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Primary aldosteronism is the most frequent cause of secondary arterial hypertension. As adrenal imaging has been shown to have only limited value for differential diagnosis, adrenal vein sampling (AVS) has been implemented as a gold standard in the guidelines. However, AVS is a not well-standardized technique, and success rates vary in a wide range. Successful AVS procedures presuppose careful preparation and operational efficiency in an interdisciplinary team. Besides ruling out malignancy, multidetector-row helical computed tomography facilitates the localization of the adrenal veins. Rapid cortisol measurement has been shown to increase cannulation rates. The values of cosyntropin stimulation and bilateral simultaneous versus sequential catheterization remain unclear, but consistency is important. AVS should be performed in specialized centers by a limited number of radiologists in order to ensure success rates of at least 70%. Standardization of cutoff values should be accomplished through a consensus statement for consistent decision-making in patient care.

Due to digitization, demographic change and a growing demand for sustainability, companies are facing great challenges. Latest research reveals the biological transformation of manufacturing as the next leap. Digital technologies enable the usage of sensitive biological materials for resource friendly production, gaining natural products and circular economy. Therefore, adaptive biology-technology interfaces are necessary in order to enable bidirectional real time information exchange between biological and technological systems, which is still a gap in research. We thus present conceptual basics of biology-technology-interface (BTI) engineering, discuss BTI examples for various industrial applications and introduce an interdisciplinary theoretical model for communication and process control across systems. We conclude with a summary and recommendations for future research.

Global urbanization processes expedite a growing demand for more sustainability and higher liveability in cities. New logistic concepts like cargo bike schemes can be a vital means towards this goal. In this respect, both logistics planning and urban planning need to address several aspects of the urban fabric, but show a lack of holistic planning tools. We develop a conceptual framework that combines planning objects and planning scales of logistics planning with urban planning. We demonstrate the application of the framework for the theoretical deployment of an urban transhipment facility (UTF). Drawing upon interdisciplinary expertise from urban logistics, urbanism, sociology and psychology, several interdependencies of an UTF implementation with the urban fabric become apparent. Regarding this, several practical recommendations for the use case can be derived. In general, we recommend the application of the framework as a guideline for urban and urban logistics planning purposes to practitioners and encourage scientists to further develop and enrich the framework.

As larger numbers of hypertensive patients are screened for primary aldosteronism with the aldosterone-to-renin ratio (ARR), automated analyzers present a practical solution for many laboratories. We report the method-specific ARR cutoff determined with direct, automated chemiluminescence immunoassays allowing the simultaneous measurement of plasma aldosterone concentrations (PACs) and plasma renin concentrations (PRCs).Method comparisons to commonly employed assays and tandem mass spectrometry were undertaken. Patients were previously diagnosed based on the local ARR cutoff of 1.2 (ng/dl)/(μIU/ml) in samples collected in upright seated position. Lack of aldosterone suppression in response to salt load to less than 5 ng/dl confirmed primary aldosteronism. For the new assays, the optimal ARR cutoff was established in 152 patients with essential hypertension, 93 with primary aldosteronism and 147 normotensive patients. Aldosterone suppression was assessed in 73 essential hypertensive and 46 primary aldosteronism patients.PAC and PRC were significantly correlated to values determined with currently available methods (P0.001). In patients with primary aldosteronism, patients with essential hypertension and controls, mean (95% confidence interval) PAC was 28.4 (25.4-31.8), 6.4 (5.9-6.9) and 6.2 (5.6-6.9) ng/dl, respectively. In the same groups, PRC was 6.6 (5.6-7.7), 12.9 (11.2-14.8) and 26.5 (22.2-31.5) μIU/ml. An ARR cutoff of 1.12 provided 98.9% sensitivity and 78.9% specificity. Employing the new assay aldosterone suppression confirmed the diagnosis of primary aldosteronism and essential hypertension using the cutoff of 5 ng/dl.Our data demonstrate that the new assays present a convenient alternative for the measurement of PAC and PRC on a single automated analyzer. Availability of these simultaneous assays should facilitate screening and diagnosis of primary aldosteronism.

Popular diffusion strategies of technical innovations are so far characterized by a type of linear modelling, following the principles of causal communication chains from the developer to the adopter. From this perspective, neither the consumer nor the technology itself is understood as an actor in the diffusion process. Especially in times in which our understanding of the functioning of social systems increase, we should use this knowledge for the initiation of system change. Diverse environmental, health and economic problems are especially in urban agglomerations of working; living and supply reason enough for implementing a sustainable infrastructure in urban logistics. This paper aims to offer an understanding of technology equally operating with humans in actor networks, which influences our behaviour. So to change our behaviour, we have to start changing our interaction models with technology and offer attractive conditions for more sustainable uses. Thus, the diffusion of an innovation won’t be the question anymore, but the translation of lifestyles into actor networks, like sustainable structures for intermodal interchanges. This paper can be assigned to the area of governance and policy development and should be read as an attempt for the development of systemic implementation strategies in urban logistics.

Purpose of review Novel high-throughput genetic techniques have increased the pace of discoveries in the field of primary aldosteronism. Mutations in the potassium channel gene KCNJ5 are a cause of familial and sporadic forms of primary aldosteronism with around 30-40% of aldosterone-producing adenomas being affected by somatic mutations. Recent findings Exome sequencing of tumors without KCNJ5 mutations revealed genetic alterations in the ATPases ATP1A1 and ATP2B3, with a combined prevalence of 5-7%. Mutations in the gene encoding a subunit of the Ca channel Cav1.3 (CACNA1D) were described with a prevalence of 5-8%. In addition, a new syndrome consisting of primary aldosteronism, seizures, and neuromuscular disease with germline CACNA1D mutations could be identified. All these genetic variants enhance Ca-mediated signalling and steroidogenesis in affected glomerulosa cells and provide the molecular basis for autonomous aldosterone secretion. Furthermore, the pattern of genetic alterations allows for subgrouping of patient cohorts with potentially distinct clinical features including sex and age distribution as well as endocrine and cardiovascular endpoints. Summary Altogether in around 50% of aldosterone-producing adenomas, a somatic point mutation can be identified as the underlying genetic cause. These findings will provide the framework for potential identification of new biomarkers and therapeutic targets of this most common form of secondary hypertension.

Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with high serum PTH concentrations and vice versa.The aim of this study was to analyze the associations of the plasma aldosterone concentration (PAC), the plasma renin concentration (PRC), or the aldosterone to renin ratio (ARR) with serum PTH concentrations in a sample from the general population of northeast Germany.We selected 3105 subjects (25-88 y) from the first 5-year follow-up examination of the Study of Health in Pomerania. The associations of PAC, PRC, or ARR with serum PTH concentrations were examined with multivariable linear regression analyses. We further calculated adjusted mean serum PTH concentrations according to PAC, PRC, and ARR categories (≥90th and90th sex specific percentiles and sex specific quartiles). The models were adjusted for age, sex, estimated glomerular filtration rate, serum 25-hydroxy vitamin D concentration, waist circumference, body mass index, hypertension, diabetes mellitus, liver disease, and intake of drugs that affect the RAAS or bone metabolism.We found no associations between PAC or PRC and serum PTH concentrations in fully adjusted linear regression models. However, fully adjusted linear regression and ANOVA models revealed higher serum PTH concentrations in subjects with an ARR 90th percentile or greater than in subjects with a lower ARR.Our data show that a high ARR is associated with high serum PTH concentrations in the general population and thus add to the increasing evidence of a relation between the RAAS and PTH.

In subjects at high risk for sleep apnea (SA), aldosterone concentrations correlate with severity of SA and primary aldosteronism (PA) is very often diagnosed. Patients with PA show a high prevalence of SA. Treatment of PA either by adrenalectomy (ADX) or mineralocorticoid receptor (MR) blockade is thought to abolish the increased comorbidities. However, no data are available regarding effectiveness of different PA treatments on quality of sleep.This prospective multi-center study included 15 patients with newly diagnosed PA evaluated before and 0.7 ± 0.2 years after treatment initiation, and a second cohort including 81 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Biochemical parameters, 24h blood pressure and three validated self-assessment questionnaires (Giessen Complaint List (GBB-24), Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality-Index (PSQI)) were analyzed.Z-scores of exhaustion tendency of GBB significantly improved in newly diagnosed PA patients after treatment initiation (1.8 ± 1.4 vs. 1.0 ± 1.2, p=0.034). In the second cohort no differences were found in GBB-24, ESS and PSQI. No differences were found in all three questionnaires independently of type of PA therapy. However, female patients scored significantly higher than males in the PSQI (8.7 ± 3.6 vs 5.7 ± 4.2, p0.005), indicating lower sleep quality, independently of the type of therapy.For the first time, we analyzed quality of sleep in patients with PA, demonstrating that therapy initiation improves exhaustion tendency. Surprisingly, female PA patients showed significantly more sleep disturbances than male PA patients several years after treatment initiation.

Eine autonome Sekretion von Nebennierenhormonen kann einen subklinischen Verlauf nehmen oder durch andere haufige Erkrankungen maskiert werden. Eine weitere diagnostische Herausforderung stellen Patienten mit zufallig entdeckten Raumforderungen der Nebennieren (Inzidentalomen) dar, die durch den universellen Einsatz bildgebender Techniken eine steigende Pravalenz zeigen. Obwohl der Anteil maligner oder hormonaktiver Lasionen insgesamt gering ist sollten alle Patienten mit Nebennieren-Inzidentalom (> 1 cm) einer endokrinen Diagnostik unterzogen werden, um subklinische Verlaufe eines Cushing-Syndroms, eines Phaochromozytoms oder eines primaren Hyperaldosteronismus zu entdecken. Mittels Kontrastmittel unterstutzten CT Aufnahmen kann die Dignitat der Lasion beurteilt werden. Zur Untersuchung der hormonellen Aktivitat sollten zunachst ein niedrig dosierter Dexamethason-Hemmtest durchgefuhrt, die Plasma Metanephrine sowie der Aldosteron-Renin-Quotient (bei arterieller Hypertonie) bestimmt werden. Die Therapie des subklinischen Cushing-Syndroms (operativ vs. medikamentose Therapie) bleibt in Abwesenheit groser randomisierter, prospektiver Studien eine Einzelfallentscheidung. Alle Tumoren mit malignitatsverdachtigen Kriterien (insbesondere wenn > 4 cm Grose) und die subklinischen Phaochromozytome und Aldosteron produzierenden Adenome sollten operiert werden. Bei nicht resezierten Tumoren werden jahrliche biochemische Kontrollen fur eine Dauer von 5 Jahren empfohlen, insbesondere bei Tumoren > 3 cm. Bei einer Grosenzunahme im Follow-up sollte eine Adrenalektomie in Erwagung gezogen werden.

Context: Primary aldosteronism (PA) represents the most frequent cause of secondary arterial hypertension. Conflicting data have been published regarding the effect of aldosterone excess on glucose metabolism. Objective: Our aim was to analyze insulin sensitivity and beta-cell function in a cohort of PA patients. Prospective follow-up investigations were performed in a subgroup of patients before and after adrenalectomy to assess the metabolic outcome. Design: Oral glucose tolerance test, combined intravenous glucose tolerance test, hyperinsulinemic-euglycemic glucose clamp test, and arginine test were carried out after a 12-hour fasting period. Patients: Twenty-two consecutive patients with both unilateral aldosterone-producing adenoma and bilateral idiopathic adrenal hyperplasia were recruited through the Munich center of the German Conn's Registry. The control group of patients with essential hypertension (n = 11) of corresponding age and body mass index was recruited from our hypertension unit. Anormotensive cohort (n = 11) served as a further control group. Results: At baseline, first-phase insulin reaction in intravenous glucose tolerance test was significantly reduced in patients with PA as compared to normal controls(36.0 [24.0; 58.7] vs 90.1 [52.6; 143.8] mu U/mL, P = .031) and lower in comparison to essential hypertension without reaching statistical significance (53.2 [30.8; 73.3] mu U/mL, P = .123). The study was repeated 6 months after unilateral adrenalectomy in 9 consecutive patients with aldosterone-producing adenoma. At this time point, blood pressure had been normalized in most of the patients while body mass index remained unchanged (26.9 [25.5; 37.6] vs 27.5 [25.1; 35.6] kg/m(2), P = .401). First-phase insulin reaction in response to glucose significantly increased at follow-up (from 36.0 [25.5; 58.7] to 48.5 [40.4; 95.2] mu U/mL, P = .038, n = 9). In contrast, insulin sensitivity and response to iv arginine did not differ before and after adrenalectomy. Conclusion: Aldosterone excess has a direct negative effect on beta-cell function in patients with PA. After adrenalectomy, glucose-induced first-phase insulin secretion improves significantly in the patients.

ObjectivePrimary aldosteronism (PA) has deleterious effects on kidney function independent of blood pressure levels. Up to now, data on effectiveness of different PA therapies regarding renal function are scarce.Design and methodsThis prospective multi-center study included 29 patients with newly diagnosed PA evaluated before and 1 year after treatment initiation, and a second cohort including 119 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Glomerular filtration rate (GFR), spot urine albumin excretion/urinary creatinine (UAE/Ucrea) ratio, biochemical parameters, and 24-h blood pressure were measured. In a larger cross-sectional cohort, renal function was evaluated depending on the type of treatment (adrenalectomy (ADX; n=86); spironolactone (n=65); and eplerenone (n=18)).ResultsGFR and UAE/Ucrea ratio significantly decreased in newly diagnosed PA patients after treatment initiation. In the second cohort, GFR and UAE/Ucrea ratio did not change during study period, and blood pressure was well controlled. In the larger cross-sectional cohort, no differences were seen in GFR and UAE/Ucrea ratio between PA patients on different treatment regimens. However, eplerenone treatment showed lower potassium levels and higher number of required antihypertensive medications.ConclusionsRenal dysfunction with elevated albuminuria was seen in PA patients and was reversible after treatment initiation. Medical therapies with spironolactone or eplerenone seem to be as effective as ADX regarding renal function and blood pressure; however, sufficient daily doses need to be given.

Psychopathological symptoms in patients with primary aldosteronism (PA) have been reported. In a cross-sectional design the self-reported physical and mental condition among patients with PA of the German Conn's Registry differently treated during the course of the disease were analysed. 27 patients were investigated before initiation of specific therapy (U), 56 patients were on chronic mineralocorticoid antagonist treatment (MRA) and 49 patients had undergone adrenalectomy (ADX). Patient's quality of life was analysed with the SF-12 for a Physical (PCS) and a Mental Component (MCS). Statistically significant lower scores for PCS were found for female PA patients treated with MRA in comparison to ADX patients and the German reference population (36.4 ± 11.1 vs. 49.1 ± 10.9 (p = 0.024) vs. 47.9 ± 9.7 (p = 0.001)), respectively. Concerning MCS, untreated female patients scored significantly lower (36.5 ± 7.4) than females from the German population (51.3 ± 8.4, p = 0.000). Furthermore, untreated females appear to differ significantly from MRA and ADX females, scoring the lowest reading (U vs. MRA: p = 0.029; U vs. ADX: p = 0.005). Significant correlations were found between plasma aldosterone (r = -0.819, p = 0.013) and the MCS and between plasma renin concentration and MCS (r = -0.938, p = 0.001) in female MRA patients. In summary, PA patients report a worse physical and mental condition than the one reported for the German reference population. Untreated and mineralocorticoid antagonist treated patients report the lowest readings. Females were found to be more impaired than males in QoL. MRA treatment seems to affect the MCS of female patients.

Context Primary aldosteronism (PA) is mainly caused by aldosterone-producing adenoma and idiopathic bilateral adrenal hyperplasia (IHA). Recently, spontaneous resolution of IHA has been described. Objective We aimed to determine the frequency of spontaneous remission of PA during long-term treatment with mineralocorticoid receptor (MR) antagonists. Design, setting and patients Thirty-seven patients of the Munich PA registry with IHA treated by MR antagonists were investigated. The patients were identified retrospectively by chart review and prospectively assessed by clinical and biochemical means. Main outcome measures Complete remission of IHA was defined as normal aldosterone to renin ratio (ARR), normal suppression test and normalization of hypokalaemia in the presence of normal blood pressure. Partial remission was defined as normalization of normal ARR, normal suppression test and normalization of hypokalaemia in the presence of persistent hypertension. Results The mean period of MR antagonist treatment was 5·8 ± 0·7 years in the patients. We identified two of 37 (5·4%) patients with spontaneous remission: one with complete remission and one with partial remission. Conclusion Remission of IHA in PA may occur in some patients after long-term mineralocorticoid antagonist treatment.

Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, n=380) and peripheral (APA, n=344; bilateral adrenal hyperplasia, n=174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; P −3 ) and in younger patients (42.1±1.0 versus 47.6±0.7 years; P −3 ) and were associated with higher preoperative aldosterone levels (455±26 versus 376±17 ng/L; P =0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism.

Item does not contain fulltext CONTEXT: In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically challenging, difficult to interpret, and commonly held to be risky. OBJECTIVE: The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers. DESIGN AND SETTINGS: The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide. PARTICIPANTS: Eligible centers were identified from those that had published on PA and/or AVS in the last decade. MAIN OUTCOME MEASURE: The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS. RESULTS: Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19-100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007). CONCLUSIONS: Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure. 01 mei 2012

The Endocrine Society guidelines suggest to screen patients with primary aldosteronism (PA) free of hypertensive medications or alternatively to switch to drugs known to have minimal influence on the aldosterone to renin ratio (ARR). We retrospectively investigated the impact of such strategy on clinical outcome. 25 patients with PA and 25 with essential hypertension (EH) were studied. Initially all subjects were evaluated biochemically and received if possible an adjustment of their medication following the guidlines. Mineralocorticoid antagonists were discontinued in all subjects. Only 26 of 50 patients could be studied under optimal conditions (drug free or on medication with minimal influence on ARR) whereas the remaining 24 subjects had to receive additional drugs (such as ACE inhibitor, angiotensin-2 receptor blocker, or betablockers) because of initial blood pressure or comorbidities. Every fifth patient with a switch of the medication experienced a significant increase in blood pressure. 13 of 25 of PA patients needed potassium supplementation (105+/−25 mEq per day; range 8–320 mEq). Nine of these patients remained hypokalemic despite substitution (serum K 2.82+/−0.07 mmol/l), with 7 classified severely hypokalemic (

Coexisting prolactinoma-primary aldosteronism (PA) is infrequently reported.The objective of the study was to identify patients with prolactinoma-PA and test the hypothesis that elevated prolactin (PRL) concentrations play a role in PA pathogenesis.Hyperprolactinemia/prolactinoma was diagnosed in PA patients from two referral centers (Munich, Germany, and Turin, Italy) and in essential hypertensive (EH) patients from one center (Turin). PRL receptor (PRLR) gene expression was determined by microarrays on aldosterone-producing adenomas and normal adrenals and validated by real-time PCR. H295R adrenal cells were incubated with 100 nM PRL, and gene expression levels were determined by real-time PCR and aldosterone production was quantified.Seven patients with prolactinoma-PA were identified: four of 584 and three of 442 patients from the Munich and Turin PA cohorts, respectively. A disproportionate number presented with macroprolactinomas (five of seven). There were five cases of hyperprolactinemia with no cases of macroprolactinoma of 14 790 patients in a general EH cohort. In a population of PA patients case-control matched 1:3 with EH patients there were two cases of hyperprolactinemia of 270 PA patients and no cases in the EH cohort (n = 810). PRLR gene expression was significantly up-regulated in the aldosterone-producing adenomas compared with normal adrenals (1.7-fold and 1.5-fold by microarray and real-time PCR, respectively). In H295R cells, PRL treatment resulted in 1.3-fold increases in CYP11B2 expression and aldosterone production.Elevated PRL caused by systemic hyperprolactinemia may contribute to the development of PA in those cases in which the two entities coexist.

Purpose We aimed to evaluate the accuracy of multidetector computed tomography (MDCT) venous mapping for the localization of the right adrenal veins (RAV) in patients suffering from primary aldosteronism. Methods MDCT scans of 75 patients with primary aldosteronism between March 2008 and November 2011 were evaluated by two readers (a junior [R1] and a senior [R2] radiologist) according to the following criteria: quality of RAV depiction (scale, 1-5), localization of the RAV confluence with regard to the inferior vena cava, and depiction of anatomical variants. Results were compared with RAV venograms obtained during adrenal vein sampling and corroborated by laboratory testing of cortisol in selective RAV blood samples. Kappa statistics were calculated for interobserver agreement and for concordance of MDCT mapping with the gold standard. Results Successful RAV sampling was achieved in 69 of 75 patients (92%). Using MDCT mapping, adrenal veins could be visualized in 78% (R1, 54/69) and 77% (R2, 53/69) of patients. MDCT mapping led to correct identification of RAV in 70% (R1, 48/69) and 88% (R2, 61/69) of patients. Venograms revealed five cases of anatomical variants, which were correctly identified in 60% (R1, R2). MDCT-based localizations were false or misleading in 16% (R1, 11/69) and 7% (R2, 5/69) of cases. Conclusion Preinterventional MDCT mapping may facilitate successful catheterization in adrenal vein sampling.

Air pollution is an important risk factor for global burden of disease. There has been recent interest in its possible role in the etiology of diabetes mellitus. Experimental evidence is suggestive, but epidemiological evidence is limited and mixed. We therefore explored the association between air pollution and prevalent diabetes, in a population-based Swiss cohort.We did cross-sectional analyses of 6392 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults [SAPALDIA], aged between 29 and 73 years. We used estimates of average individual home outdoor PM10 [particulate matter

Context: Adrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). AVS protocols are not standardized and vary widely between centers. Objective: The objective of the study was to retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA. Setting: The study was carried out in eight different referral centers in Italy, Germany, and Japan. Patients: From 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses. Results: Overall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared with basal procedures (90% vs 77%). The CL ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P = .02 and P = .01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters, and patients with CL suppression underwent a significantly larger reduction in the aldosterone levels after adrenalectomy. Conclusions: For patients with lateralizing indices of greater than 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.

ObjectiveAdrenal vein sampling (AVS) is a technically demanding procedure required for the identification of suitable candidates for unilateral adrenalectomy in primary aldosteronism. Recently, somaticKCNJ5K+-channel mutations in aldosterone-producing adenoma (APA) patients have been shown to influence steroid gradients during AVS. These and other recently identified genetic modifiers (ATP1A1andATP2B3) might affect the final diagnosis and treatment of the affected patients.DesignFifty-nine patients with APAs who had undergone successful AVS (adrenal vein cortisol:peripheral cortisol ratio ≥2) and had undergone a mutation analysis of their tumor tissue were studied. The mutation status of the APAs was as follows: 19KCNJ5mutations, eight ATPase mutations (fiveATP1A1and threeATP2B3), and 32 patients with none of these mutations.MethodsThe lateralization index (ratio of aldosterone:cortisol on the side of the adenoma to aldosterone to cortisol on the contralateral side) and the contralateral suppression index (ratio of aldosterone:cortisol on the contralateral side to aldosterone to cortisol in the periphery) were calculated for theKCNJ5-mutated, ATPase-mutated, and theKCNJ5/ATPase mutation-negative APA patients.ResultsThe lateralization indices of the ATPase mutation carriers had a median of 19.9 compared with a median of 16.0 in theKCNJ5mutation carriers and that of 20.5 in theKCNJ5/ATPase mutation-negative patients. The contralateral suppression indices of the ATPase-mutated patients had a median of 0.1 compared with a median of 0.4 in theKCNJ5mutation carriers and that of 0.2 in theKCNJ5/ATPase mutation-negative patients. The differences between the genetic groups were not statistically significant.ConclusionsWe did not find evidence for a clinically important impact of mutation status on steroid gradients during AVS.

Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. The aldosterone to renin ratio (ARR) is the gold standard for screening, but variability between biochemical methods used remains of concern. The aim of the study was to analyze center-specific features of biochemical diagnostic strategies prior to the 2008 consensus within the German Conn's Registry. The study was designed as a retrospective study in 5 tertiary care hospitals. Patients analyzed for PA between 1990 and 2006 were studied. Characteristics of the assays used to determine ARR during establishing the diagnosis of PA were analyzed in the retrospective part of the German Conn's Registry. Eighty-six out of 484 documented ARR values had to be excluded from further evaluations because the laboratory or the assays were unknown. In the remaining 398 patients ARR was determined using 10 different assay combinations in the centers (aldosterone plus plasma renin activity or concentration). Considerable differences were seen between the mean concentrations for aldosterone (p0.0001), renin concentration (p0.001), and renin activity (p=0.009) for the different assays. The differences between the absolute concentrations measured by the different assays also had significant impact upon the resulting mean ratios. If published cutoff values are applied, the use of different commercial assays to determine the ARR in clinical routine results in major differences in positive screening rates. This heterogeneity affects sensitivity and specificity of screening for PA. Our data emphasize the importance of standardized screening procedures, which must include standardization of biochemical methods.

Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na+/K+ ATPase α subunit) and ATP2B3 (encoding a Ca2+ ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion. Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.

Context:Unilateral adrenalectomy is the therapy of choice in aldosterone-producing adenoma (APA). Zona glomerulosa (ZG) insufficiency causing hyperkalemia after adrenalectomy has been described in case reports.Objective:Our aim was to analyze the clinical relevance of ZG insufficiency causing hyperkalemia after adrenalectomy in a large series of patients with APA.Design:This was a retrospective chart review.Setting:The study was conducted at two tertiary university referral centers in Germany.Patients:Data from 110 patients with confirmed APA adrenalectomized at the centers in Munich and Berlin between 2004 and 2012 were analyzed.Main Outcome Measures:The primary outcome was the incidence of ZG insufficiency causing hyperkalemia after adrenalectomy; the secondary outcome was the identification of risk factors predisposing for hyperkalemia.Results:Eighteen of 110 patients (16%) developed postoperative hyperkalemia. The majority of these patients (n = 14) had undetectable plasma aldosterone levels after adrenalectomy; four had low aldosterone levels. In 12 of these patients, hyperkalemia was documented only once and resumed spontaneously. Prolonged hypoaldosteronism accompanied by hyperkalemia was observed in six patients (5% of total cohort). These patients needed continuous mineralocorticoid replacement therapy for 11–46 months. Mineralocorticoid antagonist treatment for 4 wk prior to surgery did not prevent hyperkalemia. In multivariate analysis, preoperatively decreased glomerular filtration rate and increased serum creatinine as well as increased postoperative creatinine and microalbuminuria remained significant predictors of hyperkalemia.Conclusion:Persistent postoperative hypoaldosteronism with hyperkalemia occurs in 5% of adrenalectomized PA patients through prolonged ZG insufficiency, requiring long-term fludrocortisone treatment. Potassium levels after adrenalectomy must be monitored to avoid life-threatening hyperkalemia.

The renin-angiotensin-aldosterone-system (RAAS) has gained increasing attention in the investigation of the pathogenesis of depression. Primary hyperaldosteronism (PA) is associated with a marked aldosterone excess. Prior studies on PA describe an increased prevalence of anxiety and sub-threshold depressive symptoms in these patients.In a cross-sectional exploratory study we investigated 132 patients with PA. Twenty-seven patients were studied before initiation of specific treatment (U = untreated), 56 were studied 5.4 years after initiation of mineralocorticoid antagonist treatment (MRA) and 49 patients were studied 4.3 years after unilateral adrenalectomy (ADX). GAD-7 and PHQD self-rating questionnaires were used to assess symptoms for anxiety and depression.No significant difference was found between the three investigated groups. A higher prevalence for depression and anxiety compared to the normal population was found. Women of all groups had higher mean values compared to men, for depression in untreated patients this difference was found to be significant. Correlations between the psychopathology and hormones were only found for renin. Plasma renin concentration correlated significantly with anxious symptoms of untreated females.This study supports the RAAS to be involved in the pathogenesis of depression as patients with PA seem to be more depressive and anxious compared to the normal population. Gender differences in the regulation of the RAAS seem to be apparent, as females were more affected by the dysregulation than males.

Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. To date 3 forms of familial hyperaldosteronism (FH) have been described accounting for a small percentage of all PA cases. In Germany, the prevalence of FH is currently unknown. Our aim was to determine the prevalence of familiarity in a large cohort of patients with PA. A total of 166 patients with apparently sporadic PA in Munich were investigated. FH types I, II, and III were identified using established clinical, biochemical, and molecular criteria. Among the 166 patients with PA, 2 patients (1.2%) reported a family history suggestive of FH. None of the 166 patients showed clinical, endocrine, or genetic evidence of FH type I. The 2 families had characteristic features of FH type II. Family A had 3 subjects affected out of 11 evaluated family members. Family B had 3 out of 4. Bilateral adrenal hyperplasia and unilateral adrenal adenoma were found within the same family. FH type I and FH type III are rare in Germany. With a prevalence of 1.2%, FH type II seems to be more common in apparently sporadic PA than had been assumed so far.

In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conn's registry and identified risk factors for adverse outcome in a case-control study. Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA ( P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03–1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04–12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07–6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/L [95% CI, 0.17–0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; P

Der Dienstleistungssektor ist ein Wachstumsfeld der Zukunft, dessen Potenzial die gesellschaftliche und wirtschaftliche Entwicklung in Deutschland wesentlich pragt. Obgleich rund 70 % der Erwerbstatigen heute im Dienstleistungsbereich beschaftigt sind, sind viele Fragen der Forderung von Innovation und Wertschopfung, Professionalisierung und Wertschatzung in der Dienstleistungsarbeit nach wie vor offen (vgl. Reichwald et al. 2010) [30].

Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism–affected subjects from an Italian family and 3 somatic mutations in aldosterone-producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K + selectivity, Na + influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca 2+ channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype.

Primary aldosteronism (PA) is mainly caused by aldosterone-producing adenoma and idiopathic bilateral adrenal hyperplasia (IHA). Recently, spontaneous resolution of IHA has been described.We aimed to determine the frequency of spontaneous remission of PA during long-term treatment with mineralocorticoid receptor (MR) antagonists.Thirty-seven patients of the Munich PA registry with IHA treated by MR antagonists were investigated. The patients were identified retrospectively by chart review and prospectively assessed by clinical and biochemical means.Complete remission of IHA was defined as normal aldosterone to renin ratio (ARR), normal suppression test and normalization of hypokalaemia in the presence of normal blood pressure. Partial remission was defined as normalization of normal ARR, normal suppression test and normalization of hypokalaemia in the presence of persistent hypertension.The mean period of MR antagonist treatment was 5·8 ± 0·7 years in the patients. We identified two of 37 (5·4%) patients with spontaneous remission: one with complete remission and one with partial remission.Remission of IHA in PA may occur in some patients after long-term mineralocorticoid antagonist treatment.

ObjectiveAdrenal vein sampling (AVS) is considered the gold standard in the differential diagnosis of primary aldosteronism (PA), but success rates vary between centers. We hypothesized that rapid (intraprocedure) cortisol measurement can improve performance in a center with initially low AVS success rate.DesignWe analyzed 46 patients with confirmed PA studied between 2008 and 2010. Forty-seven PA patients studied between 2004 and 2008 identified by retrospective chart review served as controls. All patients were treated at a single tertiary care university hospital.MethodsStarting in 2008, rapid cortisol assays (RCA) were performed in all patients during the AVS procedure. A cortisol gradient of ≥2.0 between adrenal vein and a femoral vein sample was used as success criterion. Up to two repeat samples were drawn if adrenal vein cortisol was below this threshold.ResultsDuring the control period 26 of 47 AVS were successful (55%). After introduction of RCA, 39 out of 46 AVS (85%) were successful (P=0.003). In 21 of the 46 cases (46%) a resampling was necessary. The increase in overall success was due to an increase in successful right AVS (85 vs 62% before introduction of RCA; P=0.02) and a training effect (P=0.024 for trend).ConclusionRCA during AVS are useful in centers with an initially low AVS success rate.