Apparent Mineralocorticoid Excess Research Articles

A Rare Case of Apparent Mineralocorticoid Excess Presenting as Endocrine Hypertension

A 3-year-old boy presented with polyuria and polydipsia for 18 months, along with growth failure. He was born prematurely, at 34 weeks of gestation, with a low birth weight. On examination, the child was severely underweight and hypertensive. Clinical history and evaluation could not identify any secondary causes of hypertension. There was no significant family history. An endocrine workup was planned, considering hypokalemia and metabolic alkalosis. This demonstrated hyporeninemic hypoaldosteronism and raised the possibility of apparent mineralocorticoid excess (AME) and Liddle syndrome. Clinical exome sequence analysis of HSD11B2 revealed a homozygous mutation in exon 5 (911A>G; p.His304Arg), which resulted in a missense mutation that confirmed the diagnosis of AME. A novel homozygous variant was found in the HSD11B2 gene in a subject with early onset hypertension associated with hypokalemic metabolic alkalosis, establishing the diagnosis of AME.

Syndrome of imaginary excess of mineralocorticoids: a clinical case

The syndrome of apparent mineralocorticoid excess (AME) is a rare genetic disease characterized by juvenile hypertension, hypokalemia, suppression of renin and aldosterone. AME syndrome is caused by a mutation in the HSD11B2 gene, which encodes 11ß-hydroxysteroid dehydrogenase type 2, that converts cortisol into cortisone.The purpose of the article is to describe a clinical case of genetically confirmed (mutation C.911A>G of the HSD11B2 gene) AME syndrome. The disease manifested in the first years of life; the patient was prescribed mineralocorticoid receptor antagonists, potassium preparations, potassium-sparing diuretics, and other antihypertensive therapy. Due to the absence of normotonia and normokalemia, dexamethasone has been prescribed since the age of 12. Due to uncontrolled arterial hypertension and hypokalemia, complications developed (medullary nephrocalcinosis, myocardial remodeling), and prolonged dexamethasone intake led to a slowdown in puberty and a decrease in bone mineral density.

Apparent mineralocorticoid excess in Israel: a case series and literature review.

Apparent mineralocorticoid excess (AME) syndrome is an ultra-rare autosomal-recessive tubulopathy, caused by mutations in HSD11B2, leading to excessive activation of the kidney mineralocorticoid receptor, and characterized by early-onset low-renin hypertension, hypokalemia, and risk of chronic kidney disease (CKD). To date, most reports included few patients, and none described patients from Israel. We aimed to describe AME patients from Israel and to review the relevant literature. Retrospective cohort study. Clinical, laboratory, and molecular data from patients' records were collected. Five patients presented at early childhood with normal estimated glomerular filtration rate (eGFR), while 2 patients presented during late childhood with CKD. Molecular analysis revealed 2 novel homozygous mutations in HSD11B2. All patients presented with severe hypertension and hypokalemia. While all patients developed nephrocalcinosis, only 1 showed hypercalciuria. All individuals were managed with potassium supplements, mineralocorticoid receptor antagonists, and various antihypertensive medications. One patient survived cardiac arrest secondary to severe hyperkalemia. At last follow-up, those 5 patients who presented early exhibited normal eGFR and near-normal blood pressure, but 2 have hypertension complications. The 2 patients who presented with CKD progressed to end-stage kidney disease (ESKD) necessitating dialysis and kidney transplantation. In this 11-year follow-up report of 2 Israeli families with AME, patients who presented early maintained long-term normal kidney function, while those who presented late progressed to ESKD. Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment.

A case of chronic licorice intoxication-induced apparent mineralocorticoid excess syndrome

Licorice is a perennial herb belonging to the legume family that mainly grows in northeastern China, Mongolia, Siberia, and other regions. It is used in traditional medicine in the form of dried roots in the East and the West. The main active component of licorice, glycyrrhizin, is known to produce mineralocorticoid effects when consumed chronically, which can lead to apparent mineralocorticoid excess syndrome. Herein, we present the case of a 72-year-old woman who was admitted to the emergency room with severe generalized weakness and difficulty keeping her neck upright, which had developed after daily consumption of licorice-infused water for the past 2 months. Blood tests revealed metabolic alkalosis and severe hypokalemia, and an electrocardiogram showed ventricular bigeminy. The patient was treated with daily potassium and spironolactone supplements, leading to a significant improvement in muscle strength after a week. One week later, the patient was discharged, showing rare ventricular premature contractions on electrocardiography, but with no specific complaints. Chronic licorice ingestion leading to hypokalemia and muscle weakness can be life-threatening, necessitating the discontinuation of the causative agent, close monitoring, and cautious supplementation of potassium and spironolactone as treatment.

Therapeutic management of congenital forms of endocrine hypertension.

Congenital forms of endocrine hypertension are rare and potentially life-threatening disorders, primarily caused by genetic defects affecting adrenal steroid synthesis and activation pathways. These conditions exhibit diverse clinical manifestations, which can be distinguished by their unique molecular mechanisms and steroid profiles. Timely diagnosis and customized management approach are crucial to mitigate unfavorable outcomes associated with uncontrolled hypertension and other related conditions. Treatment options for these disorders depend on the distinct underlying pathophysiology, which involves specific pharmacological therapies or surgical adrenalectomy in some instances. This review article summarizes the current state of knowledge on the therapeutic management of congenital forms of endocrine hypertension, focusing on familial hyperaldosteronism, congenital adrenal hyperplasia, apparent mineralocorticoid excess, and Liddle syndrome. We provide an overview of the genetic and molecular pathogenesis underlying each disorder, describe the clinical features, and discuss the various therapeutic approaches available and their risk of adverse effects, aiming to improve outcomes in patients with these rare and complex conditions.

FRI159 Syndrome of Apparent Mineralocorticoid Excess (AME) from Licorice Tea

Abstract Disclosure: P.C. Lambert: None. We report a patient who had Syndrome of Apparent Mineralocorticoid Excess (AME) from licorice tea. Pt is a 65 y/o man with past medical history of HLD, HTN who presented to clinic for routine follow up. BMP was normal. Six months later patient reported diarrhea, bloating and gas after visiting family. To alleviate symptoms, he tried apple cider vinegar, herbal teas and stopped coffee and caffeinated drinks. His BP was 162/92. BMP showed Na 145, K 3.1, CO 37 and 20 meq of potassium daily was started. Follow up in 5/2020 found persistent elevated BP of 160/102 with elevated BP on home monitor and leg edema. Lisinopril-HCTZ was changed to amlodipine 5 mg. BMP showed Na 146, K 2.2, CO 44. Potassium was increased to 40 meq bid. Two weeks later BP was 160/90. Amlodipine was increased to 10 mg daily. He reported resolution of his edema. BMP showed Na 131, K 3.1, CO 33. At this point, the renin/aldosterone axis was tested with aldosterone <1.0 ng/dL and PRA <0.167 ng/mL/hr. On subsequent discussion it was found pt was taking black licorice tea. After cessation, pt’s BP improved and pt was gradually titrated off potassium supplements and blood pressure meds entirely. Repeat lab testing on 6/2020 found aldosterone 2.4 ng/dL, PRA 0.455 ng/mL/hr, Na 142, K 4.8, CO 31. On return to clinic on 8/2020 BP was 124/72 off medication. His labs were Na 143, K 4.1, CO 30. Syndrome of Apparent Mineralocorticoid Excess (AME) is caused by a deficiency in the 11-beta-hydroxysteroid dehydrogenase enzyme type 2 isoform (11-beta-HSD2). The enzyme converts cortisol to cortisone which cannot bind to the mineralocorticoid receptor. Deficiency of this enzyme will lead to more cortisol binding to the mineralocorticoid receptor which binds just as avidly as aldosterone. This leads to increased mineralocorticoid activity without increased aldosterone. Causes of AME can be genetic or induced by the steroid glycyrrhetinic acid, in licorice, that inhibits 11-beta-HSD2. Licorice candy in the USA generally does not have licorice root. It can be found in many sources including chewing tobacco and flavored chewing gum besides tea. Pt can take as low as 50 g daily of confectionery licorice for two weeks to produce elevated blood pressure. Patients will present with hypokalemia hypertension, metabolic alkalosis, low plasma renin activity and low plasma aldosterone levels. Urinary free cortisone and cortisol levels can assist with diagnosis but as in this case review of history was enough to diagnose and treat the patient. Presentation Date: Friday, June 16, 2023

THU599 Serum And Urinary Free Cortisone As Novel Predictor Of Low-renin Arterial Hypertension

Abstract Disclosure: A. Tapia-Castillo: None. J. Perez: None. A. Sandoval: None. F. Allende: None. S. Solari: None. C.E. Fardella: None. C. Carvajal: None. A large proportion of low-renin hypertensive (LRH) patients correspond to primary aldosteronism (PA) caused by excessive MR activation mediated by excess of aldosterone. However, some of these LRH patients have low to normal serum aldosterone levels, where is thought the MR activation is aldosterone-independent and more likely due to glucocorticoid-mediated MR activation, as occurs in the nonclassical apparent mineralocorticoid excess (NCAME), which is characterized by high cortisol/cortisone ratio and low cortisone, affecting not only blood pressure (BP) control and urinary potassium excretion but also causing cardiac and renal damage, endothelial dysfunction and subclinical inflammation. Objective: To evaluate cortisone as a predictor of LRH and its association with parameters of kidney and vascular damage. Design: A cross-sectional study was carried out in 206 adult subjects. The subjects were classified according to low-renin phenotype (plasma renin activity (PRA) <1ng/ml*h) and low serum cortisone (<p25th). We measured clinical, biochemical, renal and vascular parameters. Statistical analyses as group comparisons were performed by Mann Whitney, and discriminatory analyses by ROC curves. Results: We identified 43% of subjects with low-renin phenotype. PRA was associated with serum aldosterone (r=0.36; p<0.001) and serum cortisone (r=0.22; p=0.001). A binary logistic regression analysis shows that cortisone predicts low-renin phenotype (OR=0.4 [95% CI, 0.21 – 0.78]). The ROC curves show an AUC for serum cortisone was 0.62 (95% CI: 0.54 to 0.69; p = 0.004) and urinary cortisone 0.6 (95% CI: 0.52 to 0.67; p = 0.02) to discriminate subjects with low-renin from controls. Subjects with low serum cortisone showed a higher albuminuria, PAI-1 and lower sodium renal excretion. Urinary free cortisone was also associated to blood pressure and serum potassium (p<0.05). Conclusion: These findings highlight the concept that the low-renin phenotype is dictated not only by serum aldosterone levels but also by low cortisone, suggesting it should be considered in endocrine arterial hypertension screening, complementary in the diagnosis of primary aldosteronism since it could generate false positives in the calculation of the aldosterone to renin ratio. Moreover, our study suggests that low cortisone levels could be associated with future occurrence of vascular and kidney damage. Presentation: Thursday, June 15, 2023

A Case of Liquorice-Infused Marijuana Causing Syndrome of Apparent Mineralocorticoid Excess.

First report of liquorice-laced marijuana causing syndrome of apparent mineralocorticoid excess (SAME).Since its legalisation, marijuana is reported to be the most used substance second only to alcohol. With the increased availability of marijuana, the health care providers and consumers must be cognisant of its side effects.It is a dose-dependent phenomenon. The effects vary from minor clinical symptoms to fatal arrhythmias based on the amount consumed.

Hereditary forms of apparent mineralocorticoid excess (AME): Report of a further case and literature review

The syndrme of apparent mineralocorticoid excess (AME) is an extremly. rare autosomal recessive disorder. To date, more than 100 reported cases in the medical literature world-wide. It is caused by an impairment in the enzym 11-b-hydroxy steroid dehydrogenase (11-b-HSD) enzyme type 2, characterized by early onset hypertension, hypokalemia, metabolic alkalosis, low levels of seum renin and aldosterone. The majority of patients are usually have a low birth weight and failure to thrive (FTT). Nephrocalcinosis could be present. We describe an 11.5 year old girl, who presented in early infancy with poor growth, and not until a gene study done recently, which revealed a homozygous pathogenic variant in the HSD 11B2 gene c. 622 C >Tp. (Arg208 Cys ). This is consistent with the diagnosis of AME This emphasizes the importance of genetic testing in the diagnosis of AME. A high index of suspicion required in managing such patients. Increased awarness among health care professionals is needed to avoid potential health hazards.

Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study

AbstractHistorically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD. We demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy.

Clinical case of apparent mineralocorticoid excess

Clinical case of apparent mineralocorticoid excess

Urinary extracellular vesicles carry valuable hints through mRNA for the understanding of endocrine hypertension.

Urinary extracellular vesicles (uEVs), released from cells of the urogenital tract organs, carry precious information about originating tissues. The study of molecules transported through uEVs such as proteins, lipids and nucleic acids provides a deeper understanding of the function of the kidney, an organ involved in the pathogenesis of hypertension and a target of hypertension-mediated organ damage. Molecules derived from uEVs are often proposed for the study of disease pathophysiology or as possible disease diagnostic and prognostic biomarkers. Analysis of mRNA loading within uEVs may be a unique and readily obtainable way to assess gene expression patterns of renal cells, otherwise achievable only by an invasive biopsy procedure. Interestingly, the only few studies investigating transcriptomics of hypertension-related genes through the analysis of mRNA from uEVs are inherent to mineralocorticoid hypertension. More specifically, it has been observed that perturbation in human endocrine signalling through mineralcorticoid receptors (MR) activation parallels changes of mRNA transcripts in urine supernatant. Furthermore, an increased copy number of uEVs-extracted mRNA transcripts of the 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene were detected among subjects affected by apparent mineralocorticoid excess (AME), a hypertension-inducing autosomal recessive disorder due to a defective enzyme function. Moreover, by studying uEVs mRNA, it was observed that the renal sodium chloride cotransporter (NCC) gene expression is modulated under different conditions related to hypertension. Following this perspective, we illustrate here the state of the art and the possible future of uEVs transcriptomics towards a deeper knowledge of hypertension pathophysiology and ultimately more tailored investigational, diagnostic-prognostic approaches.

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

A Severe Case of Hypokalemic Metabolic Alkalosis: A Quiz

In vitro methods to assess 11β-hydroxysteroid dehydrogenase type 2 activity.

11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts active 11β-hydroxyglucocorticoids to their inactive 11-keto forms, fine-tuning the activation of mineralocorticoid and glucocorticoid receptors. 11β-HSD2 is expressed in mineralocorticoid target tissues such as renal distal tubules and cortical collecting ducts, and distal colon, but also in placenta where it acts as a barrier to reduce the amount of maternal glucocorticoids that reach the fetus. Disruption of 11β-HSD2 activity by genetic defects or inhibitors causes the syndrome of apparent mineralocorticoid excess (AME), characterized by hypernatremia, hypokalemia and hypertension. Secondary hypertension due to 11β-HSD2 inhibition has been observed upon consumption of excessive amounts of licorice and in patients treated with the azole fungicides posaconazole and itraconazole. Furthermore, inhibition of 11β-HSD2 during pregnancy with elevated exposure of the fetus to cortisol can cause neurological complications with a lower intelligence quotient, higher odds of attention deficit and hyperactivity disorder as well as metabolic reprogramming with an increased risk of cardio-metabolic disease in adulthood. This chapter describes in vitro methods for the determination of 11β-HSD2 activity that can be applied to identify inhibitors that may cause secondary hypertension and characterize the enzyme's activity in disease models. The included decision tree and the list of methods with their advantages and disadvantages aim to enable the reader to select and apply an in vitro method suitable for the scientific question and the equipment available in the respective laboratory.

PMON87 A Case of Mineralocorticoid Induced Hypertension Secondary to Cushing's Syndrome

Abstract We present a case of mineralocorticoid induced hypertension secondary to Cushing's syndrome in a hospitalized patient with uncontrolled hypertension and hypokalemia. A 78-year-old female with hypertension, hypothyroidism, and known pituitary (1.6 cm) and left-sided adrenal mass (2.9 cm) since 2012, presented to the hospital with altered mental status and rectal bleeding with hemoglobin of 5.8 g/dL. On arrival, she was afebrile, blood pressure 87/51 mm Hg, pulse 95 bpm, and saturating at 97% on room air. The patient was altered and had bloody stool positive for fecal occult blood test, with the rest of the examination being normal. Her hospital course was complicated by uncontrolled hypertension (on lisinopril and amlodipine) and severe hypokalemia. During her hospital stay, her potassium ranged 2-2.5 mEq/L (3.5-5.1) and she had persistent metabolic alkalosis. Aldosterone <1 ng/dL, plasma renin activity (PRA) 0.38 ng/mL/hr and aldosterone/PRA ratio 2.6 (0.9-28.9). Thyroid function: TSH 0.709 uIU/mL (0.30-5.00), free T4 1.4 ng/dL (0.7-1.7). Catecholamines were not significantly elevated: free metanephrines <25 pg/mL (<57), normetanephrines 158 pg/mL (<148). Further investigation revealed severe hypercortisolism: 24-hour urinary free cortisol 422 mcg/24 hours, cortisol AM 29.2 mcg/dL (3.7-19.4), and cortisol 31 mcg/dL with 1 mg dexamethasone suppression test. Late-night salivary cortisol was not obtained. ACTH was 138 pg/mL (9-46) and cortisol level after 8 mg dexamethasone suppression test was elevated at 17.2 ug/dL. MRI brain showed a pituitary macroadenoma sized 1.6×1.4×1.1 cm, stable since 2012. CT abdomen showed a left adrenal nodule measuring 2.3×3.3×2.8 cm. Further workup revealed free testosterone 10.6 pg/mL(0.2-3.7), total testosterone 22 ng/dL (2-45), DHEA-Sulfate 533 mcg/dL (45-430), IGF-1 81 ng/mL(34-245), Human growth hormone 0.2 ng/mL (<10), FSH 0.3 mIU/mL, LH 0.1 mIU/mL, prolactin 18.9 ng/mL(0-29), and deoxycorticosterone <16 ng/dL (<16). Given the patient's clinical presentation (rectal bleeding, altered mental status) with associated laboratory abnormalities, the plausible explanation for her hypertension and hypokalemia was ACTH-mediated hypercortisolism resulting in increased mineralocorticoid activity. Other possible etiologies considered were syndrome of apparent mineralocorticoid excess, Liddle's syndrome, deoxycorticosterone tumors, and exogenous intake of steroids. The patient was started on spironolactone and amiloride, both blood pressure and potassium levels improved. A decision was made to proceed with inferior petrosal sinus sampling, to determine the exact source of ACTH, however, prior to completion patient developed COVID pneumonia and expired. Our case highlights the importance of considering hypercortisolism in patients presenting with hypertension, hypokalemia, and metabolic alkalosis with suppressed aldosterone and renin levels. Furthermore, Cushing's syndrome should be a consideration even in the absence of classic cushingoid features as in this patient. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP442 Posaconazole-induced Pseudohyperaldosteronism (PIPH) in Patient Treated for Acute Myeloid Leukemia

Abstract Case summary A 62-year-old Caucasian female presented to our institute with mechanical fall complicated by cervical spine fracture. She had known history of essential hypertension and recently diagnosed acute myeloid leukemia with myelodysplasia related changes (AML-MRC). She had undergone induction chemotherapy with combination of daunorubicin and cytarabine, resulting in chemotherapy induced prolonged pancytopenia. She was initially started on primary prophylaxis with fluconazole, but was switched to voriconazole due to persistent neutropenia. Patient then developed bilateral upper and lower extremity erythematous popular rash on voriconazole. Decision at that time was to switch to Posaconazole 300 mg orally daily. Three months after initiating Posaconazole, patient presented with severe hypokalemia (2.1 mmol/L) and hypertension. Previously her blood pressure was under control with amlodipine, lisinopril and nadolol. Hypokalemia persisted despite aggressive oral and intermittent intravenous potassium replacement therapy. No sources of potassium loss were identified on clinical history. She had persistently elevated blood pressure (systolic blood pressure of 150-180 mmHg) despite being on her home anti-hypertensive regimen. Further work up showed undetectable plasma aldosterone of less than 1 ng/dL (normal < 28 ng/dL) and plasma renin activity level was suppressed to 0.14 ng/mL/h (normal 0.25–5.82 ng/mL/h) with concurrent potassium of 2.9 mmol/L (normal 3.5-5.3 mmol/l). Diagnosis of pseudohyperaldosteronism was made at this time. Posaconazole gradually stopped and eplerenone 25 mg daily was commenced to selectively block mineralocorticoids receptors to control blood pressure. Subsequently hypokalemia resolved after stopping posaconazole and blood pressure normalized with her original home anti-hypertensive regimen. Eplerenone was eventually stopped. Her potassium level and blood pressure remained normal 2 weeks after discharge. Discussion Recent studies have shown the presentation of hypokalemia and hypertension in nearly a quarter of patients on Posaconazole. The clinical presentation of hypokalemia and hypertension with apparent mineralocorticoid excess was evident in our patient and was consistent with posaconazole-induced pseudohyperaldosteronism (PIPH). Posaconazole interference with the steroid synthesis pathway has been described in various literature. Both cortisol and aldosterone activate aldosterone receptors. In the case of posaconazole, excess mineralocorticoid effect is due to relative selectivity of posaconazole for 11ΒHSD2 inhibition. 11ΒHSD2 inhibition causes increased serum cortisol level by preventing the conversion to inactive cortisone. The high cortisol level cross-reacts with the mineralocorticoid receptor leading to apparent mineralocorticoid excess with low serum aldosterone level and low plasma renin activity. The degree of pseudohyperaldosterone effect on systolic blood pressure and hypokalemia has been strongly associated with serum posaconazole level in some studies. Our patient had resolution of uncontrolled hypertension and hypokalemia after withholding the posaconazole and short term treatment with selective mineralocorticoid receptor blocker. Conclusion Early diagnosis and to allow for early intervention with cessation of the offending agent or treatment with mineralocorticoid antagonists, such as spironolactone and eplerenone is necessary in PIPH. Presentation: No date and time listed

Clinical, biochemical, and miRNA profile of subjects with positive screening of primary aldosteronism and nonclassic apparent mineralocorticoid excess.

To identify and characterize clinical and biochemical parameters of subjects with both PA and NCAME conditions (NCAME&PA) and study the miRNA cargo in their urinary extracellular vesicles as potential biomarkers for this novel condition. We performed a cross-sectional study of 206 Chilean adult subjects from a primary care cohort. We measured blood pressure (BP), cortisol (F), cortisone (E), aldosterone, plasma renin activity (PRA), microalbuminuria (MAC), plasma NGAL, MMP9, fractional-potassium-excretion (FEK). Subjects were classified as NCAME&PA, PA, NCAME, essential hypertensives (EH), or healthy controls (CTL). EV-miRNAs were quantified by Taqman-qPCR. We found that 30.6% subjects had an abnormal endocrine phenotype: NCAME&PA (6.8%), PA (11.2%) or NCAME (12.6%), and the prevalence of AHT was 92.9%, 82.6%, and 65%, respectively. NCAME&PA subjects had both lower cortisone (p < 0.05) and lower PRA (p < 0.0001), higher FEK (p = 0.02) and higher MAC (p = 0.01) than EH or CTL. NCAME&PA subjects had also higher NGAL levels than CTL and PA (p < 0.05). Exosome miR-192, miR-133a and miR-21 expression decreased with phenotype severity and correlated with BP and PRA (p < 0.05). We identified adult subjects with a combined condition of NCAME and PA associated with higher BP, increased renal and endothelial damage markers than control and EH. Additionally, we observed a differential expression of a specific miRNAs, suggesting a potential role of these miRNAs associated to this novel combined phenotype.

Review of the Pathophysiologic and Clinical Aspects of Hypokalemia in Children and Young Adults: an Update.

This article examines the regulatory function of the skeletal muscle, renal, and adrenergic systems in potassium homeostasis. The pathophysiologic bases of hypokalemia, systematic approach for an early diagnosis, and therapeutic strategy to avert life-threatening complications are highlighted. By promoting skeletal muscle uptake, intense physical exercise (post), severe trauma, and several toxins produce profound hypokalemia. Hypovolemia due to renal and extra-renal fluid losses and ineffective circulation activate secondary aldosteronism causing urinary potassium wasting. In addition to hypokalemic alkalosis, primary aldosteronism causes low-renin hypertension. Non-aldosterone mineralocorticoid activation leading to low-renin and low-aldosterone hypertension occurs in Liddle’s syndrome and apparent mineralocorticoid excess. Although there is enzymatic inhibition of cortisol synthesis in congenital adrenal hyperplasia, precursors of aldosterone produce low-renin hypokalemic hypertension. In addition to the glucocorticoid effect, hypercortisolism activates mineralocorticoid receptors in Cushing’s syndrome. Genetic mutations involving furosemide-sensitive Na+-K+-2Cl− co-transporters and thiazide-sensitive Na+-Cl− transporters result in (non-hypertensive) salt-wasting nephropathy. Proximal and distal renal tubular acidosis is associated with hypokalemia. Eating disorders causing hypokalemia include bulimia, laxative abuse, and diuretic misuse. Low urinary potassium (<15 mmol/day) and/or low urinary chloride (<20 mol/L) suggest a gastrointestinal pathology. Co-morbidity of hypokalemia with chronic pulmonary and cardiovascular diseases may increase the fatality rate.

Clinical and HSD11B2 gene analysis of a patient with apparent mineralocorticoid excess

患儿 女，12岁，因“发现血压高、血钾低11年，血压控制不佳1个月”就诊于北京儿童医院内分泌遗传代谢科。经过体格检查、血液电解质、血气分析、醛固酮检测、影像学检查、基因检测等手段，确诊为表观盐皮质增多综合征。表观盐皮质增多综合征是一种罕见的单基因原发性高血压，诊断相对困难。及早基因检测有助于早期诊断和规范治疗方可避免靶器官损伤。.

Interrogation of Novel Aldosterone‐induced Genes Associated With Acute Stimulation Of ENaC In Primary Collecting Duct Cells

Aldosterone (ALDO) is a key volume‐regulating hormone which promotes Na+ reabsorption in the distal nephron. ALDO sensitivity is conferred by the enzyme 11βHSD2 which breaks down the related more abundant steroid, cortisol. Mutations in Hsd11b2 give rise to the syndrome of apparent mineralocorticoid excess, where hypertension is associated with excessive renal Na+ reabsorption. In the distal nephron corticosteroid‐induced Na+ transport, via the epithelial Na+ channel ENaC, is due to transcriptional processes and previous studies have identified key genes including Sgk1. Our lab carried out transcriptomic analysis of mCCDcl1 cells following acute corticosteroid induced ENaC‐mediated Na+ transport, identifying several novel ALDO induced genes. The present study aimed to elucidate the effects of corticosteroids on these target genes in the collecting duct (CD), utilising an in vitro and in vivo approach.A CD‐specific reporter mouse was generated using Aqp2Cre to express eGFP. Primary cells were isolated by FACS and either grown in culture or RNA was extracted immediately. Cells were grown on filter membranes to allow development of polarised monolayers and electrometric properties were assessed using an epithelial volt‐ohm‐meter. Target gene expression was determined by qRT‐PCR.Assessment of nephron segment‐specific gene expression revealed an enrichment of genes encoding α‐ENaC, ROMK and 11βHSD2 but not NHE3 or NKCC2. NCC was detected but parvalbumin was absent, demonstrating isolation of cells from the late distal tubule onwards. In addition to genes associated with principal cells we also detected genes encoding pendrin and AE1, indicative of intercalated cells therefore this population reflects CD cells. When grown in culture for 9‐11 days, these cells exhibited Vt and Rt of ‑20.3±3.1 mV and 5.1 ±0.1 kΩ∙cm2, respectively. This gave rise to an Ieq of ‑3.9±0.6 μA·cm‑2 which was near abolished with 10 µM amiloride – indicating Na+ transport via ENaC.Acute application of steroid hormones to cells for 3h: ALDO (3 nM), DEX (100 nM) and CORT (10 nM) – the latter only when 11βHSD2 activity was inhibited using carbenoxolone (CBX, 10 µM) – stimulated amiloride‐sensitive currents by 2.0‐, 3.6‐ and 2.4‐fold, respectively. Analysis of ALDO‐induced genes revealed both ALDO and CORT upregulated Sgk1, Zbtb16 and Rasd1. ALDO also upregulated Sult1d1 whereas CORT also upregulated an unannotated gene Gm43305. DEX upregulated all of these as well as 2 additional genes previously detected: Defb1 and Gm16178.To determine the relevance of these findings in vivo reporter mice were administered ALDO, vehicle or CORT, by ip injection, the latter under control conditions or following CBX treatment for 8 days. Cells were isolated after 3h. The previously identified Zbtb16, Rasd1, Gm43305 and Sult1d1 were upregulated in both ALDO and CBX+CORT groups, though no change was detected in either Sgk1 or Defb1. Scnn1a was also upregulated in both groups and additionally Per1 and Sult1a1 were upregulated in mice treated with CBX‐CORT.Together these data confirm 4 novel corticosteroid‐induced genes in primary CD cells associated with acute stimulation of ENaC activity.