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ZusammenfassungDie Prävalenz der arteriellen Hypertonie mit ihren kardiovaskulären Folgeerkrankungen wie Herzinfarkt, Schlaganfall, chronischer Nierenkrankheit und peripherer Gefäßerkrankung nimmt in unserer immer älter werdenden Gesellschaft stetig zu. Weltweit sterben jährlich knapp 8 Millionen Menschen an den Folgen einer nicht adäquat kontrollierten Hypertonie. Jeder 3. Erwachsene in Deutschland leidet unter Bluthochdruck. Zum aktuellen Zeitpunkt ist weniger als die Hälfte der Hypertoniker in Deutschland kontrolliert. Zahlreiche Ursachen können dem Nichterreichen der Therapieziele zugrunde liegen. Der aktuelle Beitrag soll Hilfestellungen geben, eine mögliche sekundäre Hypertonieursache zu erkennen. Es ist nicht zielführend, bei allen Hypertonikern eine breite Palette von Screeninguntersuchungen anzufordern oder durchzuführen. Eine sinnvolle Selektion potenziell betroffener Patienten muss vorab erfolgen. Die häufigsten Formen der sekundären Hypertonie werden genannt und die zielführende Diagnostik sowie deren Therapie dargestellt.

Aims We aimed at determining the rate of drug-resistant arterial hypertension in patients with an unambiguous diagnosis of primary aldosteronism (PA). Moreover, we sought for investigating the diagnostic performance of adrenal vein sampling (AVS), and the effect of adrenalectomy on blood pressure (BP) and prior treatment resistance in PA patients subtyped by AVS in major referral centres. Methods and results The Adrenal Vein Sampling International Study-2 (AVIS-2) was a multicentre international study that recruited consecutive PA patients submitted to AVS, according to current guidelines, during 15 years. The patients were over 18 years old with arterial hypertension and had an unambiguous diagnosis of PA. The rate of resistant hypertension was assessed at baseline and after adrenalectomy using the American Heart Association (AHA) 2018 definition. Information on presence or absence of resistant hypertension was available in 89% of the 1625 enrolled PA patients. Based on the AHA 2018 criteria, resistant hypertension was found in 20% of patients, of which about two-thirds (14%) were men and one-third (6%) women (χ2 = 17.1, P Conclusions (i) Resistant hypertension is a common presentation in patients seeking surgical cure of PA; (ii) AVS is key for the optimal management of patients with PA due to resistant hypertension; and (iii) AVS-guided adrenalectomy allowed resolution of treatment-resistant hypertension.

Many of the patients with primary aldosteronism (PA) are denied curative adrenalectomy because of limited availability or failure of adrenal vein sampling. It has been suggested that adrenal vein sampling can be omitted in young patients with a unilateral adrenal nodule, who show a florid biochemical PA phenotype. As this suggestion was based on a very low quality of evidence, we tested the applicability and accuracy of imaging, performed by computed tomography and/or magnetic resonance, for identification of unilateral PA, as determined by biochemical and/or clinical cure after unilateral adrenalectomy. Among 1625 patients with PA submitted to adrenal vein sampling in a multicenter multiethnic international study, 473 were ≤45 years of age; 231 of them had exhaustive imaging and follow-up data. Fifty-three percentage had a unilateral adrenal nodule, 43% had no nodules, and 4% bilateral nodules. Fifty-six percentage (n=131) received adrenalectomy and 128 were unambiguously diagnosed as unilateral PA. A unilateral adrenal nodule on imaging and hypokalemia were the strongest predictors of unilateral PA at regression analysis. Accordingly, imaging allowed correct identification of the responsible adrenal in 95% of the adrenalectomized patients with a unilateral nodule. The rate raised to 100% in the patients with hypokalemia, who comprised 29% of the total, but fell to 88% in those without hypokalemia. Therefore, a unilateral nodule and hypokalemia could be used to identify unilateral PA in patients ≤45 years of age if adrenal vein sampling is not easily available. However, adrenal vein sampling remains indispensable in 71% of the young patients, who showed no nodules/bilateral nodules at imaging and/or no hypokalemia. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01234220.

Context Adrenal gland imaging is recommended by the current guidelines for the workup of primary aldosteronism (PA). However, its diagnostic performance has not been established in large, multiethnic cohorts of patients who undergo adrenal vein sampling (AVS) and adrenalectomy. Objective This work aims to assess the diagnostic accuracy of cross-sectional adrenal imaging. Methods This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy. Results In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients. Conclusion Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA.

The serum sodium to urinary sodium ratio divided by the (serum potassium)2 to urinary potassium ratio (SUSPPUP formula) reflects aldosterone action. We here prospectively investigated into the usefulness of the SUSPPUP ratio as a diagnostic tool in primary hyperaldosteronism. Parallel measurements of serum and urinary sodium and potassium concentrations (given in mmol/L) in the fasting state were done in 225 patients. Of them, 69 were diagnosed with primary aldosteronism (PA), 102 with essential hypertension (EH), 26 with adrenal insufficiency (AI) and 28 did not suffer from the above-mentioned disorders and were assigned to the reference group (REF). The result of the SUSPPUP formula was highest in the PA group (7.4, 4.2&ndash, 12.3 L/mmol), followed by EH (3.2, 2.3&ndash, 4.3 L/mmol), PA after surgery (3.9, 3.0&ndash, 6.0 L/mmol), REF (3.4 &plusmn, 1.4 L/mmol) and AI (2.9 +/&minus, 1.2 L/mmol). The best sensitivity in distinguishing PA from EH was reached by multiplication of the aldosterone to renin-ratio (ARR) with the SUSPPUP formula (92.7% at a cut off &gt, 110 L/mmol), highest specificity was reached by the SUSPPUP determinations (87.2%). The integration of the SUSPPUP ratio into the ARR helps to improve the diagnosis of hyperaldosteronism substantially.

Context Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the management of PA patients. Objectives To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS. Design and settings In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes. Results AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as Conclusion Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020)

Background Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. Methods We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. Results Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation. Conclusions Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

The prevalence of arterial hypertension with its cardiovascular diseases like myocardial infarction, stroke, chronic kidney disease and peripheral artery disease is increasing in our aging population. Despite numerous efficient and well-tolerated antihypertensive drugs more than eight million people die worldwide from the consequences of insufficiently controlled hypertension every year. One third of the german adult population suffers from high blood pressure. The fact that in only 50 % of hypertonic patients the blood pressure is on a string is even more disturbing. Several factors can counteract sufficient blood pressure control. This article should help to identify patients with possible secondary hypertension. It is certainly not decisive to request a broad screening for all hypertensive patients. A certain pre-selection of potential patients is mandatory. The most common types of secondary hypertension are discussed and the diagnostic and therapeutic pathways are specified.

Baroreceptor activation therapy (BAT) has been available for several years for treatment of therapy-refractory hypertension (trHTN). This procedure is currently being carried out in a limited number of centers in Germany, also with the aim of offering a high level of expertise through sufficient experience; however, a growing number of patients who are treated with BAT experience problems that treating physicians are confronted with in routine medical practice. In order to address these problems, a consensus conference was held with experts in the field of trHTN in November 2016, which summarizes the current evidence and experience as well as the problem areas in handling BAT patients.

Lasst eine langfristige intensive Blutdruckkontrolle die verbleibende Lebenserwartung steigen? Die Ergebnisse einer Nachauswertung der SPRINT-Studie scheinen darauf hinzudeuten.

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men ( P P =0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications ( P P The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01234220.

Early conversion to everolimus was assessed in kidney transplant recipients participating in the Eurotransplant Senior Program (ESP), a population in whom data are lacking. The SENATOR multicenter study enrolled 207 kidney transplant recipients undergoing steroid withdrawal at week 2 post-transplant (ClinicalTrials.gov [NCT00956293]). At week 7, patients were randomized (1:2 ratio) to continue the previous calcineurin inhibitor (CNI)-based regimen with mycophenolic acid (MPA) and cyclosporine or switch to a CNI-free regimen with MPA, everolimus (5–10 ng/mL) and basiliximab at weeks 7 and 12, then followed for 18 weeks to month 6 post-transplant. The primary endpoint was estimated GFR (eGFR). At week 7, 77/207 (37.2%) patients were randomized (53 everolimus, 24 control). At month 6, eGFR was comparable: 36.5±10.8ml/min with everolimus versus 42.0±13.0ml/min in the control group (p = 0.784). Discontinuation due to adverse events occurred in 27.8% of everolimus-treated patients and 0.0% of control patients (p = 0005). Efficacy profiles showed no difference. In conclusion, eGFR, safety and efficacy outcomes at month 6 post-transplant showed no difference between groups. The everolimus group experienced a higher rate of discontinuation due to adverse events. However, the high rate of non-randomization is highly relevant, indicating this to be a somewhat unstable patient population regardless of treatment. CA extern

Background: Renal artery stenosis (RAS) can lead to hypertension and renal failure. Nevertheless, its treatment by percutaneous transluminal renal angioplasty (PTRA) remains controversial. It is unknown, whether patients with global kidney ischemia (GKI), that means patients with bilateral RAS or RAS with a single functioning kidney, may benefit from PTRA or not. Methods: We retrospectively analyzed 93 patients with RAS (25 bilateral or single functioning kidney) undergoing PTRA. Patients had refractory hypertension (≥3 medications). Blood pressure, antihypertensive drugs and serum-creatinine were compared pre-/post-intervention and at 1 year’s follow-up. Results: At 1 year after PTRA of patients with GKI, systolic and diastolic blood pressure were significantly reduced compared to patients with unilateral PTRA (systolic: −19.1 ± 10.5 [bilateral] vs. −11.4 ± 12.1 mmHg [unilateral], P

Objective and Methods: Hypertensive nephropathy is associated by increased renal sympathetic nerve activity. Alpha2A-adrenoceptors (alpha2A-AR) regulate sympathetic tone by controlling norepinephrine (NE) release by a negative feedback mechanism. Recently, we have shown that deletion of alpha2A-adrenoceptors increases renal sympathetic neurotransmission. To investigate whether deletion of alpha2A-AR play a role in the development of hypertensive nephropathy, we induced hypertension by infusing angiotensin (Ang)II (1000ng/kg/min) for 4 weeks in uninephrectomized wild-type (WT) and alpha2A-AR knockout (alpha2A-AR-/-) mice on an FVB background. Blood pressure was assessed by radiotelemetry. Results: NE release stimulated by renal nerve stimulation 5Hz was significantly higher in untreated kidneys of alpha2A-AR-/- compared controls. During AngII infusion (1000ng/kg/min) urinary NE excretion was significantly higher in alpha2A-AR-/- than control mice (4.3±0.6 vs. 2.1±0.4mg/dl creatinine, P P P Conclusion: Deletion of alpha2A-ARs exaggerates hypertensive nephropathy by increasing sympathetic NE activity. Reduction of NE release by RDN reduced blood pressure and albuminuria in alpha2A-AR-/- mice suggesting an important role of renal sympathetic tone in the pathogenesis of hypertensive nephropathy.

Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic blood pressure reductions. Clinical trial data available thus far have been obtained primarily in patients with resistant hypertension, defined as standardized systolic clinic blood pressure ≥ 160 mm Hg (or ≥ 150 mm Hg in patients with type 2 diabetes) despite appropriate pharmacologic treatment with at least 3 antihypertensive drugs, including a diuretic agent. Accordingly, these criteria and blood pressure thresholds should be borne in mind when selecting patients for renal nerve ablation. Secondary forms of hypertension and pseudoresistance, such as nonadherence to medication, intolerance of medication, and white coat hypertension, should have been ruled out, and 24-h ambulatory blood pressure monitoring is mandatory in this context. Because there are theoretical concerns with regard to renal safety, selected patients should have preserved renal function, with an estimated glomerular filtration rate ≥ 45 ml/min/1.73 m(2). Optimal periprocedural management of volume status and medication regimens at specialized and experienced centers equipped with adequate infrastructure to cope with potential procedural complications will minimize potential patient risks. Long-term safety and efficacy data are limited to 3 years of follow-up in small patient cohorts, so efforts to monitor treated patients are crucial to define the long-term performance of the procedure. Although renal nerve ablation could have beneficial effects in other conditions characterized by elevated renal sympathetic nerve activity, its potential use for such indications should currently be limited to formal research studies of its safety and efficacy.

Dieses Positionspapier ist eine Stellungnahme der Deutschen Gesellschaft fur Kardiologie – Herz- und Kreislaufforschung e.V., der Deutschen Gesellschaft fur Nephrologie e.V. sowie der Deutschen Hochdruckliga und fasst die Kriterien zur Zertifizierung von „Renale-Denervations-Zentren (RDZ)“ zusammen. Neben den personellen, apparativen und raumlichen Voraussetzungen werden auch die Patientenselektion, die notwendigen Vor- und Nachsorgeuntersuchungen sowie der Zertifizierungsprozess diskutiert. Die Zertifizierung soll Arzten, Patienten und Kostentragern bei der Identifikation geeigneter Zentren und der Etablierung des neuen Therapieverfahrens helfen.

Background— Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. Less is known about the effect of RDN on 24-hour BP measured by ambulatory BP monitoring and correlates of response in individuals with true or pseudoresistant hypertension. Methods and Results— A total of 346 uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 303 with true resistant (office systolic BP [SBP] 172.2±22 mm Hg; 24-hour SBP 154±16.2 mm Hg) and 43 with pseudoresistant hypertension (office SBP 161.2±20.3 mm Hg; 24-hour SBP 121.1±19.6 mm Hg), from 10 centers were studied. At 3, 6, and 12 months follow-up, office SBP was reduced by 21.5/23.7/27.3 mm Hg, office diastolic BP by 8.9/9.5/11.7 mm Hg, and pulse pressure by 13.4/14.2/14.9 mm Hg (n=245/236/90; P for all P P P P Conclusions— RDN reduced office BP and improved relevant aspects of ambulatory BP monitoring, commonly linked to high cardiovascular risk, in patients with true-treatment resistant hypertension, whereas it only affected office BP in pseudoresistant hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00664638 and NCT00888433.

Renal denervation (RDN) as a catheter-based procedure was introduced in 2009. As a reinvention of an old concept this approach in treating resistant hypertension has been gathering an unprecedented momentum in the world of hypertension. The incredible success in introducing this technique, followed by its quick and wide distribution, introduced new challenges and requirements for hypertension centres in offering optimal patient care. The challenges of these new parameters and requirements have to be met not only by a multidisciplinary team of doctors who can provide excellent evaluation, treatment and follow-up of these patients, but also by the hypertension centres themselves, who wish to provide this treatment option to their patients.

Besonders bei alteren Patienten mit eingeschrankter Nierenfunktion besteht bei Vorhofflimmern ein erhohtes Schlaganfallrisiko. Andererseits ist insbesondere unter Vitamin-K-Antagonisten mit einer erhohten Blutungsrate zu rechnen, sodass eine sorgfaltige Indikationsstellung und Uberwachung dieser Risikopatienten erforderlich ist. Auch ist die Effektivitat der Vitamin-K-Antagonisten bei praterminaler und terminaler Niereninsuffizienz, insbesondere aufgrund des hohen Blutungsrisikos eingeschrankt. Bei den grosen Zulassungsstudien ist beim Einsatz der neuen oralen Antikoagulantien bis zu einer Nierenfunktionseinschrankung von ≥ 30 ml/min mit einem besseren Nutzen/Risiko-Verhaltnis als bei den Vitamin-K-Antagonisten zu rechnen. Der Einsatz der neuen oralen Antikoagulantien (NOAK) erfordert die Kenntnis ihrer Pharmakokinetik, insbesondere der renalen Eliminationsrate. Auch ist eine sorgfaltige Indikationsstellung gerade beim alteren Patienten > 80 Jahre wichtig, die oft unter zusatzlicher Thrombozytenaggregationshemmung stehen. Nicht zuletzt ist eine regelmasige Kontrolle der Nierenfunktion entscheidend, da sich diese innerhalb von kurzer Zeit andern kann.

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.

Der Primare Hyperaldosteronismus (PHA) ist durch eine erhohte, vom Renin-Angiotensin-Aldosteron-System (RAAS) entkoppelte Aldosteronproduktion charakterisiert. Bei Patienten, die sich in spezialisierten Zentren zur Hypertoniebehandlung vorstellen, liegt die Pravalenz des PHA bei ca. 10 %. Die Diagnose bei Patienten mit klassischer Symptomen-Trias des Conn-Syndroms Hypertonie, Hypokaliamie und metabolische Alkalose ist haufig einfach. Wichtig ist die Identifizierung von Patienten mit normokaliamischem Hyperaldosteronismus, da Patienten mit PHA im Vergleich zu Patienten mit essentieller Hypertonie ein schlechteres Outcome haben und eine kausale Therapie haufig moglich ist. Ein Screening auf das Vorliegen eines PHA mittels Aldosteron-Renin-Quotienten sollte bei Patienten mit hypokaliamischer, schwerer (Hypertonie Grad II-III) oder therapierefraktarer arterieller Hypertonie und bei jungen Patienten mit einer arteriellen Hypertonie und ggf. positiver Familienanamnese erfolgen. Ein positives Screeningergebnis mit Verdacht auf das Vorliegen eines PHA sollte immer durch einen Bestatigungstest gesichert werden. Vorzugsweise sollte dafur der intravenose Kochsalzbelastungstest verwendet werden, da er wenig zeitaufwandig und gut kontrollierbar ist. Alternative Bestatigungstests haben kaum klinische Relevanz. Zur Differenzierung des Vorliegens eines unilateralen Adenoms, einer bilateralen Hyperplasie oder einer anderen Ursache schliest sich dem Bestatigungstest eine CT/MRT-gestutzte Bildgebung an. Da in den meisten Fallen eine Raumforderung nicht sicher identifiziert bzw. ausgeschlossen werden kann, sollte zudem eine seitengetrennte Nebennierenvenenblutentnahme erfolgen. Bei Nachweis einer Lateralisierung ist von einem unilateralem Nebennierenrindenadenom auszugehen, und folglich die laparoskopische Adrenalektomie die Therapie der Wahl. Hierdurch kann der Patient in bis zu 60 % der Falle von einer arteriellen Hypertonie geheilt werden. Sollte keine Lateralisierung nachweisbar sein, muss von einer bilateralen Hyperplasie ausgegangen werden. Diese macht eine dauerhafte medikamentose Therapie mittels Mineralokortikoidrezeptor-Antagonisten notwendig. Vorzugsweise erfolgt der Einsatz von Spironolacton. Sollte die Therapie aufgrund der Nebenwirkungen nicht toleriert werden, kann alternativ Eplerenon oder auch Kalium-sparende Diuretika eingesetzt werden. Nicht selten ist eine zusatzliche antihypertensive Therapie notwendig, um eine ausreichende Blutdruckkontrolle zu erreichen.

Increased renal resistive index and urinary albumin excretion are markers of hypertensive end-organ damage and renal vasoconstriction involving increased sympathetic activity. Catheter-based sympathetic renal denervation (RD) offers a new approach to reduce renal sympathetic activity and blood pressure in resistant hypertension. The influence of RD on renal hemodynamics, renal function, and urinary albumin excretion has not been studied. One hundred consecutive patients with resistant hypertension were included in the study; 88 underwent interventional RD and 12 served as controls. Systolic, diastolic, and pulse pressure, as well renal resistive index in interlobar arteries, renal function, and urinary albumin excretion, were measured before and at 3 and 6 months of follow-up. RD reduced systolic, diastolic, and pulse pressure at 3 and 6 months by 22.7/26.6 mm Hg, 7.7/9.7 mm Hg, and 15.1/17.5 mm Hg ( P for all r =−0.46; P P =0.037/0.017) at 3- and 6-month follow-up. Mean cystatin C glomerular filtration rate and urinary albumin excretion remained unchanged after RD; however, the number of patients with microalbuminuria or macroalbuminuria decreased. RD reduced blood pressure, renal resistive index, and incidence of albuminuria without adversely affecting glomerular filtration rate or renal artery structure within 6 months and appears to be a safe and effective therapeutic approach to lower blood pressure in patients with resistant hypertension.

Patienten mit schwer einstellbarer Hypertonie haben ein deutlich gesteigertes Risiko fur kardiovaskulare Ereignisse. Wahrend bei gut kontrollierter, essenzieller Hypertonie selten eine einzelne Ursache fur die Hypertonie zugrunde liegt, ist bei schwer einstellbarer Hypertonie oft eine sekundare Hypertonieform zu finden. Zu den haufigen Formen der sekundaren Hypertonie zahlen die schlafbezogenen Atemstorungen, der primare Hyperaldosteronismus sowie die renalen Hypertonieformen (renoparenchymatos und renovaskular). Deutlich seltener sind Hyperkortisolismus, Phaochromozytom, Schilddrusenfunktionsstorungen oder Aortenisthmusstenose. Eine sorgfaltige Patientenvorselektion mittels einfacher klinischer Tests muss erfolgen, um die Trefferwahrscheinlichkeit der einzelnen sekundaren Hypertonieformen zu steigern. Ein Screening aller Hypertoniker auf die genannten Hypertonieformen ware nicht zielfuhrend. Wird eine sekundare Hypertonieform dringend vermutet oder identifiziert, empfiehlt sich die Uberweisung in ein darauf spezialisiertes Zentrum. Neben sekundaren Hypertonieformen sind Medikamenteninteraktionen (z. B. NSARs), mangelnde Adharenz, suboptimale Medikation und nicht zuletzt Lebensstilfaktoren fur einen schwer einstellbaren Bluthochdruck verantwortlich zu machen und mussen entsprechend abgefragt und modifiziert werden. Als Ultima Ratio stehen zwei neue Alternativen zur Verfugung. Die Barorezeptorstimulation und die renale Denervation sind beides sehr erfolgsversprechende, jedoch invasive Masnahmen, die nur in spezialisierten Zentren mit Hypertonieschwerpunkt durchgefuhrt werden sollten.

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

In Deutschland sind ca 20 – 30 % der Bevolkerung von einer arteriellen Hypertonie betroffen. Vor Beginn einer Therapie sollten anhand einer Basisdiagnostik das individuelle kardiovaskulare Risiko des Patienten exakt evaluiert und sekundare Ursachen einer Hypertonie ausgeschlossen werden. Bei der Erstdiagnose und zur Therapiekontrolle empfiehlt sich eine ambulante 24-Stunden-Langzeitblutdruckmessung. Wahrend fruher die Stufentherapie favorisiert wurde, beginnend mit einer Monotherapie, wird heute eine Kombinationstherapie niedrig dosierter und synergistisch wirksamer Medikamente empfohlen, um eine optimale Blutdrucksenkung ohne Nebenwirkungen zu erzielen. Ideale duale Kombinationspartner sind Hemmstoffe des Renin-Angiotensin-Systems mit Diuretika oder Dihydropyridin-Kalziumantagonisten. Die Zielblutdruckwerte haben sich in der letzten Zeit nach unten orientiert. Allerdings legen neuere prospektive Studien nahe, dass zu niedrige Blutdruckwerte insbesondere bei Patienten mit unbehandelter koronarer Herzerkrankung und Diabetes mellitus zu vermeiden sind. Blutdruckwerte von 130-135/80-85 mmHg sind insbesondere fur Diabetiker mit erhohtem kardiovaskularen Risiko anzustreben. Bei der therapieresistenten Hypertonie haben sich neue Therapiemoglichkeiten ergeben. Herausragend ist die Nierennervenablation zu nennen, die bei Patienten mit therapierefraktarer Hypertonie in ersten klinischen Studien eindrucksvolle Erfolge erzielt hat.

BACKGROUND AND PURPOSE ApolipoproteinE-deficient [apoE (−/−)] mice, a model of human atherosclerosis, develop endothelial dysfunction caused by decreased levels of nitric oxide (NO). The endogenous peptide, angiotensin-(1-7) [Ang-(1-7)], acting through its specific GPCR, the Mas receptor, has endothelium-dependent vasodilator properties. Here we have investigated if chronic treatment with Ang-(1-7) improved endothelial dysfunction in apoE (−/−) mice. EXPERIMENTAL APPROACH ApoE (−/−) mice fed on a lipid-rich Western diet were divided into three groups and treated via osmotic minipumps with either saline, Ang-(1-7) (82 µg·kg−1·h−1) or the same dose of Ang-(1-7) together with D-Ala-Ang-(1-7) (125 µg·kg−1·h−1) for 6 weeks. Renal vascular function was assessed in isolated perfused kidneys. KEY RESULTS Ang-(1-7)-treated apoE (−/−) mice showed improved renal endothelium-dependent vasorelaxation induced by carbachol and increased renal basal cGMP production, compared with untreated apoE (−/−) mice. Tempol, a reactive oxygen species (ROS) scavenger, improved endothelium-dependent vasorelaxation in kidneys of saline-treated apoE (−/−) mice whereas no effect was observed in Ang-(1-7)-treated mice. Chronic treatment with D-Ala-Ang-(1-7), a specific Mas receptor antagonist, abolished the beneficial effects of Ang-(1-7) on endothelium-dependent vasorelaxation. Renal endothelium-independent vasorelaxation showed no differences between treated and untreated mice. ROS production and expression levels of the NAD(P)H oxidase subunits gp91phox and p47phox were reduced in isolated preglomerular arterioles of Ang-(1-7)-treated mice, compared with untreated mice, whereas eNOS expression was increased. CONCLUSION AND IMPLICATIONS Chronic infusion of Ang-(1-7) improved renal endothelial function via Mas receptors, in an experimental model of human cardiovascular disease, by increasing levels of endogenous NO.

Background— Hypertension is associated with impaired glucose metabolism and insulin resistance. Chronic activation of the sympathetic nervous system may contribute to either condition. We investigated the effect of catheter-based renal sympathetic denervation on glucose metabolism and blood pressure control in patients with resistant hypertension. Methods and Results— We enrolled 50 patients with therapy-resistant hypertension. Thirty-seven patients underwent bilateral catheter-based renal denervation, and 13 patients were assigned to a control group. Systolic and diastolic blood pressures, fasting glucose, insulin, C peptide, hemoglobin A 1c , calculated insulin sensitivity (homeostasis model assessment–insulin resistance), and glucose levels during oral glucose tolerance test were measured before and 1 and 3 months after treatment. Mean office blood pressure at baseline was 178/96±3/2 mm Hg. At 1 and 3 months, office blood pressure was reduced by −28/−10 mm Hg ( P P P =0.039). Insulin levels were decreased from 20.8±3.0 to 9.3±2.5 μIU/mL ( P =0.006) and C-peptide levels from 5.3±0.6 to 3.0±0.9 ng/mL ( P =0.002). After 3 months, homeostasis model assessment–insulin resistance decreased from 6.0±0.9 to 2.4±0.8 ( P =0.001). Additionally, mean 2-hour glucose levels during oral glucose tolerance test were reduced significantly by 27 mg/dL ( P =0.012). There were no significant changes in blood pressure or metabolic markers in the control group. Conclusions— Renal denervation improves glucose metabolism and insulin sensitivity in addition to a significantly reducing blood pressure. However, this improvement appeared to be unrelated to changes in drug treatment. This novel procedure may therefore provide protection in patients with resistant hypertension and metabolic disorders at high cardiovascular risk. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov . Unique identifiers: NCT00664638 and NCT00888433.

Nephrin, the key molecule of the glomerular slit diaphragm, is expressed on the surface of podocytes and is critical in preventing albuminuria. In diabetes, hyperglycemia leads to the loss of surface expression of nephrin and causes albuminuria. Here, we report a mechanism that can explain this phenomenon: hyperglycemia directly enhances the rate of nephrin endocytosis via regulation of the β-arrestin2-nephrin interaction by PKCα. We identified PKCα and protein interacting with c kinase-1 (PICK1) as nephrin-binding proteins. Hyperglycemia induced up-regulation of PKCα and led to the formation of a complex of nephrin, PKCα, PICK1, and β-arrestin2 in vitro and in vivo. Binding of β-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by PKCα. Further, cellular knockdown of PKCα and/or PICK1 attenuated the nephrin-β-arrestin2 interaction and abrogated the amplifying effect of high blood glucose on nephrin endocytosis. In C57BL/6 mice, hyperglycemia over 24 h caused a significant increase in urinary albumin excretion, supporting the concept of the rapid impact of hyperglycemia on glomerular permselectivity. In summary, we have provided a molecular model of hyperglycemia-induced nephrin endocytosis and subsequent proteinuria and highlighted PKCα and PICK1 as promising therapeutic targets for diabetic nephropathy.

Aging of the population and improvements in diabetes therapy have led to an increased number of older pancreas transplant candidates. The aim of our retrospective study was to evaluate pancreas transplantation (PT) outcomes in patients ≥ 50 years, as limited data exist in these patients. We analyzed 398 consecutive pancreas transplant patients from June 1994 to June 2009 for different outcomes (patient/graft survival, rejection rate, and surgical complications) between the age groups ≥ 50 years (n = 69) and

Primary aldosteronism is the most frequent cause of secondary hypertension. Three variants of familial hyperaldosteronism are known today. Early onset hypertension and severe target organ damage are hallmarks of the heritable forms. The underlying gene defect has already been identified in familial hyperaldosteronism type I. In type II and III research is ongoing. A highly variable phenotype often precludes the discovery of the familial appearance of these syndromes. Taking a sound family history is extremely important to discover the Mendelian pattern of inheritance. The identification of affected families is highly rewarding because all variants can potentially be cured or at least specifically treated. Testing the relatives of an index patient sometimes even allows preemptive treatment. However, the availability of specific treatment options necessitates a solid differentiation between the three syndromes to avoid unnecessary medical therapy or surgery.

Hyperaldosteronismus ist mit erhohtem kardiovaskularem Risiko verbunden. Bei Herzinsuffizienz konnte durch Blockade der Mineralokortikoid-Rezeptoren eine Reduktion in der Mortalitat erreicht werden. Aber auch bei therapierefraktarer essentieller Hypertonie und metabolischem Syndrom scheint Aldosteron eine bedeutende Rolle zu spielen. Eine Therapie mit Mineralokortikoidrezeptor (MR)-Antagonisten ist bei Nachweis erhohter Aldosteronspiegel insbesondere bei Patienten mit Aldosteron-Escape angebracht. Eine besondere Stellung nimmt der primare Hyperaldosteronismus (PHA) ein. Er gilt als eine der haufigsten Ursachen einer sekundaren Hypertonie. Da er klinisch meist normokaliam verlauft, ist er unter Zuhilfenahme des Aldosteron-Renin Quotienten zu identifizieren. So sollten Patienten mit schwer einstellbarer Hypertonie , hypertensive jungere Patienten und Patienten mit Inzidentalom ein PHA-Screening durchlaufen. Bei den Untersuchungen ist darauf zu achten, dass Medikamente, die mit dem Renin-Angiotensin-Aldosteron-System interagieren, abgesetzt beziehungsweise umgestellt werden. Nach dem Screening erfolgt ein Bestatigungstest (z.B. Kochsalzbelastungstest). Um zwischen idiopathischer bilateraler Nebennierenrinden-Hyperplasie und Aldosteron-produzierendem Adenom unterscheiden zu konnen, schliesen sich CT und seitengetrennte Nebennierenvenenblutentnahme an. Bei einseitigem Adenom ist die unilaterale peritoneoskopische Adrenalektomie die Therapie der Wahl. Die bilaterale Nebennierenrinden-Hyperplasie wird medikamentos mit den MR-Antagonisten Spironolacton oder Eplerenon behandelt. Bei einer positiven Familienanamnese fur primaren Hyperaldosteronismus ist an familiaren Hyperaldosteronismus (FH) zu denken. Derzeit werden FH Typ I, Typ II und Typ III unterschieden. Bei FH I liegt ein hybrides Gen aus CYP11B1 und CYP11B2 vor, welches eine ACTH-abhangig Aldosteron-Synthese vermittelt. Der Nachweis erfolgt zuverlassig durch PCR. Eine monogenetische Ursache fur FH II und FH III konnte bislang nicht gefunden werden. Hyperaldosteronismus kann durch seine Wirkungen, die weit uber die Wasser- und Salzregulation hinausgehen, negativen Einfluss auf kardiovaskulare Ereignisse haben und sollte demnach einen festen Stellenwert in Diagnostik und Therapie der arteriellen Hypertonie erhalten.

Cardiovascular morbidity and mortality is exceedingly high in patients with chronic renal failure. Sympathetic overactivity is an important pathomechanism contributing to progression of renal disease as well as cardiovascular complications. For more than 30 years it has been known that plasma levels of norepinephrine are elevated in chronic renal failure pointing to increased sympathetic nerve activity. The kidneys are richly innervated by efferent sympathetic and afferent sensory nerves. They participate in many reflex adjustments of renal function. Initially, this finding had not been attributed to increased efferent sympathetic drive, but rather to reduced renal clearance and defective neuronal reuptake of norepinephrine. At this time, however, the evidence for increased sympathetic drive is solid. Interventions to reduce sympathetic overactivity will provide new therapeutic approaches. The available experimental and clinical evidence to suggest such a pathophysiological role of sympathetic overactivity is summarized in this current review.

Adequate kidney function is crucial in sustaining vertebrate homeostasis. Certain diseases can diminish renal function and lead to end-stage renal disease. Diabetes mellitus and hypertension are the main causes of glomerulosclerosis and albuminuria in adults. The molecular mechanisms that trigger these maladaptive changes are still unsatisfyingly described. We previously introduced 2-D DIGE in combination with focused tissue isolation methods to analyze protein expression in glomeruli. Glomeruli, the crucial compartments in albuminuric renal diseases, were extracted using magnetic particles from subtotally nephrectomized FVB mice (n = 6); this 5/6 nephrectomy in FVB mice is a model of chronic kidney disease. Analysis of protein expression levels from glomerular protein lysates was performed using 2-D DIGE and compared with glomerular protein lysates from mice that underwent sham surgery. The comparison of about 2100 detectable spots between both groups revealed 48 protein spots that showed significant differential expression. Of those, 33 proteins could be identified using nanoLC-ESI MS. The metalloproteinase meprin 1 alpha, the beta galactoside-binding-lectin galectin-1 and dimethylarginine dimethylaminohydrolase 1, a key enzyme in NO metabolism, were found to be differentially regulated, thus implying a role in the pathogenesis and pathophysiology of progressive kidney disease. In conclusion, 2-D DIGE protein analysis of smallest sample sizes from specific organ compartments provides focused protein expression results, which help in gaining an understanding of the molecular mechanisms of chronic kidney disease.

BACKGROUND AND OBJECTIVES There is a high prevalence for primary hyperaldosteronism (PHA) in hypertensive patients. This retrospective study was performed to determine the role of adrenal scanning and adrenal vein sampling (AVS) in distinguishing unilateral autonomous adenoma from idiopathic bilateral hyperplasia (IHA). METHODS 93 patients, admitted to the radiology department for AVS between 1996 and 2004, were enrolled. 44 had a diagnosis of PHA, 22 or whom had an adenoma and 22 had IHA. RESULTS 17 of the 22 patients with adenoma and 15 with IHA had an aldosterone-renin ratio > 50. Adrenal CT or MR scanning was performed in 73 patients. Sensitivity and specificity were 56 % and 60 %, respectively, for CT and 57% and 67% for MR. In 87 patients AVS provided values for aldosterone (A) and cortisol (C) from the adrenal veins and vena cava inferior (VCI). Successful sampling (C-adrenal vein/C-VCI > 1.1) was achieved from 55 % of the right and from 92 % of the left adrenal veins. When AVS was successful on both sides, localizing adenoma was possible using A/C (site of adenoma) vs. A/C (contralateral) at a cut-off point > 3 (sensitivity 85 %, specifity 88 %). In patients with adenoma, aldosterone release was suppressed on the contralateral site (A/C-adrenal vein/A/C-VCI ratio = 0.8). CONCLUSION AVS is a useful tool for localizing unilateral autonomous adenoma. However, selective sampling often fails on the right adrenal vein, which limits its significance. In this case the A/C-adrenal vein/A/C-VCI in combination with the posture test should be utilized. CT or MRI are of limited value.

Background. The prevalence of primary hyperaldosteronism (PHA) in the hypertensive population has increased in recent years. Glucocorticoid-remediable aldosteronism (GRA) is a rare monogenic form of PHA. Here we report a German family with GRA. Since the phenotype of GRA varies widely, we asked whether recommended algorithms for PHA diagnosis distinguish GRA from other forms of PHA. Methods. Plasma aldosterone (pg/ml) and renin (pg/ml) levels were determined in three hypertensive family members with GRA before and after sodium loading with 2 l of saline (0.9%), during posture and after 1 week of 2 mg dexamethasone daily. 24 h blood pressure and urinary excretion of aldosterone, cortisol precursors and metabolites were measured before and after dexamethasone. Southern blot hybridization and long-range PCR were performed to identify the chimeric gene. Results. All three affected patients had normal potassium levels but markedly increased aldosterone/ renin ratios of 472, 213 and >322 (normal range

Background and purpose: In the present study, a rodent model was used to investigate whether the α2A-adrenoceptor (α2A) represents the presynaptic autoinhibitory receptor regulating sympathetic transmitter release in the kidney. Moreover, the potential role of α2A as a heteroceptor regulating adenosine triphosphate (ATP) release was tested. Experimental approach: Kidneys from wild-type (WT) and α2A-knockout (KO) mice were isolated and perfused. Renal nerves were stimulated with platinum-electrodes. Endogenously released noradrenaline (NA) was measured by HPLC. The perfusion pressure was monitored continuously. Key results: Renal nerve stimulation (RNS) induced a frequency (1,2,5,7.5,10,15 Hz)-dependent release of NA in WT mice (994±373, 2355±541, 6375±950, 11626±1818, 19138±2001 pg NA g-1 kidney (means±s.e.m.)). There was a 2.7-fold (5 Hz) increase of NA release in α2A-KO mice. In WT animals α-adrenoceptor blockade by phentolamine increased RNS-induced NA release in a concentration-dependent manner up to 350% of control. No facilitation by phentolamine was observed in α2A-KO mice. Pressor responses to 1 Hz and 2 Hz were resistant to α1-adrenoceptor blockade (0.03 μM prazosin) but abolished by P2 receptor blockade (5 μM PPADS). Blockade of α2-adrenoceptors (1 μM rauwolscine) increased these purinergic pressor responses to 296±112% (1 Hz) in WT but not in α2A-KO mice. Exogenous ATP (100 μM) increased basal but not RNS-induced NA release. Conclusions and Implications: α2A-Adrenoceptor-activation inhibits NA and ATP release from renal sympathetic nerves. Pressor responses to RNS at higher stimulation frequencies (>2 Hz) are mediated by NA. At lower frequencies neuronally released ATP seems to be the predominant transmitter mediating renovascular resistance. British Journal of Pharmacology (2007) 150, 121–127. doi:10.1038/sj.bjp.0706961

Loss of renal function is often associated with the injury of kidney glomeruli. It is therefore necessary to understand the mechanisms leading to progressive glomerular diseases; this may be addressed using proteomics. Until now, however, analysis of the glomeruli proteome using 2-DE has been technically hampered by low protein yields from scarce samples. To circumvent this problem, we developed a procedure which allows the human and mouse glomeruli proteome to be analysed. In this study, two different approaches were used to isolate mouse and human glomerular protein from kidney cortex. Mouse glomeruli were extracted by embolisation magnetic beads into the glomerular capillaries. Laser capture microdissection (LCM) was utilised to harvest glomeruli from human biopsy material. Human and murine samples were analysed using a fluorescence saturation labelling technique. Using 3 microg mouse glomerular protein a total of 2900 spots were resolved for differential proteome analysis. Moreover, it was also demonstrated for the first time that only ten glomeruli (0.5 microg) picked by LCM from a slide of a human kidney biopsy material were sufficient to visualise 900 spots. This novel strategy paves the way for future experiments aimed at investigating functional proteomics of glomerular diseases in humans and in mice.