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Focal segmental glomerulosclerosis is a rare complication of acromegaly. A 74-year-old man was found to have acromegaly features such as enlargement of the forehead, nose, and hands. Laboratory tests showed a urine protein/creatinine ratio of 3.16 g/gCr and serum creatinine of 1.34 mg/dL. The levels of growth hormone and insulin-like growth factor I were markedly elevated, and the growth hormone level was not suppressed after 75 g oral glucose loading. Magnetic resonance imaging revealed a pituitary tumor with a diameter of 1.2 cm. Renal biopsy confirmed the diagnosis of focal segmental glomerulosclerosis. Transsphenoidal resection of the pituitary tumor led to remission of acromegaly and reduction in proteinuria highlighting the causal link between growth hormone overproduction and proteinuria. Treatment of acromegaly may be effective for acromegaly-associated focal segmental glomerulosclerosis.

The rapid progression of chronic kidney disease and higher incidence of cardiovascular complications are well known in patients with hyperaldosteronism. However, detailed renal histopathologic characteristics of this disease have remained unknown. Therefore, renal biopsy specimens of 19 cases with unilateral hyperaldosteronism were compared with 22 autopsy renal cases of estimated glomerular filtration rate-matched essential hypertension without nephropathy or endocrine disorders to explore the hyperaldosteronism-specific histopathologic renal changes in this study. Global and segmental glomerulosclerosis, interstitial fibrosis, infiltration of inflammatory cells, arteriosclerosis, hyalinization of arterioles and immunoreactivity of mineralocorticoid receptor, 11β-hydroxysteroid dehydrogenase type 1 and 2, and renin were all quantitatively evaluated. The ultrastructural analysis was added in 3 hyperaldosteronism cases. Both mineralocorticoid receptor ( P P P P P =0.08). Glomerular size was significantly larger in hyperaldosteronism ( P P =0.08), and intima-to-media ratio was significantly lower ( P =0.02) in hyperaldosteronism. Arteriolar hyalinization was significantly more pronounced ( P P

Primary aldosteronism (PA) is the most common cause of secondary hypertension, and is associated with an increased incidence of cardiovascular events. PA itself is clinically classified into the following two types: unilateral PA, mostly composed of aldosterone-producing adenoma (APA); and bilateral hyperaldosteronism, consisting of multiple aldosterone-producing micronodules (APMs) and aldosterone-producing diffuse hyperplasia. Histopathologically, those disorders above are all composed of compact and clear cells. The cellular morphology in the above-mentioned aldosterone-producing disorders has been recently reported to be closely correlated with patterns of somatic mutations of ion channels including KCNJ5, CACNA1D, ATP1A1, ATP2B3, and others. In addition, in non-pathological adrenal glands, APMs are frequently detected regardless of the status of the renin-angiotensin-aldosterone system (RAAS). Aldosterone-producing nodules have been also proposed as non-neoplastic nodules that can be identified by hematoxylin and eosin staining. These non-neoplastic CYP11B2-positive nodules could represent possible precursors of APAs possibly due to the presence of somatic mutations. On the other hand, aging itself also plays a pivotal role in the development of aldosterone-producing lesions. For instance, the number of APMs was also reported to increase with aging. Therefore, recent studies indicated the novel classification of PA into normotensive PA (RAAS-independent APM) and clinically overt PA.

Background While previous studies indicate that the zonae reticularis (ZR) and glomerulosa (ZG) diminish with aging, little is known about age-related transformations of the zona fasciculata (ZF). Objectives To investigate the morphological and functional changes of the adrenal cortex across adulthood, with emphasis on (i) the understudied ZF and (ii) sexual dimorphisms. Methods We used immunohistochemistry to evaluate the expression of aldosterone synthase (CYP11B2), visinin-like protein 1 (VSNL1), 3β-hydroxysteroid dehydrogenase type II (HSD3B2), 11β-hydroxylase (CYP11B1), and cytochrome b5 type A (CYB5A) in adrenal glands from 60 adults (30 men), aged 18 to 86. Additionally, we employed mass spectrometry to quantify the morning serum concentrations of cortisol, 11-deoxycortisol (11dF), 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, and androstenedione in 149 pairs of age- and body mass index–matched men and women, age 21 to 95 years. Results The total cortical area was positively correlated with age (r = 0.34, P = 0.008). Both the total (VSNL1-positive) and functional ZG (CYP11B2-positive) areas declined with aging in men (r = −0.57 and −0.67, P < 0.01), but not in women. The CYB5A-positive area declined with age in both sexes (r = −0.76, P < 0.0001). In contrast, the estimated ZF area correlated positively with age in men (r = 0.59, P = 0.0006) and women (r = 0.49, P = 0.007), while CYP11B1-positive area remained unchanged across ages. Serum cortisol, corticosterone, and 11-deoxycorticosterone levels were stable across ages, while 11dF levels increased slightly with age (r = 0.16, P = 0.007). Conclusion Unlike the ZG and ZR, the ZF and the total adrenal cortex areas enlarge with aging. An abrupt decline of the ZG occurs with age in men only, possibly contributing to sexual dimorphism in cardiovascular risk.

Although adrenal resection is a major option to control hypercortisolemia in patients with bilateral macronodular adrenal hyperplasia, a predictive method for postoperative cortisol production has not been established. A 53-year-old man with ulcerative colitis was referred to our hospital for bilateral multiple adrenal nodules and hypertension. Physical and endocrinological examination revealed inappropriate cortisol production and suppressed secretion of adrenocorticotropic hormone with no typical signs of Cushing's syndrome. Imaging analysis revealed bilateral adrenal nodular enlargement, the nodules of which had the radiological features of adrenocortical adenomas without inter-nodular heterogeneity. In addition, computed tomography volumetry demonstrated that the left adrenal gland (70 mL) accounts for three quarters of the total adrenal volume (93 mL). The patient was diagnosed as subclinical Cushing's syndrome due to bilateral macronodular adrenal hyperplasia, and subsequently underwent a left laparoscopic adrenalectomy with the estimation of 75% decrease in the cortisol level based on the adrenal volume. The surgical treatment ultimately resulted in control of the cortisol level within the normal range, which was compatible to our preoperative prediction. However, regardless of the sufficient cortisol level, ulcerative colitis was exacerbated after the surgery, which needed a systemic therapy for remission. This case indicates successful surgical control of hypercortisolemia based on computed tomography volumetry in bilateral macronodular adrenal hyperplasia, as well as the perioperative exacerbation risk for inflammatory diseases in Cushing's syndrome. We report the potential utility of computed tomography volumetry as a quantitative method with retrospective evaluation of our historical cases.

Aldosterone plays pivotal roles in renin-angiotensin-aldosterone system in order to maintain the equilibrium of liquid volume and electrolyte metabolism. Aldosterone action is mediated by both mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Its excessive actions directly induced tissue injuries in its target organs such as myocardial and vascular fibrosis in addition to chronic kidney diseases. Excessive aldosterone actions were also reported to be involved in unbalanced electrolyte metabolism in inflammatory bowel disease and development of pulmonary diseases. Hyperaldosteronism is tentatively classified into primary and secondary types. Primary aldosteronism is more frequent and has been well known to result in secondary hypertension with subsequent cardiovascular damages. Primary aldosteronism is also further classified into distinctive subtypes and among those, aldosterone-producing adenoma is the most frequent one accounting for the great majority of unilateral primary aldosteronism cases. In bilateral hyperaldosteronism, aldosterone-producing diffuse hyperplasia and aldosterone-producing micronodules or nodules are the major subtypes. All these aldosterone-producing lesions were reported to harbor somatic mutations including KCNJ5, CACNA1D, ATP1A1 and ATP2B3, which were all related to excessive aldosterone production. Among those mutations above, somatic mutation of KCNJ5 is the most frequent in aldosterone-producing adenoma and mostly composed of clear cells harboring abundant aldosterone synthase expression. In contrast, CACNA1D-mutated aldosterone-producing micronodules or aldosterone-producing nodules were frequently detected not only in primary aldosteronism patients but also in the zona glomerulosa of normal adrenal glands, which could eventually lead to an autonomous aldosterone production resulting in normotensive or overt primary aldosteronism, but their details have remained unknown.

Mineralocorticoid receptor antagonists (MRAs) are effective in patients with resistant hypertension and/or primary aldosteronism (PA). Screening for PA should ideally be conducted after stopping medications that might interfere with the renin-angiotensin-aldosterone system, but this is challenging in patients with recalcitrant hypertension or hypokalemia. Herein, we aimed to evaluate the impact of MRAs on PA screening in clinical practice.We conducted a retrospective cohort study of patients with hypertension who had plasma aldosterone and renin measurements before and after MRA use in a tertiary referral center, over 19 years.A total of 146 patients, 91 with PA, were included and followed for up to 18 months. Overall, both plasma renin and aldosterone increased after MRA initiation (from median, interquartile range: 0.5 [0.1, 0.8] to 1.2 [0.6, 4.8] ng/mL/hour and from 19.1 [12.9, 27.7] to 26.4 [17.1, 42.3] ng/dL, respectively; P.0001 for both), while the aldosterone/renin ratio (ARR) decreased from 40.3 (18.5, 102.7) to 23.1 (8.6, 58.7) ng/dL per ng/mL/hour (P.0001). Similar changes occurred irrespective of the MRA treatment duration and other antihypertensives used. Positive PA screening abrogation after MRA initiation was found in 45/94 (48%) patients. Conversely, 17% of patients had positive PA screening only after MRA treatment, mostly due to correction of hypokalemia. An initially positive screening test was more likely altered by high MRA doses and more likely persistent in patients with confirmed PA or taking beta-blockers.MRAs commonly reduce ARR and the proportion of positive PA screening results. When PA is suspected, screening should be repeated off MRAs.ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARR = aldosterone/renin ratio; DRC = direct renin concentration; MRA = mineralocorticoid receptor antagonist; PA = primary aldosteronism; PAC = plasma aldosterone concentration; PRA = plasma renin activity; RAAS = renin-angiotensin-aldosterone system.

Objectives This study compared cardiac function, morphology, and tissue characteristics between two common subtypes of primary aldosteronism (PA) using a 3T MR scanner. Design A retrospective, single-center, observational study. Methods We retrospectively reviewed 143 consecutive patients with PA, who underwent both adrenal venous sampling and cardiac magnetic resonance. We acquired cine, late gadolinium enhancement, and pre- and postcontrast myocardial T1-mapping images. Results PA was diagnosed as unilateral aldosterone-producing adenoma (APA) in 70 patients and bilateral hyperaldosteronism (BHA) in 73. The APA group showed significantly higher plasma aldosterone concentration (PAC) and aldosterone to renin rate (ARR) than the BHA group. After controlling for age, sex, antihypertensive drugs, systolic and diastolic blood pressure, and disease duration, the parameters independently associated with APA were: left ventricular end-diastolic volume index (EDVI: adjusted odds ratio (aOR) = 1.06 (95% CI: 1.030–1.096), P < 0.01), end-systolic volume index (ESVI: 1.06 (1.017–1.113), P < 0.01), stroke index (SI: 1.07 (1.020–1.121), P < 0.01), cardiac index (CI: 1.001 (1.000–1.001), P < 0.01), and native T1 (1.01 (1.000–1.019), P = 0.038). Weak positive correlations were found between PAC and EDVI (R = 0.28, P < 0.01), ESVI (0.26, P < 0.01), and SI (0.18, P = 0.03); and between ARR and EDVI (0.25, P < 0.01), ESVI (0.24, P < 0.01), and native T1 (0.17, P = 0.047). Conclusions APA is associated with greater LV volumetric parameters and higher native T1 values, suggesting a higher risk of volume overload and myocardial damage.

Cortisol-producing adenoma (CPA) is composed of clear and compact cells. Clear cells are lipid abundant, and compact ones lipid poor but associated with higher production of steroid hormones. PRKACA mutation (PRKACA mt) in CPA patients was reported to be associated with more pronounced clinical manifestation of Cushing’s syndrome. In this study, we examined the association of histological features and genotypes with cholesterol uptake receptors and synthetic enzymes in 40 CPA cases, and with the quantitative results obtained by gas chromatography-mass spectrometry (GC-MS) analysis in 33 cases to explore their biological and clinical significance. Both cholesterol uptake receptors and synthetic enzymes were more abundant in compact cells. GC-MS analysis demonstrated that the percentage of compact cells was inversely correlated with the concentrations of cholesterol and cholesterol esters, and positively with the activity of cholesterol biosynthesis from cholesterol esters. In addition, hormone-sensitive lipase (HSL), which catalyzes cholesterol biosynthesis from cholesterol esters, tended to be more abundant in compact cells of PRKACA mt CPAs. These results demonstrated that both cholesterol uptake and biosynthesis were more pronounced in compact cells in CPA. In addition, more pronounced HSL expression in compact cells of PRKACA mt CPA could contribute to their more pronounced clinical manifestation.

Purpose of Review The study aims to verify the advantages of nonsteroidal mineralocorticoid receptor blockers (MRBs) in the management of hypertension and cardiovascular and renal diseases, comparing with conventional MRBs. Recent Findings Based on the unique structures, the nonsteroidal MRBs have higher selectivity for mineralocorticoid receptors (MRs) and show no agonist activity for major steroid hormone receptors in contrast to steroidal MRBs. Today, there are two nonsteroidal MRBs, esaxerenone and finerenone, which completed phase 3 clinical trials. Series of clinical trials have shown that both agents achieve similar MR blockade with smaller doses as compared with steroidal MRBs, but have no off-target side effect such as gynecomastia. Esaxerenone has persistent blood pressure-lowering effects in various hypertensive populations, including essential hypertension and those with diabetes and/or chronic kidney disease, while finerenone has demonstrated reduction of the cardiovascular risk rather than blood pressure in patients with diabetes and chronic kidney disease. Summary Nonsteroidal MRBs are a more refined agent which contributes to appropriate MR blocking with minimized unpleasant adverse effects.

Congestive heart failure (CHF) is rare during pregnancy. We herein report a 35-year-old woman who developed CHF with severe left ventricular dysfunction at 35 weeks' gestation. She underwent emergency Caesarean section followed by intensive-care treatment for CHF. The diagnosis of Cushing's syndrome (CS) caused by adrenal adenoma was confirmed by endocrinological examinations and histology after adrenalectomy. She was discharged on heart failure medications and glucocorticoid replacement therapy. Both the symptoms and cardiac function had recovered after 12 months of follow-up. This case highlights the importance of considering CS-induced cardiomyopathy as a cause of CHF in pregnant women.

Background Primary aldosteronism (PA) is broadly divided into unilateral and bilateral forms, and the most reliable subtyping tool available is adrenal vein sampling (AVS). Unilateral PA is generally diagnosed based on AVS lateralization indices (LI=[aldosterone/cortisol] ratio between the dominant and contralateral adrenal vein) ≥4, or even ≥2 when AVS is performed without cosyntopin stimulation. Long-term follow-up data from patients with PA treated with unilateral adrenalectomy have been minimal. Objective To assess the rates of residual and recurrent PA after AVS-guided unilateral adrenalectomy. Methods We enrolled patients with PA who underwent unilateral adrenalectomy between 09/2017 and 08/2021 in a single tertiary referral center and followed them longitudinally. Demographics, laboratory, imaging, and pathology data were collected. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue blocks. Results During the study period, 80 patients (52 men) with median age 53 (range, 19-76) years underwent unilateral adenectomy, and were followed for a median 80 days (range, 6-653 days). In total 14 (17.5%) patients had evidence of residual PA following surgery, including 3 who had complete biochemical failure, and 1 who had apparent cure of PA immediately post-operatively. All 14 patients had severe PA, with baseline plasma aldosterone concentrations between 23.4 and 496 ng/dL and suppressed renin. Baseline and post-cosyntropin stimulation LIs ranged from 2.7- 187.5 and 1.3-53.7. The LI was >4 only at baseline in 3 cases, and only after cosyntropin stimulation in 2 cases. Histology showed single adenomas, ranging from 0.7-5.3 cm in 7 (50%) patients, and multiple adenomas and/or nodular hyperplasia in 7 (50%) patients. Of the 7 cases analyzed for aldosterone-driver mutations so far, 4 harbored CACNA1D mutations, 2 ATP1A1 mutations, and 1 a KCNJ5 mutation. Conclusions Patients with severe PA and frank AVS aldosterone lateralization might have multifocal, bilateral disease. Long-term follow up and targeted medical therapy should be pursued after unilateral adrenalectomy for presumed unilateral PA. Presentation: Monday, June 13, 2022 11:15 a.m. - 11:30 a.m.

The developing neocortex exhibits spontaneous network activity with various synchrony levels, which has been implicated in the formation of cortical circuits. We previously reported that the development of callosal axon projections, one of the major long-range axonal projections in the brain, is activity dependent. However, what sort of activity and when activity is indispensable are not known. Here, using a genetic method to manipulate network activity in a stage-specific manner, we demonstrated that network activity contributes to callosal axon projections in the mouse visual cortex during a ‘critical period’: restoring neuronal activity during that period resumed the projections, whereas restoration after the period failed. Furthermore, in vivo Ca2+ imaging revealed that the projections could be established even without fully restoring highly synchronous activity. Overall, our findings suggest that spontaneous network activity is selectively required during a critical developmental time window for the formation of long-range axonal projections in the cortex.

The developing neocortex exhibits spontaneous network activity with various synchrony levels, which has been implicated in the formation of cortical circuits. We previously reported that the development of callosal axon projections, one of the major long-range axonal projections in the brain, is activity dependent. However, what sort of and when activity is indispensable are not known. Here, using a genetic method to manipulate network activity in a stage-specific manner, we demonstrated that network activity contributes to callosal axon projections in the mouse visual cortex during a “critical period”: restoring neuronal activity during that period resumed the projections, whereas restoration after the period failed. Furthermore, in vivo Ca2+ imaging revealed that the projections could be established even without fully restoring highly synchronous activity. Overall, our findings suggest that the spontaneous network activity is selectively required during a critical developmental time window for the formation of long-range axonal projections in the cortex. (150)

ContextAdrenocorticotropic hormone (ACTH) can contribute to aldosterone excess in primary aldosteronism (PA) via increased melanocortin type 2 receptor expression. Dynamic manipulation of the hypothalamic-pituitary-adrenal (HPA) axis could assist PA subtyping, but a direct comparison of dynamic tests is lacking.ObjectiveTo investigate plasma steroid differences between aldosterone-producing adenoma (APA) and bilateral PA (BPA) relative to ACTH variations.MethodsWe conducted comprehensive dynamic testing in 80 patients: 40 with APA and 40 with BPA. Peripheral plasma was collected from each patient at 6 time points: morning; midnight; after 1 mg dexamethasone suppression; and 15, 30, and 60 minutes after ACTH stimulation. We quantified 17 steroids by mass spectrometry in response to ACTH variations in all patients and compared their discriminative power between the 2 PA subtypes.ResultsPatients with APA had higher morning and midnight concentrations of 18-hydroxycortisol, 18-oxocortisol, aldosterone, and 18-hydroxycorticosterone than those with BPA (P ConclusionSteroid differences between APA and BPA are enhanced by dynamic HPA testing; such noninvasive tests could circumvent the need for adrenal vein sampling in a subset of patients with PA.

For the last seven decades, primary aldosteronism (PA) has been gradually recognized as a leading cause of secondary hypertension harboring increased risks of cardiovascular incidents compared to essential hypertension. Clinically, PA consists of two major subtypes, surgically curable and uncurable phenotypes, determined as unilateral or bilateral PA by adrenal venous sampling. In order to further optimize the treatment, surgery or medications, diagnostic procedures from screening to subtype differentiation is indispensable, while in the general clinical practice, the work-up rate is extremely low even in the patients with refractory hypertension because of the time-consuming and labor-intensive nature of the procedures. Therefore, a novel tool to simplify the diagnostic flow has been recently in enormous demand. In this review, we focus on recent progress in the following clinically important topics of PA: prevalence of PA and its subtypes, newly revealed histopathological classification of aldosterone-producing lesions, novel diagnostic biomarkers and prediction scores. More effective strategy to diagnose PA based on better understanding of its epidemiology and pathology should lead to early detection of PA and could decrease the cardiovascular and renal complications of the patients.

Objective: Laparoscopic adrenalectomy (LADX) improves hypertension in patients with primary aldosteronism (PA). However, the antihypertensive impact of LADX appears restricted in older patients with PA. In this study, we evaluated the impact of LADX in older patients focusing on the health-related quality of life (HRQoL). Methods: A total of 156 patients with PA who underwent LADX in a single institution were enrolled in this prospective cohort study. The patients were divided into 2 groups, with a boundary of 60 years. The HRQoL was evaluated using the Medical Outcomes Study’s 36-Item Short-Form Health Survey version 2 (SF-36v2) questionnaire before and after LADX. Demographics, clinical features, antihypertensive drugs before and after surgery, and perioperative evaluation were recorded. We compared all scale scores and summed scores between groups. Multivariate regression models were used to determine the associations between various covariables and the HRQoL. Results: In the older PA patients, most subscales of HRQoL at baseline were lower than the national standard values. The antihypertensive drug-free rate by LADX was only 21% in older patients, compared to 58% in younger patients. However, a significant improvement in mental HRQoL was observed after LADX (p = 0.002). The much preoperative antihypertensive drugs, lower preoperative potassium level, and smaller degree of comorbidities were predictors of improved mental HRQoL by LADX on multivariate analyses. Conclusion: The older PA patients showed lower mental HRQOL than the national standard populations. Although antihypertensive effects were limited for these patients, LADX was beneficial as PA treatment via improvement of mental HRQoL.

Context Results of previous studies demonstrated clear racial differences in the prevalence of somatic mutations among patients with aldosterone-producing adenoma (APA). For instance, those in East Asian countries have a high prevalence of somatic mutations in KCNJ5, whereas somatic mutations in other aldosterone-driving genes are rare. Objectives To determine somatic mutation prevalence in Japanese APA patients using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided sequencing approach. Method Patients with a unilateral form of primary aldosteronism who underwent adrenalectomy at the Tohoku University Hospital were studied. Based on CYP11B2 immunolocalization of resected adrenals, genomic DNA was isolated from the relevant positive area of 10% formalin-fixed, paraffin-embedded tissue of the APAs. Somatic mutations in aldosterone-driving genes were studied in APAs by direct Sanger sequencing and targeted next-generation sequencing. Results CYP11B2 IHC-guided sequencing determined APA-related somatic mutations in 102 out of 106 APAs (96%). Somatic KCNJ5 mutation was the most frequent genetic alteration (73%) in this cohort of Japanese patients. Somatic mutations in other aldosterone-driving genes were also identified: CACNA1D (14%), ATP1A1 (5%), ATP2B3 (4%), and CACNA1H (1%), including 2 previously unreported mutations. KCNJ5 mutations were more often detected in APAs from female patients compared with those from male patients [95% (36/38) vs 60% (41/68); P Conclusion IHC-guided sequencing defined somatic mutations in over 95% of Japanese APAs. While the dominance of KCNJ5 mutations in this particular cohort was confirmed, a significantly higher KCNJ5 prevalence was detected in female patients. This study provides a better understanding of genetic spectrum of Japanese APA patients.

Background: Medical treatment with mineralocorticoid receptor antagonists (MRAs) is preferred for patients with primary aldosteronism (PA) who are not surgical candidates. Adequate mineralocorticoid receptor blockade, as suggested by renin elevation above suppression levels, has been associated with lower rates of cardiovascular and renal complications as compared with PA with sustained renin suppression. Objectives: To assess the timeline and rates of achieving target renin levels in patients with PA and low renin hypertension treated with MRAs. Patients and Methods: We conducted a retrospective cohort study of adult patients with hypertension who were treated with MRAs in an academic center between 2003-2019. Of these, we included patients who had suppressed renin at baseline, and repeated renin measurement(s) during MRAs therapy. Renin suppression was defined as plasma renin activity (PRA) 1.0 ng/mL/h or direct renin concentration (DRC) 8.0 pg/mL. We excluded patients with adrenal cancer, end-stage renal disease, exogenous glucocorticoids, and critically ill. Mann-Whitney test, Wilcoxon signed rank test, Chi-Square test and multiple logistic regression analysis were employed, as appropriate. Results: So far, 89 patients (45 men), median age 56 (range, 19-84), have been included. Of these, 46% had confirmed PA; 25% had positive PA screening, but no confirmatory tests; and 29% had other forms of low-renin hypertension. On average, patients were on 2.9 1.6 antihypertensive agents; 62% of patients were prescribed beta blockers, and 38% were on K+ supplements. Overall, renin (PRA in 69 cases, and DRC in 20 cases) increased after MRA treatment (from 0.40 [0.10, 0.60] ng/mL/h to 1.10 [0.60, 2.23] ng/mL/h; and from 2.1 [2.1, 3.7] pg/mL to 5.7 [2.9, 16.7] pg/mL, respectively, p Conclusion: Although raising renin above suppression levels is important for reducing the cardiovascular risk associated with PA, this goal is achieved in less than half of patients, even after one year of treatment with MRAs, in an academic setting. Strategies for optimizing PA treatment are critically needed.

Background: Mineralocorticoid receptor antagonists (MRAs) are the mainstay of medical therapy for primary aldosteronism (PA), and MRAs also benefit patients with other forms of resistant hypertension and cardiovascular disorders. MRAs impact the renin-angiotensin-aldosterone system (RAAS), raising concerns regarding the accuracy of PA screening. The rate of false negative and/or false positive screening for PA in patients taking MRAs has not been systematically evaluated. Herein, we assessed the alterations of both renin and aldosterone after MRA initiation in a large cohort of patients with hypertension. Patients and Methods: We conducted a retrospective cohort study of patients with hypertension seen in a tertiary referral center. We employed our center’s database search engine to identify adults with hypertension who were treated with MRAs. Of these, we included patients who had renin and aldosterone measured both before and after MRA treatment. We excluded patients with adrenal cortical cancer, end-stage renal disease, exogenous glucocorticoids, and critically ill. PA screening was considered positive when plasma aldosterone concentration (PAC) was 10 ng/dL, plasma renin activity (PRA) was 1.0 ng/mL/h, and the aldosterone-to renin ratio (ARR) was 20. Mann-Whitney test and Wilcoxon signed rank test were employed to compare independent or paired groups, respectively. Results: In total, 109 patients (57 women), mean age 55+/-13 years were included. Of these, 40% had confirmed PA (14% unilateral and 26% bilateral); in 38% PA was excluded; and in the remaining 22%, testing for PA was incomplete. On average, patients were on 3 +/- 1.6 antihypertensive agents; 60% of patients were prescribed beta blockers, 49% K+-wasting diuretics and 35% were on K+ supplements. Both PAC and PRA increased after MRA treatment (from 19.0 [12.6, 26.7] to 26.3 [17.2, 36.2]; and from 0.6 [0.10, 0.80] to 1.00 [0.60, 2.80], respectively, p < 0.0001 for both), while ARR decreased from 42.5 [18.5, 109.8] to 24.0 [10.9, 55.5] (p = 0.003). Of 71 patients with positive PA screening at baseline, 31 (43.7 %) no longer met positive screening criteria during MRA therapy. Conversely, 7 of 38 patients (18 %) with negative screening at baseline met criteria for positive PA screening while on MRA treatment, including 5 patients with a PAC > 20 ng/dL along with suppressed renin. The impact on PA screening accuracy remained similar irrespective of the MRA dose, duration of treatment, changes in concomitant antihypertensive drugs, or hypertension type. Conclusions: Commonly, MRA treatment leads to renin elevation, ARR reduction, and consequential false negative PA screening. In a minority of patients, MRA therapy can be followed by aldosterone elevations asynchronous from renin, possibly via short feedback loops, mimicking PA. Whenever possible, PA testing should be conducted after MRA discontinuation.

Hypothalamic obesity is a clinical syndrome characterized by severe and refractory obesity that is caused by hypothalamic function impairment. Recently, bariatric surgery has been attempted for patients with hypothalamic obesity after craniopharyngioma, but experiences have not yet been accumulated in other hypothalamic disorders. Here, we report the case of a 39-year-old male patient with panhypopituitarism who received laparoscopic sleeve gastrectomy (LSG) after intracranial germinoma treatment. The patient was diagnosed with intracranial germinoma at age 15 and achieved complete remission after radiotherapy (total 50 Gy). He was obese during diagnosis [body mass index (BMI), 29.2 kg/m2], and his obesity gradually worsened after the intracranial germinoma treatment, and LSG was considered when his BMI was 48.6 kg/m2. After 1 month of hospitalized diet-exercise program, LSG was performed. After LSG, his BMI gradually decreased and reached 38.8 kg/m2 on the day of discharge (6 weeks after the surgery). Five months after LSG, his insulin resistance improved, but insulin hypersecretion remained. Fifteen months after the surgery, his BMI was 31.2 kg/m2, with marked decrease in visceral and subcutaneous fat areas (from 393.8 cm2 and 168.2 cm2 before the surgery to 111.5 cm2 and 56.3 cm2, respectively.). To our knowledge, this is the first case of LSG for hypothalamic obesity after intracranial germinoma treatment. Although the pathophysiology of hypothalamic obesity is different from that of primary obesity, LSG could be a successful therapeutic choice for patients with hypothalamic obesity after the intracranial germinoma treatment.

Background Measurement of plasma aldosterone and renin concentration, or activity, is useful for selecting antihypertensive agents anddetecting hyperaldosteronism in hypertensive patients. However, it takes several days to get results even if measured by inaccurateradioimmunoassay, or we must accept high-cost LC/MS, and development of a more rapid and accurate substitute has been long hoped. We havedeveloped a novel, fully-automated, high-quantitative noncompetitive chemiluminescence immunoassay (NC-CLEIA) for detecting aldosterone inserum and plasma, and its performance is evaluated as compared to LC/MS measurement. Methods Recently a unique anti-metatype antibody,which recognizes the immunocomplex of aldosterone and its monoclonal antibody, was established. Using this antibody for sensing permittedthe construction of non-competitive assay for the detection of aldosterone. The reaction protocol of novel aldosterone assay is the following. Inthe 1st reaction, aldosterone in patient’s sample is captured on anti-body coated magnetic particles. Alkaline phosphatase-conjugated antimetatypeantibody is added and incubated as 2nd reaction following a wash. Then substrate solution is added after washing immunocomplex.The resulting reaction signals are proportional to the amount of aldosterone in the sample allowing quantitative determination of in serum orplasma sample. The overall reaction is completed within 30 min. Results Limit of blank (LoB), limit of detection (LoD) and limit of quantitation(LoQ) of our NC-CLEIA aldosterone assay were 0.09 ng/dL, 0.21 ng/dL and 0.57 ng/dL, respectively. NC-CLEIA aldosterone measurements werelinearly well correlated with LC/MS aldosterone measurements (N = 130, y = 1.027x - 0.23 ng/dL, Spearman’s ρ = 0.996, P< 0.0001). Bland-Altmanplot analysis between NC-CLEIA and LC-MS/MS of aldosterone revealed a bias of 0.40 ng/dL with the limits of agreement of -4.60 and 5.41 ng/dLwith 95% confidence interval. Conclusion Our novel NC-CLEIA aldosterone assay was well-correlated and had only a very low bias with LC-MS/MSmethod and also was able to accurately quantify low level samples even in essential hypertension patients. This aldosterone assay can be a most equivalent to LC-MS/MS measurement with a low cost of 12 $ and a short measuring time of 30 minutes.

Introduction Aging is associated with the pathogenesis of many endocrine disorders such as cardiovascular diseases and diabetes. Cell senescence has been reported as one of their mechanisms. In addition, stress responsiveness has been reported to be associated with cell senescence. In addition, some genetic abnormalities such as mitochondrial DNA (mtDNA) damages or telomere shortening, have been detected in some endocrine disorders. Cortisol is a well-known stress-induced hormone and closely associated with aging. We previously reported that cortisol-producing adenoma (CPA) more abundantly expressed cell senescent markers such as p16 and p21 than other hormone-producing adrenocortical adenomas. However, the detailed pathophysiology of cell senescence and its association with histological features in CPAs have remained virtually unknown. Therefore, we analyzed cell senescent markers (telomere length, mtDNA copy number, mtDNA deletion and p16 and p21 immunoreactivity) and analyzed their correlation with clinicopathological factors in CPA patients. Methods & Materials Forty CPA cases was immunohistochemically evaluated. Twenty CPA, ten adjacent ZF and six non-functional adenoma (NFA) were examined for mtDNA abnormalities. mtDNA deletion was evaluated by nested-PCR and mtDNA copy number and telomere length were measured using real-time PCR. Results p21 immunoreactivity was significantly higher in CPA than that of adjacent ZF (P=0.0001) and significantly inversely correlated with tumor size (P=0.0004). Telomere length was much longer in CPA than that in adjacent ZF(P=0.0038), and NFA (P=0.0018). mtDNA copy number of NFA was significantly higher than that of CPA and adjacent ZF (P=0.0038). mtDNA copy number of compact cells was significantly higher than that of clear cells (P=0.0432). mtDNA copy number of compact cells was positively correlated with urinary free cortisol (UFC) (P=0.0428) and plasma cortisol (F) (P=0.0609). mtDNA copy number of clear cells were inversely correlated with F (0.0497). 4977 bp mtDNA deletion was more frequently detected in CPA (54%) and in adjacent ZF (50%) than in NFA (17%). Discussion Results of our present study did reveal that CPA harbored more senescent phenotype as demonstrated by abundant p16 and p21, marked telomere shortening, frequent mtDNA 4977bp deletion and relatively low mtDNA copy number, possibly caused by long-term exposure of excessive cortisol in situ compared to NFA. In addition, clear tumor cells could represent more senescent histological phenotype because of their lower mtDNA copy numbers. This is the first study to demonstrate that compact tumor cells were biologically more active than clear tumor cells and could reflect clinical cortisol biosynthesis, resulting in marked functional intratumoral heterogeneity in CPAs.

Aldosterone-producing adenoma (APA) is well known to harbor marked intratumoral heterogeneity in terms of morphology and CYP11B2 (aldosterone synthase) localization. In histology, APA is generally characterized by two distinct cell subtypes, namely “clear cells” and “compact cells”. Clear tumor cells harbor abundant lipid droplets in their cytoplasms and compact tumor cells generally featuring small round shape have abundant intracytoplasmic organelles including mitochondria. Relatively close correlation between these histological characteristics (morphology and CYP11B2 immunohistochemistry) and genotypes of aldosterone-driver gene somatic mutation has been reported. Among them, KCNJ5-mutated APAs have been reported to harbor clear cell predominant features, while APAs with other rare somatic mutations including ATP1A1, ATP2B3 and CACNA1D harbor heterogenous or relatively compact cell predominant morphometry. However, these previous evaluation were based on eyeball analysis with relatively low reproducibility. Therefore, we developed the more quantitative methods using digital image software in order to analyze the widespread area, which can reflect intratumoral heterogeneity, with high reproducibility to analyze the further detailed correlation between histopathological characteristics and genotype in APA. We explored the utility of immunohistochemistry including CYP11B2 and KCNJ5. We further attempted to propose histopathological scoring system to predict the presence of KCNJ5 somatic mutation in APAs. Results of our present study revealed that KCNJ5 was predominantly immunolocalized in zona glomerulosa among adrenal cortex (vs. ZF, P=0.0002, vs. ZR, P=0.0002), furthermore, predominantly in APCCs than in non-APCCs (P=0.0019). Among the tumors, KCNJ5 immunoreactivity was significantly higher in KCNJ5-wild type APAs than in mutated ones (P=0.0037). KCNJ5-mutated APAs had significantly lower nuclear / cytoplasm ratio and abundant clear cell components than those with wild type, harboring large tumor size. In conclusion, we firstly proposed a novel histopathological predicting scoring system for the presence of KCNJ5 somatic mutation, including the following histopathological findings; N/C ratio, clear cell (%), tumor size, CYP11B2 immunoreactivity and KCNJ5 immunoreactivity. It is true that no single histological factors above could precisely predict the presence of KCNJ5 somatic mutation but this newly developed combined histopathological predicting scoring system could provide relatively high accuracy to predict KCNJ5 somatic mutation in APAs (AUC=96%, sensitivity:100%, specificity:90%, 4 points or more). However, further prospective validation by large number of cases is required for clarification.

Introduction: Primary aldosteronism (PA) is the most common cause of secondary hypertension. More than 70% of APAs have been reported to have KCNJ5 somatic mutation in Asian countiries. Patients with KCNJ5 mutated APAs generally harbor high plasma aldosterone concentration (PAC), and are mainly composed of clear tumor cells containing abundant lipid droplets. However, an association among intracellular cholesterol metabolism, morphological features and genotypes in tumor cells has remained virtually unknown.[Materials and methods]Three cholesterol receptors (SR-B1, LDL-R, VLDL-R) were immunolocakized in 25 APA cases (KCNJ5 mt: n= 15, WT: n=10) who underwent adrenalectomy at Tohoku University Hospital. Image analysis software (HALO, India Labs) was used to quantitatively analyze the intracellular localization and immunoreactivity and expored their correlation with genotype and clinical factors.[Results]LDL-R immunoreactivity was significantly lower in KCNJ5 mt group than WT group (P = 0.0369). In KCNJ5 mt group, a significant correlation was detected between LDL-R immunoreactivity and CYP11B2 (Aldosterone synthase), (P = 0.0271, ρ = 0.5684) but not in WT group. In addition, LDL-R immunoreactivity was significantly inversely correlated with tumor size (P = 0.0142, ρ = -0.6176) and PAC (P =

Objectives To compare image quality and radiation dose of right adrenal vein (RAV) imaging computed tomography (CT) among conventional, low kV, and low kV with reduced contrast medium protocols. Methods One-hundred-and-twenty patients undergoing adrenal CT were randomly assigned to one of three protocols: contrast dose of 600 mgI/kg at 120-kV tube voltage setting (600-120 group), 600 mgI/kg at 80 kV (600-80 group), and 360 mgI/kg at 80 kV (360-80 group). Iterative reconstruction was used for 80-kV groups. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the RAV and size-specific dose estimates (SSDE) were measured. Three radiologists evaluated 4-point visualisation scores of RAV by consensus reading. Results The RAV detectability was 95%, 97.2%, and 97.3% for 600-120, 600-80, and 360-80 groups, respectively (p = 1.000). Visualisation scores were not significantly different among the groups (p = 0.152). There were no significant differences in CNR or SNR between the 600-120 and 360-80 groups. SSDE of the 360-80 group was significantly lower than that of the 600-120 group (5.86 mGy ± 1.44 vs. 7.27 mGy ± 1.81, p Conclusions 80-kV scans with 360 mgI/kg contrast media showed comparable detectability of RAV to conventional scans, while reducing 19% of SSDE.

Measurement of plasma aldosterone and renin concentration, or activity, is useful for selecting antihypertensive agents and detecting hyperaldosteronism in hypertensive patients. However, it takes several days to get results when measured by radioimmunoassay and development of more rapid assays has been long expected. We have developed chemiluminescent enzyme immunoassays enabling the simultaneous measurement of both aldosterone and renin concentrations in 10 minutes by a fully automated assay using antibody-immobilized magnetic particles with quick aggregation and dispersion. We performed clinical validation of diagnostic ability of this newly developed assay-based screening of 125 patients with primary aldosteronism from 97 patients with essential hypertension. Results of this novel assay significantly correlated with the results of radioimmunoassay (aldosterone, active renin concentration, and renin activity) and liquid chromatography–tandem mass spectrometry (aldosterone). The analytic sensitivity of this particularly novel active renin assay was 0.1 pg/mL, which was better than that of radioimmunoassay (2.0 pg/mL). The ratio of aldosterone-to-renin concentrations of 6.0 (ng/dL per pg/mL) provided 92.0% sensitivity and 76.3% specificity as a cutoff for differentiating primary aldosteronism from essential hypertension. This novel measurement is expected to be a clinically reliable alternative for conventional radioimmunoassay and to provide better throughput and cost effectiveness in diagnosis of hyperaldosteronism from larger numbers of hypertensive patients in clinical settings.

Because of its rarity, our understanding of steroidogenesis in estrogen-producing adrenocortical adenoma, including the response to adrenocorticotropic hormone (ACTH) stimulation, remains limited. A 65-year-old man was referred to us because of primary aldosteronism and a right adrenal tumor. Endocrinological evaluations revealed secondary hypogonadism due to hyperestrogenemia. Adrenal venous sampling (AVS) and subsequent liquid chromatography–tandem mass spectrometry (LC-MS/MS) indicated bilateral hyperaldosteronism and a right estrogen-producing adrenocortical tumor. He subsequently underwent right unilateral adrenalectomy, which resulted in clinical remission of hypogonadism. Subsequent histopathological analysis identified a right estrogen-producing adrenocortical adenoma and multiple, concomitant adrenocortical micronodules. Sequential evaluation of steroid profiles using LC-MS/MS revealed unique hormone production, including adrenal androgens, and less responsiveness to ACTH in the right estrogen-producing adrenocortical adenoma as compared to the nonneoplastic adrenal cortex. This case study revealed unique profiles of steroid production in estrogen-producing adrenocortical adenoma associated with concomitant primary aldosteronism. Sequential steroid profiling analysis using LC-MS/MS in combination with AVS can contribute to the diagnosis of various adrenal disorders.

Peripheral 18-oxocortisol (18oxoF) level could contribute to the detection of aldosterone-producing adenoma (APA) in patients with primary aldosteronism. However, peripheral 18oxoF varies among such patients, which is a big drawback concerning its clinical application. We studied 48 cases of APA, 35 harboring KCNJ5 mutation, to clarify the significance of clinical and pathological parameters about peripheral 18oxoF. Peripheral 18oxoF concentration ranged widely from 0.50 to 183.13 ng/dL and correlated positively with intratumoral areas stained positively for steroidogenic enzymes ( P P P P KCNJ5 mutation, the KCNJ5 -mutated group demonstrated a significantly higher concentration of peripheral 18oxoF (28.4±5.6 versus 3.0±0.9 ng/dL, P P KCNJ5 mutation status turned out to be the most associated factor involved in 18oxoF synthesis in APA ( P KCNJ5 mutation in an APA.

[Introduction] Primary hyperparathyroidism (PHPT) occasionally presents a hyperparathyroid crisis which provides a pivotal cue for its diagnosis. However, the perioperative risk for exacerbation of hypercalcemia has been unknown in PHPT. We herein report 2 cases of PHPT which presented a hyperparathyroid crisis during the perioperative period for other complications. [Case presentaion] Case 1; A 81-year-old man was referred to our center due to urinary stone and hypercalcemia. Baseline laboratory data were as follows; corrected serum Ca 11.2 mg/dl; serum P 2.0 mg/dl; whole PTH 89.6 pg/ml, eGFR 49 ml/min/1.73m2. CT revealed a neck tumor of 10 mm with 99mTc-MIBI uptake, which was considered as a cause of PHPT. Simultaneously, CT also pointed out thoracic aortic aneurysm of 70 mm. Therefore, he underwent endovascular stent graft therapy prior to tumorectomy of PHPT. The procedure of stent graft was successfully performed but also caused subarachnoid hemorrhage and acute kidney injury (AKI). Corrected Ca level was subsequently elevated to 12.4 mg/dl, implying an exacerbation of PHPT. He received 60 mg denosumab administration in order to control Ca level complicated with AKI, resulted in improvement of hypercalcemia. However, PTH level was not significantly changed (57.4 pg/ml) during the period, indicated that lower urinary excretion of calcium due to AKI was the main cause of Ca level elevation. Case 2; A 57-year-old woman was admitted to our center due to incidental hypercalcemia. Baseline laboratory data were as follows; corrected serum Ca 12.5 mg/dl; serum P 2.1 mg/dl; whole PTH 140 pg/ml, eGFR 74 ml/min/1.73m2. CT revealed a neck tumor of 17 mm with 99mTc-MIBI uptake, considered as a cause of PHPT. Unexpectedly, MR imaging revealed meningioma of 48 mm on the Turkish saddle. She underwent embolization and removal of meningioma prior to tumorectomy of PHPT. After surgery, she had a persistent disturbance of consciousness because of hypernatremia (over 160 mM) and hypercalcemia (17.2 mg/dl) complicated with AKI. As a hyperparathyroid crisis, we administered 60 mg denosumab and continued fluid replacement therapy, leading to gradual improvement of electrolyte imbalances. PTH level was significantly elevated to 443 pg/ml compatible with a hyperparathyroid crisis. Her serum Ca level was kept lower than 12 mg/dl by denosumab for more than 3 months. [Conclusion] Our cases suggested that serum Ca level in PHPT could be influenced by perioperative conditions, although the trigger for exacerbation of PHPT remains unclear. Management of PHPT should be considered before surgery for other complications. Denosumab is useful for management of PHPT regardless of renal function.

Primary aldosteronism (PA) is a major cause of secondary hypertension, accounting for 5 to 10% of all of the patients with hypertension. PA is also well known to harbor relatively higher incidence of cardiovascular complications than essential hypertension (EH) despite similar blood pressure levels. Among these complications, renal injuries are considered clinically important because up to 15% of APA (Aldosterone-producing adenoma) patients had already been chronic kidney disease at the time of its initial diagnosis (Iwakura et al., JCEM, 2014). In addition, PA patients are relatively younger than EH, which makes early clinical intervention pivotal. Many pathways of aldosterone-induced renal injuries have been proposed but the actual mechanism of aldosterone related injuries in human kidney has remained virtually unknown. Therefore, in this study, we performed the detailed histopathological analysis for kidneys and adrenal glands of the same PA patients and compared with those of EH. We analyzed 7 APA cases undergoing renal biopsy or nephrectomy with adrenalectomy. As a control group, 40 age-matched EH cases (31 autopsy, 9 biopsy) were examined. Digital image software (HALO, Indica Labs) was employed to perform quantitative histological analysis. There were no significant differences of eGFR between EH and PA before adrenalectomy (p=0.8111), but eGFR become lower in post-operative PA than in EH (p=0.0511). The prevalence of global glomerular sclerosis (GGS) and focal glomerular sclerosis (FGS) was significantly higher in PA than in EH (p=0.0031, 0.0035). Mesenchymal fibrosis was also more marked in PA than in EH (p=0.0091). Among the increased GGS groups (over 10%), the ratio of GGS/mesenchymal fibrosis tended to be lower in PA than in EH(p=0.0653). CYP11B2 positive area in adrenal cortex was more extended in autopsy EH than in adjacent cortex of PA (p=0.0209), and a significant correlation was also detected between CYP11B2 and renin immunoreactivity in autopsy EH adrenals (p=0.0067). In PA, CYP11B2 immunoreactivity in adenomas tended to be correlated with glomerular swelling (p=0.0539), probably reflecting the status of glomerular hyperfiltration. 11βHSD2 immunoreactivity of cortical tubules was significantly higher in PA than in EH (p=0.0001) and significantly correlated with the degree of renal arteriole hyalinization in PA (p

Introduction Primary aldosteronism (PA) accounts for 5-10% of all of the patients with hypertension and companies higher incidence of cardiovascular events. Calcium metabolic disorders including secondary hyperparathyroidism and osteoporosis were detected more frequently in PA patients than EH patients. Recently, it has been also reported that there was some interactive regulations between parathyroid gland and adrenal zona glomerulosa. However, its detailed mechanism has virtually remained unknown. Therefore, in order to clarify the association between Ca metabolic disorders and steroidogenesis as well as its clinical significance in PA patients, we analyzed expression profiles of Ca-related receptors in aldosterone-producing adenoma (APA), and compared the findings with clinicopathological parameters. PTH-induced steroidogenesis was also examined by in vitro study using H295R cell lines. Materials and methods Thirty formalin-fixed and paraffin-embeded APA and seventeen normal adrenal glands (NA) were examined for immunohistochemistry(IHC). 17 APA and 19 CPA cases were examined for mRNA expression levels of steroidogenic enzymes and Ca-related receptors by qRT-PCR. In vitro study was performed to analyze the responsiveness of steroidogenic enzymes by PTH treatment in H295R. Results Based on the results of IHC analysis, PTH1R and VDR were predominantly immunolocolized in the ZG among the normal adrenal cortex. VDR was positively correlated with CYP21A in normal ZG and CYP11B2 in APA. PTH1R was positively correlated with both CYP11B2 and CYP21A in APA. CaSR was inversely correlated with that of CYP11B2 in normal ZG. Both PTH1R and VDR mRNA levels were significantly higher in APA than in CPA. Also, their mRNA levels were positively correlated with CYP17A in APA. CaSR mRNA was detected in both APA and NA. For the clinical significance, VDR immunoreactivity was positively correlated with TRACP-5b. CaSR immunoreactivity was positively correlated with Bone Mineral Density (BMD). PTH1R immunoreactivity was inversely correlated with serum Ca level, and PTH1R mRNA level was positively correlated with urinary Ca. VDR mRNA level was inversely correlated with serum phosphate(P) and upregulated in KCNJ5 mutated APAs than wild type. CYP11A1 and CYP17A mRNA expression levels were significantly increased in cell line by PTH treatment. Discussion Results of our present study did demonstrate that PTH and Vitamin D could act on their receptors in APA, and could possibly activate aberrant pathways of “neoplastic” steroidogenesis including both aldosterone and cortisol, especially in stimulating CYP17A1 and CYP11A1. In addition, extracellular Ca level was closely associated with steroidogenesis in both normal ZG and PA. Finally, adrenal expression profiles of Ca-related receptors (VDR, CaSR and PTH1R) could be the predictive markers of Ca and bone metabolic disorders in PA patients.

Recent advances of molecular analysis and the development of specific monoclonal antibody against aldosterone synthase (CYP11B2) have indeed established the histological subtypes based on the localization of aldosterone overexcess and revealed the association between genotype and clinicopathological phenotype. In particular, several kinds of aldosterone-driver gene somatic mutation have been reported, including KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1. Among them, KCNJ5 somatic mutation was most frequently detected in aldosterone-producing adenoma although the prevalence of PA genotypes was markedly different among ethnic groups. The precise prevalence of genotype and histological subtypes in Japanese PA patients in large cohort has virtually remained unknown. Therefore, in this study, consecutive 125 unilateral PA cases entirely composed of Japanese patients who underwent surgery from 2012 to 2017 were histologically and genetically evaluated in order to clarify the precise prevalence of genotypes and histological subtypes among Japanese PA patients. 125 cases were precisely classified as follows based on detailed histopathological examination; single APA (84.0%), multiple (more than two) APAs (1.6%), APA + NFA (non-functional adenoma) (5.6%), MN (multiple adrenocortical micronodules) (5.6%), MN+NFA (2.4%) and DH (diffuse hyperplasia of the zona glomerulosa) (0.8%). Adrenal glands harboring single APA were further examined for genotyping. Among them, 67% harbored KCNJ5 mutated (G151R: 39.6%, L168R: 26.4%, T158A: 1.1%) and 33% harbored wild type. 5.4% of single APA clinically combined with Subclinical Cushing's syndrome, all harbored KCNJ5 mutated APAs. The results of our large-scaled analysis did firstly reveal the precise prevalence of histological subtypes and genotypes among Japanese PA patients who underwent surgery. Approximately 10% of unilateral resected PA cases histologically harbored non-neoplastic subtypes such as MN and DH. In addition to those non-neoplatic subtypes, 15% of unilateral resected PA cases other than single APA definitely required CYP11B2 immunohistochemistry in order to precisely detect the responsible lesions for aldosterone overexcess, distinguishing from the non-functional adrenocortical lesions or/and detecting more than two responsible lesions.

[Introduction] Control of uric acid level (UA) plays an important role in the protection of organs in hypertensive (HTN) patients. Newly usable xanthine oxidase inhibitors, febuxostat (FBX) and topiroxostat (TPX) are expected to lead to more reduction of organ damages. However, the effects of them in a clinical situation remain unclear. We hypothesized these drugs have different effects based on the difference in actionmechanism. [Objectives] To reveal the effects of FBX and TPX on renal functions and compare them between the drugs. [Methods] We retrospectively collected HTN patients with hyperuricemia (HU) who newly received a prescription of FBX or TPX and continued 24 weeks. Those who had other uric acid-lowering drugs, diabetes mellitus or severe proteinuria were excluded. 252 Participants were divided into FBX (128 patients) and TPX (124 patients) groups matched for age and sex. The changes of uric acid (UA), blood pressure, eGFR (defined by Japanese Society of Nephrology) and urinary albumin-to-creatinine ratio (UACR) were evaluated between the baseline and the 24-week-treatment by FBX and TPX. [Results] The almost baseline characteristics were not significantly different between both groups except the usage of renin-angiotensin inhibitors. Administration of FBX or TPX lowered UA significantly (p