Suppressed Plasma Renin Activity Research Articles

6C.03

Objective: Familial hyperaldosteronism type III (FH-III) is a rare autosomal dominant and clinically heterogeneous condition, that can display mild as well as severe phenotypes. Point mutations in the KCNJ5 gene, affecting the ion selectivity of the inward rectifier K+ channel 4 (Kir3.4), represent the molecular basis of FH-III. So far, five germline mu- tations in the KCNJ5 gene have been identified and functionally characterized in patients with FH-III. Objective of the present study was to characterized the effect of a de novo KCNJ5 germline substitution in vitro. Design and method: We describe the case of a girl affected by severe hyperaldosteronism. KCNJ5 gene was PCR amplified from peripheral blood and sequenced. Electrophysiological and gene expression studies were performed to establish the functional effects of the new mutation on the membrane potential and adrenal cell CYP11B2 (aldosterone synthase) expression. Results: The index case is a Caucasian girl born to nonconsanguineous parents. She came to medical attention at the age of two years because of polydipsia, polyuria and failure to thrive. The patient, affected by hypertension and hypokalemia, was diagnosed with primary aldosteronism on the basis of extremely high aldosterone levels and suppressed plasma renin activity. At the age of 19 she was on four antihypertensive medications and potassium supplements; transthoracic echocardiography revealed mildly dilated aortic root and ascending aorta without left ventricular hypertrophy. The patient consented to bilateral adrenalectomy which was performed laparoscopically. KCNJ5 sequencing in the index case and her parents revealed a de novo p.Glu145Gln germline mutation. The substitution resulted in Na+-dependent depolarization of adrenal cells and increased intracellular calcium concentration, which activated the transcription of NR4A2 and, in turn, CYP11B2. Pharmacological studies revealed that the mutant channel was insensitive to tertiapin-Q and calcium-channel blocker verapamil. Conclusions: Herein we report on the identification of a novel KCNJ5 germline mutation responsible for severe hyperaldosteronism that presented in infancy with symptoms of diabetes insipidus. The findings of this study further elucidate the etiology of FH-III and expand our knowledge of this rare condition.

Salt feedback on the renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system (RAAS) is a central element in the control of the salt and water balance of the body and arterial blood pressure. The activity of the RAAS is controlled by the protease renin, which is released from renal juxtaglomerular epithelioid cells (JGE cells) into the circulation. Renin release is regulated by a complex interplay of several locally acting hormones or mechanisms and longer feedback loops one of which involves salt intake. Acute NaCl loads or longer lasting high salt intakes suppress plasma renin activity, whereas reductions in NaCl intake stimulate it. Because the activation of the RAAS conserves the salt content of the body, a classical feedback loop between salt intake/body salt content and renin is established. Despite of its important role for body fluid homeostasis, the precise signaling pathways connecting salt intake with the synthesis and release of renin are only incompletely understood. Four putative controllers of the salt-dependent regulation of the RAAS have been suggested: (1) the macula densa mechanism which adjusts renin release in response to changes in the renal tubular salt concentration; (2) salt-dependent changes in the arterial blood pressure; (3) circulating salt-dependent hormones, particularly the atrial natriuretic peptide (ANP); and (4) renal sympathetic nervous activity, which is regulated by extracellular volume and arterial blood pressure. In this review, the role of these known controllers of the RAAS will be discussed with special emphasis on their relative contributions to the salt-dependent regulation of the RAAS at different time frames.

Long-term low-dose ketoconazole treatment in bilateral macronodular adrenal hyperplasia.

SummaryMedical therapy for Cushing's syndrome due to bilateral macronodular adrenal hyperplasia (BMAH) is generally administered for a limited time before surgery. Aberrant receptors antagonists show inconsistent efficacy in the long run to prevent adrenalectomy. We present a patient with BMAH, treated for 10 years with low doses of ketoconazole to control cortisol secretion. A 48-year-old woman presented with headaches and hypertension. Investigations showed the following: no clinical signs of Cushing's syndrome; enlarged lobulated adrenals; normal creatinine, potassium, and aldosterone; normal urinary aldosterone and metanephrines; elevated urinary free cortisol and steroid metabolites; and suppressed plasma renin activity and ACTH. A screening protocol for aberrant adrenal receptors failed to show any illegitimate hormone dependence. Ketoconazole caused rapid normalisation of cortisol and ACTH that persists over 10 years on treatment, while adrenals show no change in shape or size. Ketoconazole decreases cortisol in patients with Cushing's syndrome, and may prevent adrenal overgrowth. Steroid secretion in BMAH is inefficient as compared with normal adrenals or secreting tumours and can be controlled with low, well-tolerated doses of ketoconazole, as an alternative to surgery.Learning points Enlarged, macronodular adrenals are often incidentally found during the investigation of hypertension in patients harboring BMAH. Although laboratory findings include low ACTH and elevated cortisol, the majority of patients do not display cushingoid features.Bilateral adrenalectomy, followed by life-long steroid replacement, is the usual treatment of this benign condition, and alternative medical therapy is sought. Therapy based on aberrant adrenal receptors gives disappointing results, and inhibitors of steroidogenesis are not always well tolerated.However, ketoconazole at low, well-tolerated doses appeared appropriate to control adrenal steroid secretion indefinitely, while preventing adrenal overgrowth. This treatment probably constitutes the most convenient long-term alternative to surgery.

Blood pressure, fludrocortisone dose and plasma renin activity in children with classic congenital adrenal hyperplasia due to 21‐hydroxylase deficiency followed from birth to 4 years of age

Infants with congenital adrenal hyperplasia (CAH) require higher doses of fludrocortisone (FC) due to physiological mineralocorticoid resistance. The adequacy of mineralocorticoid replacement should be closely monitored to avoid hypertension. To evaluate blood pressure (BP) in infants with CAH due to 21-hydroxylase deficiency. Thirty-three patients (18f/15m) diagnosed by newborn screening were followed until the age of 4years. Mean start of HC and FC treatment was day 9·8±9·2 postnatally. Mean daily HC dose ranged from 8·6 to 12·3mg/m(2) /day. During the first year of life prevalence of systolic hypertension was up to 45·5%. At 12 and at 18months, BP was highest. Prevalence of systolic hypertension was up to 57·6% at 18months of age. After 24months BP levels were lower and at 48months prevalence of hypertension decreased to 15·2%. Systolic and diastolic BP correlated significantly with the administered fludrocortisone dose (r=0·3, P=0·005), but not with body mass index. Hypertensive children received significantly higher FC doses and had significantly lower plasma renin activity during the study period. High prevalence of transient, most likely FC induced hypertension was found in young children with classic CAH diagnosed by newborn screening. The changing mineralocorticoid sensitivity in infants is a risk factor for the development of hypertension in patients with CAH, who are treated with FC. Therefore suppressed plasma renin activity should be avoided to prevent arterial hypertension.

Effect of oleanolic acid on the regulation of water, electrolyte and the renin system (701.4)

Effect of oleanolic acid on the regulation of water, electrolyte and the renin system Yoon Hee Choi1,2, Min Chul Kho1,2, Ji Hun Park2,3, Kyung Woo Cho1,2, Dae Gill Kang1,2,3, Ho Sub Lee1,2 1Professional graduate school of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, 570‐749, Republic of Korea 2 Hanbang Body‐fluid Research Center, Wonkwang University, Shinyong‐dong, Iksan, Jeonbuk, 570‐749, Republic of Korea 3Department of Food Industry Convergence, Wonkwang University, Iksan, Jeonbuk 570‐749, Republic of Korea ABSTRACT Oleanolic acid is an active ingredient of variable plants including medicinal herbs and edible vegetables. Previously, it was shown that oral intake of oleanolic acid accentuates the atrial natriuretic peptide (ANP) system. Oleanolic acid increases cardiac ANP synthesis, plasma levels, and secretion. The purpose of the present study was to identify the effects of oleanolic acid on the regulation of fluid and electrolyte homeostasis and renal hormone balance. Experiments were performed in rats housed in metabolic cage and Oleanolic acid was administered orally everyday for 7 days. Oleanolic acid increased urinary excretion of Na+, Cl‐, and K+ . Oleanolic acid also increased urinary excretion of creatinine and clearance for creatinine. Furthermore, oleanolic acid suppressed plasma renin activity and renal renin contents. These findings suggest that oleanolic acid increases glomerular filtration rate and urinary excretion of water and electrolytes via suppression of the renin‐angiotensin system. Thus, this provides experimental evidence for beneficial effects of oleanolic acid in the cardiovascular system.Keyworlds : Oleanolic acid;Renin‐angiotensin system;Glomerular filtration rate;Urinary; Renin activity

Primary aldosteronism: a new insight into pathogenesis, diagnosis, and treatment in hypertensive patients

Primary aldosteronism (PA) seems to be a pathogenetically heterogenous disease. It is suggested that approximately 30% of all hypertensive patients are affected by this disease. Autonomous hypersecretion of aldosterone, which is observed in this patient group, may be caused by an adrenal adenoma (aldosteronoma), hyperplasia of the zona glomerulosa, mutation of the KCNJ5 potassium channel, or other rare pathogenetic factors. Contrary to what was believed before, PA may be the cause of resistant hypertension rather than mild hypertension, while 70% of the patients have normal serum potassium levels rather than hypokalemia (previously believed to be a classical PA symptom). Hypertensive patients with normal or elevated aldosteronemia (A), suppressed plasma renin activity (PRA) and an elevated A/PRA ratio should undergo further diagnostic work‑up for PA. PA is suspected to be the continuum of low‑renin hypertension. First‑choice therapy of PA should be based on long‑term administration of low‑dose mineralocorticoid receptor antagonists (spironolactone, eplerenone) and, in the nearest future, probably also aldosterone synthase antagonists such as CLI699, regardless of the morphological type of PA. It is still unknown whether pharmacological treatment will totally replace surgical treatment in some types of PA. Long‑term administration of low‑dose aldosterone antagonists is an effective and often underscored antihypertensive treatment, which rarely causes serious hyperkalemia if the kidney function is not impaired.

Abstract 354: Cardiovascular Responses to Chronic Baroreflex Activation in Aldosterone Hypertension

Both suppression of sympathetic activity (SA) by chronic electrical activation of the carotid baroreflex (BA) and renal denervation (RDX) abolish obesity-induced hypertension (HT), which is mediated by increased SA. Evidence in support of a sympathetic component to aldosterone (Aldo) HT is equivocal. Therefore, at the same stimulation parameters in each dog, cardiovascular responses to 7 days of BA were determined in 9 dogs before (no HT) and after induction of HT by infusion of Aldo for 14 days (12μg/kg/day), which increased plasma levels ~ 10-fold (control= 4.3±0.4 ng/dL). 3 dogs with Aldo HT were subjected to RDX. Aldo HT was associated with increases in plasma osmolality (293±1 to 297±1 mOsm/kg) and [vasopressin] (AVP, Table), marked polydipsia (241± 90 to 2,380 ± 382 mL/day), hypokalemia (4.2±0.1 to 2.3±0.1 mmol/L), and suppression of plasma renin activity, but no significant changes in plasma [norepinephrine] (NE, Table). MAP (mmHg), NE (pg/mL), and AVP (pg/mL) responses to BA: *P<0.05 vs Control Plasma [NE] decreased with BA during both no HT and Aldo HT, indicating suppression of SA, but MAP lowering was appreciably diminished during Aldo HT. In contrast, there was no lowering of MAP after RDX. There were no significant changes in plasma osmolality, drinking, or [AVP] during BA. These findings indicate that classic renal mineralocorticoid mechanisms, not increased SA, account for the initial progression of HT produced by pathophysiological circulating levels of Aldo. Further, they show that chronic stimulation of baroreceptors afferents has differential central effects to suppress SA without altering control of plasma osmolality by suppressing thirst or AVP secretion.

AT1 Receptors Prevent Salt-Induced Vascular Dysfunction in Isolated Middle Cerebral Arteries of 2 Kidney-1 Clip Hypertensive Rats

Elevated blood pressure, elevated angiotensin II (ANG II), and ANG II suppression with high salt (HS) diet all contribute to vascular dysfunction. This study investigated the interplay of HS diet and vascular function in a high renin model of hypertension. Male Sprague-Dawley rats were subjected to 2 kidney-1 clip (2K1C) Goldblatt hypertension for 4 weeks and compared with sham-operated controls. Middle cerebral arteries (MCA) of 2K1C rats and sham-operated controls fed normal salt (NS; 0.4% NaCl) diet dilated in response to acetylcholine (ACh) and reduced partial pressure of oxygen (PO2). Switching to HS (4% NaCl) diet for 3 days to reduce plasma renin activity (PRA) eliminated vasodilation to ACh and reduced PO2 in sham-operated controls, with no effect on vasodilation in 2K1C rats. AT1 receptor blockade (losartan, 20 mg/kg/day; 1 week) eliminated vasodilator responses to ACh and reduced PO2 in 2K1C rats fed NS or HS diet. ANG II infusion (5 ng/kg/min, intravenous) for 3 days to prevent salt-induced reductions in plasma ANG II restored vascular relaxation in MCA of sham-operated controls fed HS diet. Copper/zinc superoxide dismutase expression and total superoxide dismutase activity were significantly higher in arteries of 2K1C rats fed HS diet vs. sham-operated controls. These results suggest that the sustained effects of elevated ANG II levels in 2K1C hypertension maintain endothelium-dependent vasodilatation via AT1 receptor-mediated preservation of antioxidant defense mechanisms despite significant elevations in blood pressure and salt-induced suppression of PRA.

Mean platelet volume in patients with primary aldosteronism and its relation to left ventricular hypertrophy

Primary aldosteronism (PA) is characterized by hypertension, hypokalemia, suppressed plasma renin activity and autonomous aldosterone production. Compared to patients with similar levels of hypertension, patients with PA have greater left ventricular hypertrophy (LVH) and increased rate of cardiovascular complications [1]. On the other hand, increased mean platelet volume (MPV), an indicator of platelet activation has an important role in the pathophysiology of cardiovascular disease [2]. Larger platelets have higher thrombotic potential, and may be associated with increased rate of cardiovascular complications in patients with PA.

Brain Gαi2-subunit protein-gated pathways are required to mediate the centrally evoked sympathoinhibitory mechanisms activated to maintain sodium homeostasis

We have previously demonstrated a role of GPCR-activated brain Gαi(2)-subunit protein-gated pathways in the natriuretic responses evoked by exogenous central α(2)-adrenoceptor activation and acute intravenous (i.v.) volume expansion in vivo. Our objective was to examine the role of brain Gαi(2) proteins in the integrated neural-humoral responses evoked by i.v. isovolumetric sodium loading, which does not alter mean arterial blood pressure or total blood volume, to maintain sodium homeostasis in conscious Sprague-Dawley rats. Intact or chronic bilateral renal denervated (RDNX) rats were pretreated intracerebroventricularly (i.c.v.) with a scrambled or Gαi(2) oligodeoxynucleotide to selectively downregulate brain Gαi(2) proteins. On the day of study, an i.v. isovolumetric sodium load (1 mol/l NaCl) was administered. In naive and scrambled oligodeoxynucleotide groups, i.v. sodium loading evoked profound natriuresis, suppression of plasma renin activity (PRA) and global sympathoinhibition. Prior downregulation of brain Gαi(2) proteins significantly attenuated the natriuretic response [peak ΔUNaV (μeq/μl); scrambled 22 ± 2 vs. Gαi(2) 13 ± 2, P < 0.05] and abolished the sympathoinhibitory response [peak Δplasma norepinephrine (% control); SCR -72 ± 8 vs. Gαi(2) -7 ± 5, P < 0.05] without attenuating PRA suppression to sodium loading. In RDNX rats, Gαi(2) oligodeoxynucleotide pretreatment failed to attenuate the natriuretic response [peak ΔUNaV (μeq/μl); RDNX and scrambled 19 ± 3 vs. RDNX and Gαi(2) 20 ± 2] and only partially prevented the sympathoinhibitory response to i.v. sodium loading. These studies reveal a brain Gαi(2)-subunit protein-mediated (renin-angiotensin system-independent) sympathoinhibitory pathway that has a critical role in the central neural mechanisms activated to maintain fluid and electrolyte homeostasis.

High dietary sodium intake impairs endothelium-dependent dilation in healthy salt-resistant humans

Excess dietary sodium has been linked to the development of hypertension and other cardiovascular diseases. In humans, the effects of sodium consumption on endothelial function have not been separated from the effects on blood pressure. The present study was designed to determine if dietary sodium intake affected endothelium-dependent dilation (EDD) independently of changes in blood pressure. Fourteen healthy salt-resistant adults were studied (9M, 5F; age 33 ± 2.4 years) in a controlled feeding study. After a baseline run-in diet, participants were randomized to a 7-day high-sodium (300-350 mmol/day) and 7-day low-sodium (20 mmol/day) diet. Salt resistance, defined as a 5 mmHg or less change in a 24-h mean arterial pressure, was individually assessed while on the low-sodium and high-sodium diets and confirmed in the participants undergoing study (low-sodium: 85 ± 1 mmHg; high-sodium: 85 ± 2 mmHg). EDD was determined in each participant via brachial artery flow-mediated dilation on the last day of each diet. Sodium excretion increased during the high-sodium diet (P < 0.01). EDD was reduced on the high-sodium diet (low: 10.3 ± 0.9%, high: 7.3 ± 0.7%; P < 0.05). The high-sodium diet significantly suppressed plasma renin activity (PRA), plasma angiotensin II, and aldosterone (P < 0.05). These data demonstrate that excess salt intake in humans impairs endothelium-dependent dilation independently of changes in blood pressure.

Central Nervous System Gαi 2 -Subunit Proteins Maintain Salt Resistance via a Renal Nerve–Dependent Sympathoinhibitory Pathway

In salt-resistant phenotypes, chronic elevated dietary sodium intake evokes suppression of renal sodium-retaining mechanisms to maintain sodium homeostasis and normotension. We have recently shown that brain Gαi 2 protein pathways are required to suppress renal sympathetic nerve activity and facilitate maximal sodium excretion during acute intravenous volume expansion in Sprague-Dawley rats. Here, we studied the role of brain Gαi 2 proteins in the endogenous central neural mechanisms acting to maintain fluid and electrolyte homeostasis and normotension during a chronic elevation in dietary salt intake. Naive or bilaterally renal denervated adult male Sprague-Dawley rats were randomly assigned to receive an intracerebroventricular scrambled or Gαi 2 oligodeoxynucleotide infusion and then subjected to either a normal salt (0.4%) or high-salt (8.0%) diet for 21 days. In scrambled oligodeoxynucleotide-infused rats, salt loading, which did not alter blood pressure, evoked a site-specific increase in hypothalamic paraventricular nucleus Gαi 2 protein levels and suppression of circulating norepinephrine content and plasma renin activity. In salt-loaded rats continuously infused intracerebroventricularly with a Gαi 2 oligodeoxynucleotide, animals exhibited sodium and water retention, elevated plasma norepinephrine levels, and hypertension, despite suppression of plasma renin activity. Furthermore, in salt-loaded bilaterally renal denervated rats, Gαi 2 oligodeoxynucleotide infusion failed to evoke salt-sensitive hypertension. Therefore, in salt-resistant rats subjected to a chronic high-salt diet, brain Gαi 2 proteins are required to inhibit central sympathetic outflow to the kidneys and maintain sodium balance and normotension. In conclusion, these data demonstrate a central role of endogenous brain, likely paraventricular nucleus-specific, Gαi 2 -subunit protein–gated signal transduction pathways in maintaining a salt-resistant phenotype.

Pharmacokinetics, Pharmacodynamics, and Tolerability of ACT-077825, a New Direct Renin Inhibitor After Multiple-ascending Doses in Healthy Subjects

This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCτ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin concentration and plasma renin activity (PRA). ACT-077825 dose dependently increased active renin on days 1 and 7 and inhibited PRA dose dependently only on day 1. On day 7, the maximal PRA inhibition was attained after 250 mg of ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared with placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000-mg group and a dose of 500 mg of ACT-077825 was identified as the maximum tolerated dose. Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in patients with hypertension.

Development And Validation of An Ultra-Sensitive Method For The Measurement of Plasma Renin Activity in Human Plasma Via Lc–MS/MS

Renin catalyzes the conversion of angiotensinogen to angiotensin I (Ang I), the first and rate-limiting step in the renin-angiotensin-aldosterone system. Plasma renin activity (PRA) is an important target engagement biomarker in the clinical development of renin inhibitors. We have developed and validated an improved PRA assay that incorporates an Ang I trapping antibody followed by extraction and quantification of Ang I using a highly sensitive and specific LC-MS/MS method. The following assay performance characteristics were assessed as part of analytical validation: precision, LOQ, spike recovery, dilution linearity, stability, absolute recovery and biological variability. The assay demonstrated excellent performance characteristics. Notably, the sensitivity of the assay was increased 140-fold when compared with a previous enzyme immunoassay-based assay. The improved sensitivity allowed the measurement of >95% PRA inhibition from baseline levels. In addition, we compared the LC-MS/MS-based assay to an enzyme immunoassay-based assay.

Severe hypercalcemic hyperparathyroidism developing in a patient with hyperaldosteronism and renal resistance to parathyroid hormone

We evaluated an African American woman referred in 1986 at age 33 years because of renal potassium and calcium wasting and chronic hip pain. She presented normotensive, hypokalemic, hypocalcemic, normophosphatemic, and hypercalciuric. Marked hyperparathyroidism was evident. Urinary cyclic adenosine monophosphate (cAMP) excretion did not increase in response to parathyroid hormone (PTH) infusion, indicating renal resistance to PTH. X-rays and bone biopsy revealed severe osteitis fibrosa cystica, confirming skeletal responsiveness to PTH. Renal potassium wasting, suppressed plasma renin activity, and elevated plasma and urinary aldosterone levels accompanied her hypokalemia, suggesting primary hyperaldosteronism. Hypokalemia resolved with spironolactone and, when combined with dietary sodium restriction, urinary calcium excretion fell and hypocalcemia improved, in accord with the known positive association between sodium intake and calcium excretion. Calcitriol and oral calcium supplements did not suppress the chronic hyperparathyroidism nor did they reduce aldosterone levels. Over time, hyperparathyroid bone disease progressed with pathologic fractures and persistent pain. In 2004, PTH levels increased further in association with worsening chronic kidney disease. Eventually hypercalcemia and hypertension developed. Localizing studies in 2005 suggested a left inferior parathyroid tumor. After having consistently declined, the patient finally agreed to neck exploration in January 2009. Four hyperplastic parathyroid glands were removed, followed immediately by severe hypocalcemia, attributed to "hungry bone syndrome" and hypoparathyroidism, which required prolonged hospitalization, calcium infusions, and oral calcitriol. Although her bone pain resolved, hyperaldosteronism persisted.

Clinical Characteristics of a Cohort of 244 Patients with Congenital Adrenal Hyperplasia

Patients with congenital adrenal hyperplasia (CAH) often suffer from long-term complications secondary to chronic glucocorticoid therapy and suboptimal treatment regimens. The aim of the study was to describe clinical characteristics of a large cohort of pediatric and adult CAH patients. We conducted a cross-sectional study of 244 CAH patients [183 classic, 61 nonclassic (NC)] included in a Natural History Study at the National Institutes of Health. Outcome variables of interest were height sd score, obesity, hypertensive blood pressure (BP), insulin resistance, metabolic syndrome, bone mineral density, hirsutism (females), and testicular adrenal rest (TART). The majority had elevated or suppressed androgens, with varied treatment regimens. Mean adult height SD score was -1.0 ± 1.1 for classic vs. -0.4 ± 0.9 for NC patients (P = 0.015). Obesity was present in approximately one third of patients, across phenotypes. Elevated BP was more common in classic than NC patients (P ≤ 0.01); pediatric hypertensive BP was associated with suppressed plasma renin activity (P = 0.001). Insulin resistance was common in classic children (27%) and adults (38% classic, 20% NC); 18% of adults had metabolic syndrome. The majority (61%) had low vitamin D; 37% of adults had low bone mineral density. Hirsutism was common (32% classic; 59% NC women). TART was found in classic males (33% boys; 44% men). Poor hormonal control and adverse outcomes are common in CAH, necessitating new treatments. Routine monitoring of classic children should include measuring BP and plasma renin activity. Osteoporosis prophylaxis and TART screening should begin during childhood. A longitudinal study is under way.

Primary Aldosteronism in a Patient Who Exhibited Heart Failure

Primary aldosteronism (PA) is a common cause of secondary hypertension due to unilateral adrenocortical adenoma (APA) or idiopathic hyperplasia. There is increased awareness of the possible cardiac sequelae of aldosterone excess, including cardiac hypertrophy, fibrosis, and vascular endothelium injury. A 54-year-old woman was referred for rest and nighttime worsening dyspnea and palpitations. One year earlier she was admitted to another hospital with the same symptoms and discharged with a diagnosis of idiopathic dilated cardiomiopathy. At admission, physical examination revealed a body mass index of 21 kg ⁄m and blood pressure (BP) of 210 ⁄105 mm Hg. Chest auscultation revealed mild expiratory wheezes and rales in both lower lobes. Electrocardiography showed signs of left ventricular (LV) overloading and hypertrophy. Laboratory analysis showed severe hypokalemia (1.8 mEq ⁄L; normal range 3.5–5 mEq ⁄L) and metabolic alkalosis (pH 7.51; partial pressure of carbon dioxide 41 mm Hg; partial pressure of oxygen 86 mm Hg; HCO 3 32.6 mmol ⁄L; excess bases 10 mmol ⁄L) (Table I). Chest radiography revealed an enlarged cardiac silhouette, congested pulmonary hilum, and bilateral pleural effusion (Figure 1A). Echocardiography showed an increase in LV end-diastolic diameter (58 mm) and left atrial volume (46 mm) and a signficant decrease in global LV performance (ejection fraction [EF] 30%) (Table II). The 24hour ambulatory BP monitoring (ABPM) revealed severe systo-diastolic hypertension without physiological nocturnal fall (nondipper pattern). Subsequent investigation showed suppressed plasma renin activity (PRA) (0.08 ng ⁄mL ⁄h; normal range 0.2–2.7 ng ⁄mL ⁄h), high plasma aldosterone (PAC 16.17 ng ⁄dL; normal range 7.5–15 ng ⁄dL), and PAC ⁄ PRA ratio (202.17 ng ⁄dL: ng ⁄ml ⁄h; normal value<30 ng ⁄dL: ng ⁄mL ⁄h). Because of suspicion of PA, we performed a captopril test. After 60 minutes of captopril 50 mg, the PAC ⁄PRA ratio was still elevated (529.93 ng ⁄dL: ng ⁄mL ⁄h). Magnetic resonance imaging of the superior abdomen demonstrated a 20-mm nodule in the left adrenal gland (Figure 2). The patient underwent laparoscopy adrenalectomy, and histopathology revealed an APA. Subsequently, her BP was normalized at 140 ⁄90 mm Hg with amlodipine, ramipril, and serum potassium. After 6 months of follow-up, BP was 110 ⁄80 mm Hg, with normal serum potassium. Chest radiography showed resolution of congestive heart pulmonary imaging with a decreased cardiac silhouette (Figure 1B). Repeat echocardiography demonstrated a significant improvement in LV hypertrophy and EF (50%). Recently, the Primary Aldosteronism Prevalence in Italy Study (PAPY) reported a PA prevalence of 11.2% in patients with new-onset hypertension. The potential comorbidity and prevention of excessive cardiovascular events and organ damage led to development of accurate strategies for diagnosis of PA. PA patients display an unfavorable cardiovascular profile, suggesting a role of aldosterone beyond its well-known hypertensive effects. TABLE I. Laboratory Data and Blood Gas Analysis

Pharmacokinetics and Pharmacodynamics of Aliskiren/Hydrochlorothiazide Single‐Pill Combination Tablets and Free Combination of Aliskiren and Hydrochlorothiazide

Single-pill combinations (SPCs) of complementary antihypertensive agents provide patients with a simple and effective treatment regimen. To ensure that the efficacy and safety of an SPC is the same as that for the individual drugs administered together (free combination), SPC and free-combination formulations must be shown to be bioequivalent. Three open-label, randomized studies compared the pharmacokinetics of SPC tablets of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT), at doses of 150/25, 300/12.5, and 300/25 mg, with the corresponding free combinations in healthy volunteers. Data from 2 randomized, double-blinded studies of patients with hypertension were used to assess inhibition of plasma renin activity (PRA) by the aliskiren/HCT 300/25 mg SPC and the free combination. At all dose combinations, aliskiren and HCT systemic drug exposure was similar when administered as an SPC or free combination, indicating bioequivalence. Aliskiren/HCT 300/25 mg SPC inhibited PRA to the same extent as the free combination. HCT alone increased PRA through activation of the renin-angiotensin system; aliskiren prevented this diuretic-induced increase to the same extent when administered as the free combination or as the SPC. In conclusion, aliskiren/HCT SPCs are pharmacokinetically and pharmacodynamically bioequivalent to aliskiren and HCT in free combination.

A Case of Primary Aldosteronism Accompanied by Hypokalemic Rhabdomyolysis

Primary aldosteronism is characterized by hypertension, hypokalemia, and metabolic alkalosis, associated with excessive aldosterone production and suppressed plasma renin activity. Hypokalemia-induced rhabdomyolysis has been rarely reported in primary aldosteronism patients. This paper reports a case of primary aldosteronism presented with rhabdomyolysis due to severe hypokalemia. A 48-year-old male with a threeyear history of hypertension presented himself at the authors’ hospital with generalized weakness and myalgia in both legs over a period of several days. His laboratory findings showed hypokalemia (1.8 mEq/L) with elevations of his serum creatine phosphokinase and serum myoglobin. His plasma aldosterone level was also elevated, and his plasma renin activity was reduced. An abdominal computed tomography revealed a 2.0 cm hypodense mass in the left adrenal gland, which suggested adrenal adenoma. The accordingly underwent laparoscopic adrenalectomy. Three months later, his plasma potassium level and blood pressure became normal without the use of medications.

Augmented intratubular renin and prorenin expression in the medullary collecting ducts of the kidney as a novel mechanism of angiotensin II-induced hypertension

Augmented intratubular renin and prorenin expression in the medullary collecting ducts of the kidney as a novel mechanism of angiotensin II-induced hypertension