. In addition, although confirmatory tests are included as endpoints of biochemical outcomes in the PASO criteria, their clinical usefulness has not yet been established. We evaluated clinical parameters and confirmatory test results before and after Adx in 16 patients with PA and assessed the usefulness of the confirmatory tests. The following were the clinical outcomes after Adx: 37.5% complete success, 62.5% partial success, and 0% absent success. The ratio of biochemical complete success was as follows: 69% aldosterone/renin ratio and basal plasma aldosterone concentration, 19% as assessed by the captopril challenge test, 47% as assessed by the saline infusion test, 30% as assessed by the furosemide upright test, and 100% urine aldosterone. Of these, biochemical complete success was judged in four cases by aldosterone/renin ratio and basal plasma aldosterone concentration, one case by captopril challenge test, five cases by saline infusion test, and one case by furosemide upright test. Although clinical outcomes and urine aldosterone levels improved after Adx, confirmatory tests failed to improve in some cases. The current criteria are not considered useful for biochemical evaluation after Adx. To determine whether additional treatment with mineralocorticoid receptor antagonists is required, more accurate biochemical criteria should be established after Adx.

PS-BPR01-7: CONCURRENT SOMATIC MUTATIONS IN CTNNB1 AND GNA11 IN AN ALDOSTERONE-PRODUCING ADENOMA

Background: Aldosterone-producing adenoma (APA) is a major subtype of primary aldosteronism (PA), a common form of secondary hypertension. In the past decade, there has been significant progress in the determination of genetic causes of APA. The use of next-generation sequencing (NGS) has led to the identification of somatic mutations in APA that cause excess aldosterone production. Most of the affected genes encode ion channels or transporters. Somatic activating mutations in CTNNB1 (β;-catenin) have also been detected in 2–5% of APA. As a possible pathogenesis, an association of CTNNB1-mutated APA with pregnancy and menopause has been proposed. A recent study reported double somatic mutations in CTNNB1 and GNA11/Q in APA. However, due to its rare incidence, characteristics of APA with these mutations are not well determined. Herein, we report a case of APA harboring somatic CTNNB1 and GNA11 mutations. Case presentation: A 46-year-old Japanese woman presented with hypertension and spontaneous hypokalemia. She had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation. Endocrine testing showed elevated plasma aldosterone concentration (677.5 pg/mL) under suppressed renin (plasma renin activity, 0.3 ng/mL/h). Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling indicated excess aldosterone production from the right adrenal gland. NP-59 scintigraphy further demonstrated increased tracer uptake in the right adrenal lesion. She underwent right laparoscopic adrenalectomy. Histologic diagnosis of the resected tumor was adrenocortical adenoma based on the Weiss criteria. Notably, Ki-67 labeling index was high (6% at hotspots). After surgery, her blood pressure and serum potassium both normalized. Based on the PASO (the primary aldosteronism surgical outcome) study criteria, PA remained clinically and biochemically cured at follow-up 18 months after surgery. Methods: Formalin-fixed, paraffin-embedded adrenal tumor tissue was used for immunohistochemical and genetic analysis. Results: Immunohistochemistry (IHC) showed high and diffuse expression of CYP11B2 (aldosterone synthase) within the tumor, whereas 11β;-hydroxylase (CYP11B1, a steroidogenic enzyme for cortisol biosynthesis) was mostly negative. VSNL1, a marker for the zona glomerulosa where physiologic aldosterone biosynthesis occurs, was highly expressed within the tumor. CYP11B2 IHC-guided targeted NGS identified concurrent somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations with similar variant allele frequencies (29.5% and 29.7%, respectively). Conclusions: To best of our knowledge, this is the first Asian case of APA with CTNNB1 and GNA11 mutations. Detailed clinical and histologic examination would provide useful information for better characterization of patients with PA due to these rare mutations.

AW-APSH-2: “MINERALOCORTICOID RECEPTOR (MR)-ASSOCIATED HYPERTENSION” IN “GREEDY ORGAN HYPOTHESIS”

Spironolactone has been used for more than 60 years. Eplerenone is MR-specific MRB and esaxerenone possesses non-steroidal structure with high affinity and specificity to MR and exhibits long half-life. We conducted a double-blind phase III study of esaxerenone compared with eplerenone in patients with essential hypertension in 2020. Esaxerenone 2.5 mg elicited comparable hypotensive effect to eplerenone 50 mg and 5 mg exhibited significantly stronger effect than 2.5 mg. We also investigated the efficacy of dosage-escalation of esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes (DM) (HbA1c:6.8%) and albuminuria (212 mg/gCr). 5 mg esaxerenone induced 20/8mmHg blood pressure reduction and reduced albumin excretion significantly. Interestingly, in these studies, esaxerenone exerted similar hypotensive action in the patients with RAS inhibitors, compared to the groups without them. This observation indicates that MR can be activated being independent of renin-angiotensin-aldosterone system. In 2012, we proposed the concept of “MR-associated hypertension”, hypertension caused by over-activation of MR with wide range of plasma aldosterone level. Primary aldosteronism is the typical example of MR-associated hypertension, but even in low plasma aldosterone concentration state, such as obesity, DM, CKD, MR can be over-activated. There are several postulated mechanisms of over-activation of MR. Increased expression of MR, increased sensitivity of MR and MR protein stabilization. We are interested in the activation of MR by salt and sugar themselves. We focus on MR expressed in the intestine for sodium absorption. Administration of DOCA and high salt induced up-regulation of epithelial sodium channel, ENaC, the target molecule of MR. And intestine specific knock-out of MR mice exhibited blunted increase of blood pressure by DOCA and high salt loading. We also demonstrated that high sugar induces MR protein stabilization by PKC activation, O-GlcNac modification or EGFR-ERK activation. More recently, in relation to excessive salt and sugar intake and occurrence of non-communicable diseases (NCDs), including hypertension, we have proposed “Greedy Organ Hypothesis”. Excessive intake of salt and sugar are sensed by the kidney and the intestines, and these organs up-regulate SGLT, sodium-glucose co-transporters and come to absorb salt and sugar greedily. Excessive salt intake through SGLT2 makes the kidney greedy to induce hypertension/CKD. Excessive food intake through SGLT1 make the intestines greedy to induce obesity/DM. Furthermore, there is “crossing” relationships between “greedy organs” and NCDs. Greedy kidney and intestines over-activate MR and induce MR-associated hypertension. Therefore, MRB are effective to alleviate Greedy Organs and to suppress NCDs.

PS-R04-5: A CASE OF SEVERE RENAL FAILURE WITH HYPERTENSIVE EMERGENCY WHO SUCCEEDED IN HEMODIALYSIS WITHDRAWAL BY STRICT CONTROL OF BLOOD PRESSURE

Introduction: Hypertensive emergency is a condition in which progressive and irreversible organ damages occur as a result of extremely elevated blood pressure. Although the prognosis for renal outcomes has been improved by advances in antihypertensive therapy, the cases who result in maintenance dialysis are still not uncommon. We herein report a case of hypertensive emergency who was successfully withdrawn from hemodialysis by intensive treatment. Case presentation: A 55-year-old woman, whose systolic blood pressure was 150–160 mmHg constantly for at least 2 years, was seen by her primary care physician due to nocturnal cough and respiratory distress. She exhibited marked hypertension (diastolic blood pressure, 120–130 mmHg) and renal dysfunction (serum creatinine (sCr), 2.76 mg/dL, baseline 0.5 mg/dL). She was diagnosed as hypertensive emergency and was treated with antihypertensive agents immediately. Despite the treatment, her renal function did not improve, so that she was transferred to our hospital for further examination and intensive treatment. While imaging examination revealed a right adrenal tumor, for which primary aldosteronism was suspected, endocrinological examinations showed high plasma aldosterone concentration with high plasma renin activity; therefore it was assumed that the hormonal changes were secondary to hypertensive emergency. Although funduscopic findings were relatively mild (KW-IIb), the condition was considered as accelerated-malignant hypertension caused by essential hypertension. A renal biopsy revealed extensive interstitial damage with onion skin-like lesions, which led to a diagnosis of malignant nephrosclerosis. While continuing strict antihypertensive management including the renin-angiotensin system blockade, hemodialysis was started on day 17 due to progressive renal dysfunction (sCr 9.27 mg/dL). Continuous intensive treatment gradually alleviated renal dysfunction, and hemodialysis was finally withdrawn on day 38. There was no further deterioration seen, and the patient was discharged on day 55. After discharge, her renal function was kept improved and her sCr was 2.5 mg/dL 6 months after the discharge. Discussion and Conclusion: Hypertensive emergency may cause irreversible kidney damage without appropriate antihypertensive therapy. In particular, acute tubular damages have been suggested to correlate with both systolic and diastolic blood pressures. Controlling blood pressure appropriately is crucial to protect kidneys against disease progression and even reverse kidney damage upon acute renal failure with hypertensive emergency.

PS-BPC08-8: SEX DIFFERENCES IN IN THE SCREENING CUTOFFS OF PRIMARY ALDOSTERONISM

Title: Sex differences in in the screening cutoffs of primary aldosteronism Objective: In screening for primary aldosteronism (PA), simultaneous measurements of plasma aldosterone concentration (PAC; pg/mL) and plasma renin activity (PRA; ng/mL/hr) and the resulting PAC/PRA ratio (ARR) &gt; 200 have been actively employed. Because of the low stability and reproducibility of PRA, screening using active renin concentration (ARC; pg/mL), which can overcome these problems, is desirable but has not become a mainstream screening method in practice. This study will clarify the association between ARC and PRA and examine the impact of sex differences on PA screening. Methods: 1631 consecutive patients (1018 inpatients (51.5%; male) and 613 outpatients (58.1%; male)) who had measured PRA and ARC simultaneously at Osaka University Hospital from February 2017 to December 2020 were analyzed retrospectively. In the inpatients, blood samples were taken in the supine position at rest in the early morning. In outpatients, blood was collected without specifying the blood collection conditions. PRA, ARC, and PAC if blood was collected at the same time were analyzed. PRA was measured by enzyme immunoassay. Each of PAC and ARC was measured by chemiluminescent immunoassay. All results are represented as median (25th to 75th percentile). For the analysis of variables association Mann Whitney`s U t test was used for comparison of each measurement between the two groups, with 5% significance level. Results: PRA and ARC were correlated in the overall population and by sex (overall; r = 0.78 p &lt; 0.0001, male r = 0.90 p &lt; 0.0001, female r = 0.71, P &lt; 0.0001). Analysis of covariance showed a significant difference in the regression line between PRA and ARC by sex (p &lt; 0.0001) and PRA/ARC was significantly lower in males (0.17 [0.13–0.22] vs 0.19 [0.14–0.26] p &lt; 0.0001). In the inpatients, PRA, ARC and PAC was significantly higher in males (PRA; 1.1 [0.4–2.9] vs 0.7 [0.3–1.7] p &lt; 0.0001, ARC; 6.6 [3.0–16.8] vs 4.4 [1.8–8.3] p &lt; 0.0001, PAC; 137 [100–196] vs 130 [88–185], p = 0.003,). PAC/PRA, PAC/ARC were significantly lower in males (PAC/PRA; 120 [47–307] vs 179 [81–335] p = 0.0002, PAC/ARC; 20 [8–45] vs 32 [16–63] p &lt; 0.0001). In the outpatients, both PRA and ARC, PAC were also significantly higher, and PAC/PRA and PAC/ARC were significantly lower in males(PRA; 1.3 [0.6–3.4] vs 0.8 [0.4–2.4] p &lt; 0.0001, ARC; 6.8 [3.4–15.1] vs 4.4 [2.0–11.1] p &lt; 0.0001, PAC; 137 [98–198] vs 158 [116–220] p = 0.003, PAC/PRA; 106 [44–226] vs 179 [70–380] p &lt; 0.0001, PAC/ARC; 20 [10–40] vs 36 [15–72] p &lt; 0.0001). Conclusion: Significant differences in PRA, ARC, PAC, PRA/ARC, PAC/PRA, and PAC/ARC were observed by the sex. Sex differences should be considered in screening for PA by ARR and PAC/ARC.

PS-BPR01-4: A CASE OF ALDOSTERONE-PRODUCING ADENOMA DIAGNOSED BY ADRENAL ARTERIOGRAPHY AND BRANCH SELECTIVE ADRENAL VENOUS SAMPLING

Case report: A 43-year-old man had been followed up for hypertension and hypokalemia, but self-interrupted his hospital visits for the last four years. Based on the serum potassium level of 2.7 mEq/L, plasma aldosterone concentration of 202 pg/mL, and plasma renin activity of 1.1 ng/mL/hr, he was suspected of primary aldosteronism and was admitted to the previous hospital. A saline suppression test and a rapid ACTH stimulation test were both positive, and 24-hr urinary aldosterone level was 19 μg/day under sodium loading of 170 mEq/day, leading to the diagnosis of primary aldosteronism. Since contrast-enhanced CT showed an 8 mm-sized adenoma in the lower portion of the left adrenal gland, an aldosterone-producing adenoma was suspected and a non-segmental adrenal venous sampling (AVS) was performed. However, it yielded apparent bilateral aldosterone suppression in the main trunk of the bilateral adrenal veins, where the aldosterone-to-cortisol (A/C) ratio was lower than that in the inferior vena cava even after ACTH loading. The patient was referred to our hospital for a segmental AVS. Arteriography was first performed from the left inferior adrenal artery to confirm the outflow vessels from the adenoma. Strikingly, there was an aberrant vein which drained into the proximal segment of the left adrenal vein. CT imaging at the time of arteriography revealed, in addition to the known adenoma, a 6 mm-sized micronodule in the lateral region of the left adrenal gland, and the aberrant vein appeared to be the main outflow vessel from the micronodule. A segmental AVS was performed, and blood samples were taken from the bilateral adrenal veins including the aberrant vein and the main trunk of the left adrenal vein proximal to its confluence. The A/C ratio was highest in the aberrant vein, followed by in the main trunk of the proximal left adrenal vein, while it was markedly suppressed in other branches and the main trunk of the left adrenal vein distal to the confluence of the aberrant vein. Based on these results, the presence of aldosterone-producing adenoma in the left adrenal gland was suggested. Laparoscopic partial left adrenalectomy was performed without postoperative complications. Hypertension and hypokalemia were fully resolved afterwards. Conclusions: Adrenal arteriography and segmental AVS should be considered in such cases that apparent bilateral aldosterone suppression is noted in conventional AVS in patients with clinically suspected aldosterone-producing adenoma.

First survey on the diagnosis and treatment of primary aldosteronism by Spanish Endocrinology and Nutrition specialists

ObjectiveTo evaluate the indication and the resources for the screening/diagnosis of primary aldosteronism (PA) in Endocrinology units in Spain. Material and methodsAn anonymous 2-phase (2020/2021) online survey was conducted by the AdrenoSEEN group among SEEN members with data about screening, confirmation tests, availability of catheterisation and the treatment of PA. ResultsEighty-eight (88) specialists completed the survey. Plasma aldosterone concentration and plasma renin activity were available at all centres; urinary aldosterone was available in 55% of them. The most frequent indications for determining the aldosterone/renin ratio (ARR) were adrenal incidentaloma (82.6%), hypertension with hypokalaemia (82.6%), hypertension in patients <40 years (79.1%) and a family history of PA (77.9%). 61% and 18% of the respondents used an ARR cut-off value of PA of ≥30 and 20ng/dl per ng/mL/, respectively. The intravenous saline loading test was the most commonly used confirmatory test (66.3%), followed by the captopril challenge test (24.4%), with the 25mg dose used more than the 50mg dose (65% versus 35%). 67.4% of the participants confirmed the availability of adrenal vein catheterization (AVC). 41% of this subgroup perform it with a continuous infusion versus 30.5% with an ACTH (1–24) bolus, whereas 70.3% employ sequential adrenal vein catheterization. 48% of the participants reported an AVC success <50%. Total laparoscopic adrenalectomy was the treatment of choice (90.6%), performed by specialists in General and Digestive Surgery specialising in endocrinological pathology. ConclusionPA screening and diagnostic tests are extensively available to Spanish endocrinologists. However, there is a major variability in their use and in the cut-off points of the diagnostic methods. The AVS procedure remains poorly standardised and is far from delivering optimal performance. Greater standardisation in the study and diagnosis of PA is called for.

Adrenal Vein Sampling Results and Surgical Outcomes in Patients with a Normal Plasma Aldosterone Concentration

PurposeTo determine the utility of adrenal vein sampling (AVS) and outcomes after adrenalectomy in patients with normal plasma aldosterone concentration (PAC) and elevated aldosterone-to-renin ratio (ARR). Materials and MethodsThe study sample included 106 patients with ARR greater than 20 and PAC between 5 and 15 ng/dL (normal PAC group) who underwent AVS from 2005 to 2021. These patients were compared with a cohort of 106 patients with ARR >20 and PAC >15 ng/dL (high PAC group) who underwent AVS during the same period. Data regarding baseline clinical characteristics, lateralization indices from AVS, and outcomes after adrenalectomy were analyzed. ResultsAVS was technically successful in 210 patients (210/212, 99%). A smaller proportion of patients in the normal PAC group showed a lateralization index of >4 compared with those in the high PAC group (44% vs 64%, P <.01). A similar proportion of patients in the normal PAC group experienced improved or cured hypertension after adrenalectomy compared with that in the high PAC group (94% vs 88%, P =.31). Hypokalemia was cured in all patients in the normal PAC group after adrenalectomy compared with 98% of patients in the high PAC group (100% vs 98%, P = 1). ConclusionsAlthough lateralization is less frequent for patients with normal PAC, patients who do lateralize show similar blood pressure response and correction of hypokalemia after adrenalectomy, regardless of initial plasma aldosterone levels. Therefore, patients with PAC <15 ng/dL should still be considered for AVS provided the ARR is elevated.

Effect of Metabolic Adaptation by Voluntary Running Wheel Activity and Aldosterone Inhibition on Renal Function in Female Spontaneously Hypertensive Rats.

Metabolic effects of physical activity may be reno-protective in the context of hypertension, although exercise stresses kidneys. Aldosterone participates in renal disease in hypertension, but exercise affects the plasma concentration of aldosterone. This study was designed to evaluate whether physical activity and pharmacological treatment by aldosterone have additive effects on renal protection in hypertensive rats. Female spontaneously hypertensive rats (SHR) or normotensive Wistar rats performed voluntary running wheel activity alone or in combination with aldosterone blockade (spironolactone). The following groups were studied: young and pre-hypertensive SHR (n = 5 sedentary; n = 10 running wheels, mean body weight 129 g), 10-month-old Wistar rats (n = 6 sedentary; n = 6 running wheels, mean body weight 263 g), 10-month-old SHRs (n = 18 sedentary, mean body weight 224 g; n = 6 running wheels, mean body weight 272 g; n = 6 aldosterone, mean body weight 219 g; n = 6 aldosterone and running wheels, mean body weight 265 g). Another group of SHRs had free access to running wheels for 6 months and kept sedentary for the last 3 months (n = 6, mean body weight 240 g). Aldosterone was given for the last 4 months. SHRs from the running groups had free access to running wheels beginning at the age of 6 weeks. Renal function was analyzed by microalbuminuria (Alb/Cre), urinary secretion of kidney injury molecule-1 (uKim-1), and plasma blood urea nitrogen (BUN) concentration. Molecular adaptation of the kidney to hypertension and its modification by spironolactone and/or exercise were analyzed by real-time PCR, immunoblots, and histology. After six months of hypertension, rats had increased Alb/Cre and BUN but normal uKim-1. Voluntary free running activity normalized BUN but not Alb/Cre, whereas spironolactone reduced Alb/Cre but not BUN. Exercise constitutively increased renal expression of proprotein convertase subtilisin/kexin type 9 (PCSK9; mRNA and protein) and arginase-2 (mRNA). Spironolactone reduced these effects. uKim-1 increased in rats performing voluntary running wheel activity exercise irrespectively of blood pressure and aldosterone blockade. We observed independent but no additive effects of aldosterone blockade and physical activity on renal function and on molecules potentially affecting renal lipid metabolism.

Aldosterone Immunoassay-Specific Cutoff Value for Seated Saline Suppression Test for Diagnosing Primary Aldosteronism.

A seated saline loading test (SLT) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is one of the most accepted confirmatory tests of primary aldosteronism. However, LC-MS/MS is time-consuming and is not widely available in diagnostic laboratories compared to immunoassay. With immunoassay, it is unknown whether SLT in the seated position is more accurate than that of the supine position, and a cutoff value of post-seated SLT plasma aldosterone concentration (PAC) must be established in the Korean population. Ninety-eight patients underwent SLT in both positions, and post-SLT PAC was measured by LC-MS/MS and radioimmunoassay. We confirmed primary aldosteronism if post-seated SLT PAC by LC-MS/MS exceeded 5.8 ng/dL. The area under the receiver operating characteristic curve was greater for seated than supine SLT (0.928 vs. 0.834, P=0.003). The optimal cutoff value of post-seated SLT by radioimmunoassay was 6.6 ng/dL (sensitivity 83.3%, specificity 92.2%).