Plasma Aldosterone Levels Research Articles

Role of aldosterone in various target organ damage in patients with hypertensive emergency: a cross-sectional study

BackgroundHypertensive emergency is a critical disease that causes multiple organ injuries. Although the renin-angiotensin-aldosterone system (RAS) is enormously activated in this disorder, whether the RAS contributes to the development of the organ damage has not been fully elucidated. This cross-sectional study was conducted to characterize the association between RAS and the organ damage in patients with hypertensive emergencies.MethodsWe enrolled 63 patients who visited our medical center with acute severe hypertension and multiple organ damage between 2012 and 2020. Hypertensive target organ damage was evaluated on admission, including severe kidney impairment (eGFR less than 30 mL/min/1.73 m2, SKI), severe retinopathy, concentric left ventricular hypertrophy (c-LVH), thrombotic microangiopathy (TMA), heart failure with reduced ejection fraction (HFrEF) and cerebrovascular disease. Then, whether each organ injury was associated with blood pressure or a plasma aldosterone concentration was analyzed.ResultsAmong 63 patients, 31, 37, 43 and 8 cases manifested SKI, severe retinopathy, c-LVH and ischemic stroke, respectively. All populations with the organ injuries except cerebral infarction had higher plasma aldosterone concentrations than the remaining subset but exhibited a variable difference in systolic or diastolic blood pressure. Twenty-two patients had a triad of SKI, severe retinopathy and c-LVH, among whom 5 patients manifested TMA. Furthermore, the number of the damaged organs was correlated with plasma aldosterone levels (Spearman’s coefficient = 0.50), with a strong association observed between plasma aldosterone (≥ 250 pg/mL) and 3 or more complications (odds ratio = 9.16 [95%CI: 2.76–30.35]).ConclusionIn patients with hypertensive emergencies, a higher aldosterone level not only contributed to the development of the organ damage but also was associated with the number of damaged organs in each patient.

Hipertensão arterial resistente: um desafio diagnóstico

Introduction: Primary hyperaldosteronism is a leading cause of secondary arterial hypertension, affecting approximately 10% to 20% of the hypertensive population worldwide and in Brazil. This condition involves excessive aldosterone production due to factors such as adrenal adenoma, hyperplasia, or, less commonly, adrenal carcinoma and familial hyperaldosteronism. This study reports a case of resistant hypertension secondary to aldosterone-producing adenoma. Clinical Case: A 70-year-old male patient presented with episodes of dizziness, syncope, cramps, and asthenia. His medical history included resistant hypertension for over 30 years, despite treatment with five classes of antihypertensive medications. Additionally, he had a history of dyslipidemia, type 2 diabetes mellitus, non-dialysis chronic renal failure, and obstructive coronary arterydisease. Physical examination showed a BMI of 29 kg/m² (overweight), mean blood pressure of 140/90 mmHg (right arm) and 150/100 mmHg (left arm), and palpable nodules in both thyroid lobes, classified as Bethesda V based on aspiration cytopathology. Subsequently, he underwent total thyroidectomy and lymph node dissection. Laboratory tests revealed high plasma aldosterone levels with suppressed renin and an elevated aldosterone-renin ratio, raising suspicion of primary hyperaldosteronism. This diagnosis was confirmed by a computed tomography scan, which identified a 1.2 cm nodule in the right adrenal gland consistent with an adenoma. The patient underwent unilateral laparoscopic adrenalectomy. Two years post-surgery, the patient’s blood pressure was well-controlled with three antihypertensive medications, and his blood sugar, aldosterone, and renin levels were normal. Discussion and Conclusion: Most patients undergoing unilateral adrenalectomy for aldosterone-producing adenomas experience significant clinical improvement. Early screening and diagnosis of primary hyperaldosteronism are crucial for effective management, reducing the risk of complications in the cardiovascular and renal systems.

Severe hydronephrosis complicated with primary aldosteronism: a case report and review of the literature

BackgroundPrimary aldosteronism is characterized by high plasma aldosterone and low renin. The plasma aldosterone-to-renin ratio is recommended for screening. Severe hydronephrosis leads to renal parenchymal ischemia, resulting in increased renin secretion. Since nonsuppression of renin may cause a negative result in the aldosterone-to-renin ratio test, severe hydronephrosis and primary aldosteronism occurring simultaneously in a patient are challenging to diagnose.Case presentationA 54-year-old Chinese man of Han ethnicity was diagnosed with hypertension and severe hypokalemia (minimum 1.57 mmol/L) 13 years prior, and was also diagnosed with severe hydronephrosis due to congenital ureteral stenosis on the left side. His clinical features suggested primary aldosteronism, but the aldosterone-to-renin ratio result of the patient was negative every time he underwent the primary aldosteronism screening test. No further treatment for primary aldosteronism was performed, which led the patient to suffer from severe hypokalemia, such that he was taking 12–15 g/day potassium chloride orally to keep his blood potassium between 3.0 and 3.5 mmol/L (reference value, 3.5–5.5 mmol/L) for 13 years, and the patient needed to be hospitalized in the intensive care unit for rescue several times. At admission, although the aldosterone-to-renin ratio result of the patient was negative, we still did the saline stress test and captopril inhibition test, and the results showed that the plasma aldosterone level was not lower after the test than before the test. Adrenal enhanced computed tomography suggested an adenoma in the left adrenal gland, and the results of adrenal vein sampling suggested that the left side was the dominant side. Therefore, laparoscopic total resection of the left adrenal gland was performed, and 2 weeks later, the patient developed short-term renal function impairment and hyperkalemia, but his renal function and blood potassium returned to normal after treatment that included fluid rehydration. The patient’s biochemical test results and clinical symptoms were completely normal after 1 year.ConclusionWe suggest that for patients with a high suspicion of primary aldosteronism in the clinic, comprehensive analysis must be performed in combination with clinical characteristic assessments, such as severe hydronephrosis, if renin is within the normal range or if the aldosterone-to-renin ratio result is negative at screening and diagnostic tests, and adrenal vein sampling should be performed if necessary. It can help avoid misdiagnoses and contribute to the treatment of patients with severe hydronephrosis and primary aldosteronism.

7439 Mercury toxicity presenting as Pheochromocytoma

Abstract Disclosure: A. Ansar: None. K. McNerney: None. B.A. Marshall: None. Background: Mercury intoxication is a rare cause of hypertension in children and can mimic other endocrinopathies such as pheochromocytoma. Mercury affects catecholamine metabolism and can cause elevated catecholamine levels, thereby incorrectly suggesting a catecholamine-secreting tumor. Clinical Case: An 8-year-old girl presented to the ED with progressive night sweats, intractable migratory myalgias, hypertension and tachycardia. Patient was in her usual state of health until 2 weeks before presentation when she started to have worsening intermittent pains in her chest, arms, back, and knees. She also experienced restlessness and inability to sleep. On presentation she was hypertensive, with blood pressure of 146/116 mm Hg while calm, heart rate 125 bpm, afebrile. She was anxious, irritable, and seemed uncomfortable. Her skin was dry and rough with a scaly eczematous rash on the arms and legs. She had persistently elevated blood pressure in upper and lower extremities, unremarkable echocardiogram and electrocardiogram, and a normal result on fundoscopic examination. Her initial electrolytes, creatinine, and urinalysis were all normal and remained so on serial evaluations. Urine drug screen was negative. Thyroid function panel showed normal TSH with slightly elevated Free T4 2.28 ng/dL (0.9-1.7), but a normal Free T3 3.9 pg/mL (2.0-4.4) and Free T4 by equilibrium dialysis 1.8 ng/dL (0.8 - 2.0). CT of the chest, abdomen and pelvis was negative and did not show any lesions. Plasma renin activity was 4.6 ng/mL/hour, supine, (<2.0) and plasma aldosterone level < 4.0 ng/dL (< 40 supine) were normal. 24-hour urinary norepinephrine was 90 μg/24h (13-65), epinephrine 37 μg/24h (0.2-10), urine metanephrines 195 μg/24h (18-144), urine normetanephrines 305 μg/24h (29-145), all elevated. Further history taking revealed that patient was taking Ayurvedic supplements prepared by hand by medicinal personnel in India for 3 months prior to presentation. These were stopped 2 weeks prior to her presentation, when she first became symptomatic. Her blood mercury level was 11 ng/mL (n <9), and urinary mercury excretion 67 μg/24 hours (n<10), both obtained 3 weeks after stopping supplementation. She was started on oral chelation therapy with succimer 10 mg/kg/day. Her hypertension was controlled with doxazosin. One week after initiation of therapy, her symptoms improved, and she became normotensive. Her acrodynia and irritability resolved. Urine metanephrine levels will be repeated at upcoming clinic follow up. Conclusion: Mercury toxicity should be considered in the differential of pheochromocytoma to avoid extensive diagnostic testing and morbidity associated with it. Lead, mercury, and arsenic have been detected in traditionally prepared Ayurvedic supplements. A careful history of intake of supplements can be important in cases with unusual symptomatology. Presentation: 6/3/2024

Primary hyperaldosteronism secondary to right adrenal hyperplasia with non-functioning left adrenal adenoma elucidated by adrenal vein sampling: A case report with in-depth physiological review on utility of aldosterone renin ratio.

In cases of primary hyperaldosteronism, the aldosterone renin ratio (ARR) is crucial for determining the need for adrenal vein sampling (AVS). Our case highlights the importance of utilizing ARR with AVS, contextual interpretation of plasma renin and aldosterone levels, and stresses that sole reliance on imaging without AVS may result in unnecessary or contralateral adrenalectomy.

Bilateral adrenal artery embolization for the treatment of idiopathic hyperaldosteronism: A proof-of-principle single center study.

Unilateral adrenal artery embolization (AAE) has emerged as an alternative treatment for patients with primary aldosteronism due to aldosterone-producing adenomas or idiopathic hyperaldosteronism with bilateral adrenal hyperplasia. This study aimed to investigate the effectiveness and safety of bilateral AAE in idiopathic hyperaldosteronism. We enrolled a total of 58 patients with idiopathic hyperaldosteronism who underwent successful bilateral AAE, and 55 of them completed 6-month follow-up. Bilateral AAE significantly lowered blood pressure of patients with IHA at 1, 3, and 6 months (all P < 0.01). Six months after the procedure, office, home, and 24-hour ambulatory blood pressure decreased by 20.3/13.5, 18.4/12.6, and 13.7/9.9 mmHg, respectively. Among them, 92.7%, 90.9%, and 89.1% had significant or moderate improvement in blood pressure control at 1, 3, and 6 months after the procedure. Bilateral AAE substantially decreased plasma aldosterone levels, reversed plasma renin suppression, decreased aldosterone-to-renin ratio, and corrected hypokalemia. Importantly, the procedure did not significantly change serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, and the cortisol and ACTH circadian rhythms remained intact three months after the procedure. Additionally, 16 patients underwent ACTH stimulation tests three months post-procedure and all of them had normal results except for one with a decreased response due to exogenous steroid therapy. Flank pain was the most common side effect which happened in 96.4% of the patients and resolved within 48 h. There were no long-term side effects in the 6 months. The present study provides evidence that bilateral AAE is an effective and safe alternative treatment for patients with IHA. Changes in office and 24h ambulatory blood pressure at 1, 3, and 6 months after bilateral adrenal artery embolization in patients with idiopathic hyperaldosteronism.

3-epi-18β-Glycyrrhetinic Acid or Its Glucuronide, the Metabolites of Glycyrrhizinic Acid with Individual Differences, Correlated with Diagnostic Marker for Licorice-Induced Pseudoaldosteronism in Humans.

Licorice is a crude drug that is used in traditional Japanese Kampo medicine and is also used as a sweetener. Occasionally, it causes pseudoaldosteronism (PsA) as a side effect. The major symptoms include hypokalemia, hypertension, edema, and low plasma aldosterone levels. PsA might be caused by the metabolites of glycyrrhizinic acid (GL), a component of licorice. The development of PsA markedly varies among individuals; however, the factors that cause these individual differences remain unknown. In this study, 78 patients who consumed Kampo medicines containing licorice were enrolled, and their laboratory data, including serum potassium levels, plasma aldosterone concentrations (PAC), and the concentrations of GL metabolites in the residual blood and/or urine samples were evaluated. Of the 78 participants, 18β-glycyrrhetinic acid (GA), 3-epi-GA, 3-oxo-GA, 18β-glycyrrhetinyl-30-O-glucuronide (GA30G), and 3-epi-GA30G were detected in the serum samples of 65, 47, 63, 62, and three participants, respectively. Of the 29 urine samples collected, GA30G and 3-epi-GA30G were detected in 27 and 19 samples. 3-epi-GA30G is a newly found GL metabolite. Moreover, 3-epi-GA, 3-oxo-GA, and 3-epi-GA30G were identified in human samples for the first time. High individual differences were found in the appearances of 3-epi-GA in serum and 3-epi-GA30G in urine, and the concentrations of these metabolites were correlated with serum PsA markers. The inhibitory titers of 3-epi-GA, 3-oxo-GA, GA30G, and 3-epi-GA30G on human 11β-hydroxysteroid dehydrogenase type 2 were almost similar. These findings suggest that 3-epi-GA and/or 3-epi-GA30G are associated with individual differences in the development of PsA. SIGNIFICANCE STATEMENT: In this study, we detected 3-epi-18β-glycyrrhetinic acid (3-epi-GA) in human serum for the first time. We also identified 3-epi-18β-glycyrrhetinyl-30-O-glucuronide (3-epi-GA30G) as a novel glycyrrhizinic acid (GL) metabolite in human urine. These GL metabolite levels showed correlations with markers of PsA. Additionally, there are individual differences in whether they appear in the serum/urine. In conclusion, 3-epi-GA/3-epi-GA30G correlates with individual differences in the development of PsA.

Abstract 37: Targeted Deletion of NKCC1 in Vascular Smooth Muscle Cells Lowers Blood Pressure in Normotensive and Hypertensive Mice

Background: Salt plays a major role in blood pressure homeostasis and the pathogenesis of arterial hypertension. While numerous mechanisms have been described by which Na + can influence arterial blood pressure, the role of Cl - in blood pressure regulation is still largely unexplored. The Na + -K + -2Cl - cotransporter NKCC1 is an important Cl - import pathway in vascular smooth muscle cells (VSMC). To investigate the role of NKCC1 in blood pressure regulation, we generated mice with an inducible VSMC-specific disruption of Slc12a2 . Methods: Mean arterial blood pressure and heart rate were measured by radiotelemetry in unrestrained mice lacking vascular NKCC1 (KO) and wildtype littermates (WT). Cardiac function was assessed by echocardiography. Plasma renin activity and aldosterone concentrations were quantified by radioimmunoassay. Protein expression of renal sodium transporters and channels was analyzed by Western blotting. Results: Mean arterial blood pressure was markedly decreased in Nkcc1 -deficient mice 6 weeks after induction of gene disruption (from 116±2 mm Hg to 103±4 mm Hg, n=18, p&lt;0.001, 2-way ANOVA and Bonferroni post-test), while it did not change in WT control animals (n=17). Heart rate, stroke volume, fractional shortening, and ejection fraction remained unchanged compared to non-induced controls. We did not observe a compensatory increase in plasma renin activity or aldosterone levels, and the blood pressure response to ANG II receptor 1 antagonism by losartan treatment for 7 days was similar in both groups (ΔMAP KO -8.8±3.0 mm Hg, n=8, ΔMAP WT -12.4±1.9 mm Hg, n=7; p&gt;0.05, 2-way ANOVA). In the kidney, the relative expression of total NCC (1.5- fold , n=7-8; p=&lt;0.05, Student’s t-test) and pNCCThr53 (1.9- fold , n=7-8; p=&lt;0.05, Student’s t-test) were modestly increased. The hypotensive effect of Nkcc1 disruption was maintained after induction of hypertension by either infusion of ANG II for 10 days (ΔMAP KO 43.8±6.5 mm Hg, n=6, ΔMAP WT 50.2±7.2 mm Hg, n=4; p&gt;0.05, 2-way ANOVA) or a high salt diet for 10 days (ΔMAP KO 21.7±7.0 mm Hg, n=8, ΔMAP WT 34.0±7.3 mm Hg, n=5; p&gt;0.05, 2-way ANOVA). Conclusions: Our findings indicate that NKCC1 in vascular smooth muscle contributes significantly to the maintenance of arterial blood pressure. Inhibition of NKCC1 in VSMC may provide additional blood pressure reduction in resistant hypertension.

Safety and efficacy of bilateral superselective adrenal arterial embolization for treatment of idiopathic hyperaldosteronism: a prospective single-center study

ObjectiveThis study aimed to assess the efficacy and safety of bilateral superselective adrenal arterial embolization (SAAE) in patients with bilateral idiopathic hyperaldosteronism (IHA), a subtype of PA.MethodsNinety-eight patients with bilateral IHA underwent bilateral SAAE between August 2022 and August 2023. Sixty-eight patients were followed up for up to 12 months. The study outcomes were evaluated using the criteria provided by the Primary Aldosteronism Surgical Outcome (PASO) guidelines.ResultsThe mean reductions in systolic and diastolic blood pressure were 27.4 ± 21.3 mmHg and 23.1 ± 17.4 mmHg, respectively (p < 0.001). The rates of clinical success and biochemical success after adrenal artery ablation were 63.2% (43/68) and 39.7% (27/68), respectively. Overall, there were significant reductions in daily defined doses (DDD), aldosterone/renin ratio (ARR), and plasma aldosterone levels (p < 0.001). Plasma renin levels increased by a mean value of 10.4 ± 39.0 pg/mL (p = 0.049), and potassium levels increased by 0.40 ± 0.63 mmol/L (p < 0.001). No significant adverse events were reported during SAAE or the follow-up period of up to one year. Additionally, no abnormalities were detected by adrenal 68Ga-Pentixafor PET/CT scans before or after SAAE.ConclusionBilateral SAAE appears to lead to sustained improvements in blood pressure and biochemical parameters in patients with bilateral PA, with minimal adverse effects. This suggests that bilateral SAAE could serve as an effective alternative approach for treating bilateral IHA, potentially curing this condition.

Efficacy and safety of adrenal arterial embolization for primary aldosteronism: a systematic review and meta-analysis.

Primary aldosteronism (PA) is related with resistant hypertension and cardiovascular events. Adrenal artery embolization (AAE) is a choice for patients who refused surgery and medical therapy. However, whether AAE can effectively and safely treat PA is unclear. We performed this meta-analysis to determine the efficacy and safety of AAE for patients with PA. Databases including Cochrane Library, Embase, PubMed and Web of Science were used to obtain relevant articles published before July 30, 2023. The primary outcome was blood pressure before and after AAE. The second outcomes included changes in plasma aldosterone level, serum potassium level, and plasma cortisol level. Finally, 7 prospective studies with 222 patients were included. The results showed that systolic and diastolic blood pressure was reduced by 21.68 mmHg (P<0.001) and 10.54 mmHg (P=0.007) respectively after AAE. The change in plasma aldosterone and serum potassium level was -11.52 ng/dL and 0.61 mmol/L respectively (P<0.001), whereas the reduction in cortisol level was not apparent. Moreover, AAE is a relatively safe procedure which only causes some minor complications such as back pain and fever. This meta-analysis indicated that AAE could effectively and safely treat PA. It is a good choice for patients that are not suitable for adrenalectomy or drug therapy.

Myeloid Cell Glucocorticoid, Not Mineralocorticoid Receptor Signaling, Contributes to Salt-Sensitive Hypertension in Humans via Cortisol.

Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality, yet the etiology is poorly understood. We previously found that serum/glucocorticoid-regulated kinase 1 (SGK1) and epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel (ENaC)-dependent sodium entry into monocyte-derived antigen-presenting cells (APCs) and activation of NADPH oxidase, leading to the formation of isolevuglandins (IsoLGs) in SSBP. Whereas aldosterone via the mineralocorticoid receptor (MR) activates SGK1 leading to hypertension, our past findings indicate that levels of plasma aldosterone do not correlate with SSBP, and there is little to no MR expression in APCs. Thus, we hypothesized that cortisol acting via the glucocorticoid receptor (GR), not the MR in APCs mediates SGK1 actions to induce SSBP. We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) analysis on peripheral blood mononuclear cells of humans rigorously phenotyped for SSBP using an inpatient salt loading/depletion protocol to determine expression of MR, GR, and SGK1 in immune cells. In additional experiments, we performed bulk transcriptomic analysis on isolated human monocytes following in vitro treatment with high salt from a separate cohort. We then measured urine and plasma cortisol, cortisone, renin, and aldosterone. Subsequently, we measured the association of these hormones with changes in systolic, diastolic, mean arterial pressure and pulse pressure as well as immune cell activation via IsoLG formation. We found that myeloid APCs predominantly express the GR and SGK1 with no expression of the MR. Expression of the GR in APCs increased after salt loading and decreased with salt depletion in salt-sensitive but not salt-resistant people and was associated with increased expression of SGK1. Moreover, we found that plasma and urine cortisol/cortisone but not aldosterone/renin correlated with SSBP and APCs activation via IsoLGs. We also found that cortisol negatively correlates with EETs. Our findings suggest that renal cortisol signaling via the GR but not the MR in APCs contributes to SSBP via cortisol. Urine and plasma cortisol may provide an important currently unavailable feasible diagnostic tool for SSBP. Moreover, cortisol-GR-SGK1-ENaC signaling pathway may provide treatment options for SSBP.

The role of sex hormones in aldosterone biosynthesis and their potential impact on its mineralocorticoid receptor

Blood pressure (BP) regulation is a complex process involving various hormones, including aldosterone and its mineralocorticoid receptor. Mineralocorticoid receptor is expressed in several tissues, including the kidney, and plays a crucial role in regulating BP by controlling the sodium and water balance. During different stages of life, hormonal changes can affect mineralocorticoid receptor activity and aldosterone levels, leading to changes in BP. Increasing evidence suggests that sex steroids modulate aldosterone levels. Estrogens, particularly estradiol, mediate aldosterone biosynthesis by activating classical estrogen receptors and the G protein-coupled receptor. Progesterone acts as an anti-mineralocorticoid by inhibiting the binding of aldosterone to the mineralocorticoid receptor. Moreover, progesterone inhibits aldosterone synthase enzymes. The effect of testosterone on aldosterone synthesis is still a subject of debate. However, certain studies show that testosterone downregulates the mRNA levels of aldosterone synthase, leading to decreased plasma aldosterone levels.

Commensal microbiota regulate aldosterone.

The gut microbiome regulates many important host physiological processes associated with cardiovascular health and disease; however, the impact of the gut microbiome on aldosterone is unclear. Investigating whether gut microbiota regulate aldosterone can offer novel insights into how the microbiome affects blood pressure. In this study, we aimed to determine whether gut microbiota regulate host aldosterone. We used enzyme-linked immunosorbent assays (ELISAs) to assess plasma aldosterone and plasma renin activity (PRA) in female and male mice in which gut microbiota are intact, suppressed, or absent. In addition, we examined urinary aldosterone. Our findings demonstrated that when the gut microbiota is suppressed following antibiotic treatment, there is an increase in plasma and urinary aldosterone in both female and male mice. In contrast, an increase in PRA is seen only in males. We also found that when gut microbiota are absent (germ-free mice), plasma aldosterone is significantly increased compared with conventional animals (in both females and males), but PRA is not. Understanding how gut microbiota influence aldosterone levels could provide valuable insights into the development and treatment of hypertension and/or primary aldosteronism. This knowledge may open new avenues for therapeutic interventions, such as probiotics or dietary modifications to help regulate blood pressure via microbiota-based changes to aldosterone.NEW & NOTEWORTHY We explore the role of the gut microbiome in regulating aldosterone, a hormone closely linked to blood pressure and cardiovascular disease. Despite the recognized importance of the gut microbiome in host physiology, the relationship with circulating aldosterone remains largely unexplored. We demonstrate that suppression of gut microbiota leads to increased levels of plasma and urinary aldosterone. These findings underscore the potential of the gut microbiota to influence aldosterone regulation, suggesting new possibilities for treating hypertension.

Calcineurin inhibitor-related hyperkalemia is caused by hyporeninemic hypoaldosteronism and fludrocortisone is an effective treatment: Report of a case series and review of the literature.

Calcineurin inhibitors (CNIs) are widely used in transplantation. Although CNI-related hyperkalemia is common (10%-60.6%), the underlying pathogenetic mechanism is not well-elucidated and may lead to dose adjustment or treatment withdrawal. The aim of this study is to describe CNI-related hyperkalemia due to hyporeninemic hypoaldosteronism in pediatric transplant recipients who were successfully treated with fludrocortisone. In a total of 55 hematopoietic stem cell (HSCT) and 35 kidney transplant recipients followed according to institutional immunosuppression protocols, recipients diagnosed with CNI-related hyperkalemia were reviewed. Recipients who were receiving intravenous fluid, potassium, or were diagnosed with hemolysis, acute graft rejection, or had an eGFR < 30 mL/min/1.73m2, were excluded. A detailed analysis of clinical history as well as biochemical studies was carried out to reveal possible pathophysiology. Three pediatric transplant recipients (one HSCT, two kidney transplantation) with findings of hyperkalemia, hyponatremia, and a mild elevation in blood urea nitrogen while on CNIs were recruited. Urinary potassium excretion was diminished while sodium excretion was increased. Plasma aldosterone levels were low, and renin was not increased in response. Primary adrenal insufficiency was ruled out, and hyporeninemic hypoaldosteronism was diagnosed. CNI-related hyperkalemia was detected earlier in case 1, who had HSCT (22 days), than in the second and third cases, who had kidney transplantation (24 and 30 months post-transplantation, respectively). The discrepancy was hypothesized to be explained by higher overall CNI dose due to higher serum target CNI used in HSCT than kidney transplantation. Electrolyte imbalance was reversed upon administration of physiologic dose fludrocortisone (0.05 mg, daily), while fludrocortisone was ceased after CNI withdrawal in case 1, which is additional evidence for the etiological association of CNIs and hyporeninemic hypoaldosteronism. Our three cases strengthen the premise that CNI-related hyperkalemia may be due to hyporeninemic hypoaldosteronism, and the timing and severity may be related to CNI dose. Fludrocortisone is a safe and effective treatment in CNI-related hyperkalemia, providing maintenance of CNIs, which are one of the essential therapeutic agents for pediatric transplantation.

DOPAMINE-DEPENDENT FORM OF ARTERIAL HYPERTENSION IN PATIENTS WITH A HIGH DEGREE OF NUTRITIONAL-CONSTITUTIONAL OBESITY

Objective: Despite significant advances in the study of the pathogenesis, clinical picture and treatment of arterial hypertension (AH), the role of the dopaminergic system in obese patients remains insufficiently studied. Aim: To evaluate the effectiveness of the use of D2 receptor agonists in patients with arterial hypertension (AH) and nutritional-constitutional obesity (NCO) of the 3rd degree. Design and method: We examined 151 patients aged 30-60 years (65 men, 86 women) with AH and NCO. The control group (CG) consisted of 78 hypertensive patients. Daily monitoring of blood pressure (BP), body mass index (BMI), daily excretion of dopamine, plasma levels of aldosterone, prolactin, leptin, adrenaline, creatinine, lipid spectrum - obese patients were divided into two groups. In addition to basic antihypertensive therapy, patients 1 group (n=74) were prescribed bromocriptine (0.08 mg/kg in three doses), patients 2 group (n=71) – pramipexole (0.125 mg 3 times/day). Results: During the baseline examination, daily dopamine excretion in obese patients was 1.6 times lower (p&lt;0.001) than in control group patients. A negative correlation was found between dopamine excretion and BMI (r=-0.6; p&lt;0.001). In patients with hypertension and NCO, a basic examination revealed a significant (p&lt;0.001) increase in the plasma concentrations of prolactin (2.5 times), aldosterone (1.5 times), leptin (3.4 times) and adrenaline (by 1.3 times) compared to CG. Taking bromocriptine for 8 weeks in patients 1 group led to a decrease in blood pressure, BMI and plasma levels of prolactin and aldosterone. In 41.9% of patients 1 group with dopamine excretion levels less than 300 nmol/day, normalization of blood pressure was observed. In patients 2 group pramipexole was discontinued due to side effects. Conclusions: In the majority of patients with hypertension and NCO (58.1%), the main pathogenetic factor in increasing blood pressure is a low level of dopamine and a compensatory increase in prolactin, aldosterone, and adrenaline in plasma. The use of the D2-dopamine receptor agonist bromocriptine helps to normalize the daily excretion of dopamine, reduce the levels of prolactin, aldosterone and adrenaline, blood pressure and BMI. The use of pramipexole in patients with hypertension and NCO seems inappropriate

Functional in vivo effects of an ENaC Na+ self inhibition-enhancing mutation

Background: Epithelial Na+ channel (ENaC)-mediated Na+ reabsorption in the distal nephron is a critical regulator of extracellular fluid volume and K+ homeostasis. Physiologic concentrations of extracellular Na+ reduce channel activity (open probability; PO) via an allosteric mechanism termed “Na+ self-inhibition,” which involves Na+ ions binding to specific sites in the channel’s extracellular domains. Recent studies have identified human ENaC mutations that alter the Na+ self-inhibition response when assayed in vitro. Such mutations may confer sensitivity or resistance to salt-induced blood pressure changes. Using CRISPR-Cas9 technology, we generated mice carrying a mutation previously shown to enhance Na+ self-inhibition (αH282R) to assess the effects on ENaC-dependent Na+ transport in vivo. We predicted that ENaC activity would be reduced in these mice, leading to enhanced sensitivity to Na+ deprivation or K+ loading, along with accompanying compensatory changes to overcome the predicted loss of function. Methods: We measured urinary electrolyte handling in wild type (WT) and αH282R mice maintained on normal, low Na+, or high K+ diets using metabolic cages. We assessed ENaC activity ex vivo using patch clamp and Ussing chamber methods. We also measured blood chemistry and aldosterone levels in WT and αH282R mice under the dietary conditions described above. Results: When maintained on a normal chow diet (0.3% NaCl), αH2832R mice expressed ENaCs in the distal nephron with reduced PO compared to WT littermates (0.026 vs. 0.067; p&lt;0.01), while ENaC subunit protein expression was unaltered. Amiloride-sensitive short-circuit currents were reduced in the distal colons of αH283R mice versus WT littermates (-12.6 vs. -3.9 μA/cm2; p&lt;0.01). Plasma aldosterone levels were also higher in αH283R versus WT mice on a control diet (610 vs 288 pg/mL; p=0.02), while no other differences in baseline blood chemistry were observed. When challenged with either dietary Na+ restriction (&lt;0.01% NaCl) or K+ loading (10% KCl), WT and αH283R mice responded similarly in terms of body weight maintenance, urinary Na+ and K+ excretion, and systemic electrolyte and metabolic parameters, with the exception of higher aldosterone levels in Na+-restricted αH282R mice compared to WT littermates (2,759 vs. 1271 pg/mL; p&lt;0.01). Conclusions: The αH282R mutation, which enhances Na+ self-inhibition, confers reduced ENaC activity in mice. However, this loss of function may be compensated by ENaC-independent Na+/K+ handling mechanisms and/or increased aldosterone signaling during adaptation to dietary salt stressors. P30DK079307, T32DK061296. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

XX Chromosome Complement Predisposes Females to Obesity-induced, Leptin-mediated Aldosterone Production and Hypertension

Despite the historical dogma that premenopausal women are protected from cardiovascular disease, clinical and experimental evidence indicate that obesity abolishes this protection, placing women at increased risk for hypertension. Previously, our laboratory demonstrated that the adipokine leptin contributes to obesity-associated hypertension in both males and females but via sex specific mechanisms: leptin-mediated sympatho-activation in males and leptin-induced aldosterone production in females. However, the origin of these sex-specific mechanisms remains unknown. Therefore, we aimed to test the contribution of both sex hormones and chromosomes. Female sex hormones were preserved (sham) or depleted via ovariectomy (OVX) in lean control and obese female agouti yellow mice. Blood pressure (BP) recording via radiotelemetry indicated that obesity increased BP (2-way ANOVA, p&lt;0.0001) but OVX did not alter BP in agouti mice. Vascular function measured via mesenteric wire myography indicated obesity impaired (3-way ANOVA, p&lt;0.05) endothelial-dependent relaxation but OVX did not inflict further impairment in agouti mice. OVX did not alter plasma aldosterone levels or adrenal aldosterone synthase (CYP11B2) expression in agouti mice. Leptin receptor blockade (Allo-Aca) decreased BP (2-way ANOVA, p&lt;0.05), restored endothelial-dependent relaxation and decreased (2-way ANOVA, p&lt;0.05) adrenal CYP11B2 expression in both intact and OVX agouti mice indicating a preservation of leptin-mediated BP elevation in the absence of female sex hormones and ruling out sex steroids as the origin of the sex specific mechanisms. Additionally, neither estrogen, progesterone, a combination of estrogen and progesterone, or dihydrotestosterone increase CYP11B2 expression in primary isolated human adrenal cells in culture further supporting that sex hormones do not mediate aldosterone production. These data suggest female sex hormones are not the source for the sex difference prompting us to utilize the four-core genotype (FCG) mouse model to assess the role of sex chromosomes. In order to mimic obesity conditions, BP was recorded at baseline and in response to leptin infusion in OVX FCG XX and XY female mice (XXF and XYF). XX females displayed higher baseline BP than XY (XXF: 109.1±2.4 vs. XYF: 100.4±1.1 mmHg, p&lt;0.05) but leptin infusion increased BP and concurrently ablated the difference. Similarly, XXF displayed heightened plasma aldosterone (2-way ANOVA, 183.7±27 vs. 89.4±34 pg/mL, p&lt;0.05) but leptin infusion abolished the difference. Collectively, these results indicate that XX chromosome rather than female sex steroid hormones regulates aldosterone production, and that sex chromosomes are likely the source for the sexual dimorphism in the mechanism for hypertension associated with obesity. R01HL130301, R01HL155265 (E.J.B.) F31HL168963-01 (C.T.B.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Zona Glomerulosa-Derived Klotho Modulates Aldosterone Synthase Expression in Young Female Mice.

Klotho plays a critical role in the regulation of ion and fluid homeostasis. A previous study reported that haplo-insufficiency of Klotho in mice results in increased aldosterone synthase (CYP11B2) expression, elevated plasma aldosterone, and high blood pressure. This phenotype was presumed to be the result of diminished Klotho expression in zona glomerulosa (zG) cells of the adrenal cortex; however, systemic effects on adrenal aldosterone production could not be ruled out. To examine whether Klotho expressed in the zG is indeed a critical regulator of aldosterone synthesis, we generated a tamoxifen-inducible, zG-specific mouse model of Klotho deficiency by crossing Klotho-flox mice with Cyp11b2-CreERT mice (zG-Kl-KO). Tamoxifen-treated Cyp11b2-CreERT animals (zG-Cre) served as controls. Rosa26-mTmG reporter mice were used for Cre-dependent lineage-marking. Two weeks after tamoxifen induction, the specificity of the zG-Cre line was verified using immunofluorescence analysis to show that GFP expression was restricted to the zG. RNA in situ hybridization revealed a 65% downregulation of Klotho messenger RNA expression in the zG of zG-Kl-KO female mice at age 12 weeks compared to control mice. Despite this significant decrease, zG-Kl-KO mice exhibited no difference in plasma aldosterone levels. However, adrenal CYP11B2 expression and the CYP11B2 promotor regulatory transcription factors, NGFIB and Nurr1, were enhanced. Together with in vitro experiments, these results suggest that zG-derived Klotho modulates Cyp11b2 but does not evoke a systemic phenotype in young adult mice on a normal diet. Further studies are required to investigate the role of adrenal Klotho on aldosterone synthesis in aged animals.

Mineralocorticoid receptor and aldosterone: Interaction between NR3C2 genetic variants, sex and age in a mixed cohort.

Hypertension, a prevalent cardiovascular risk, often involves dysregulated aldosterone and its interaction with the mineralocorticoid receptor (MR). Experimental designs in animal models and human cohorts have demonstrated a sex and age dependency of aldosterone secretion that expands our pathophysiologic understanding. This study explores the genetic variation of NR3C2, which encodes MR, in relation to aldosterone, considering age, sex, and race. Incorporating 720 Caucasians and 145 Africans from the HyperPATH cohort, we investigated the impact of rs4835490, a single nucleotide risk allele variant, on aldosterone levels and vasculature. Notably, a significant association between rs4835490 and plasma aldosterone under liberal salt conditions emerged in individuals of European ancestry (P=0.0002). Homozygous carriers of the risk A allele exhibited elevated plasma aldosterone levels (AA=8.1±0.9 vs GG=4.9±0.5 ng/dl). Additionally, aldosterone activation through posture (P=0.025) and urinary excretion (P=0.0122) showed notable associations. Moreover, genetic interactions with race, sex, and age were observed. Caucasian females under 50 years displayed higher plasma aldosterone, urine aldosterone, and posture aldosterone with the AA genotype compared to females over 50 years, suggesting a potential connection with menopausal or estrogen influences. Interestingly, such age-dependent interactions were absent in the African cohort. our study highlights the significance of NR3C2 genetic variation and its interplay with age, sex, and race in aldosterone activation. The findings point towards an estrogen-modulating effect on MR activation, particularly in women underlining the role of aldosterone dysregulation in hypertension development. This insight advances our comprehension of hypertension's complexities and opens avenues for personalized interventions.

T- and L-Type Calcium Channels Maintain Calcium Oscillations in the Murine Zona Glomerulosa.

The zona glomerulosa of the adrenal gland is responsible for the synthesis and release of the mineralocorticoid aldosterone. This steroid hormone regulates salt reabsorption in the kidney and blood pressure. The most important stimuli of aldosterone synthesis are the serum concentrations of angiotensin II and potassium. In response to these stimuli, voltage and intracellular calcium levels in the zona glomerulosa oscillate, providing the signal for aldosterone synthesis. It was proposed that the voltage-gated T-type calcium channel CaV3.2 is necessary for the generation of these oscillations. However, Cacna1h knock-out mice have normal plasma aldosterone levels, suggesting additional calcium entry pathways. We used a combination of calcium imaging, patch clamp, and RNA sequencing to investigate calcium influx pathways in the murine zona glomerulosa. Cacna1h-/- glomerulosa cells still showed calcium oscillations with similar concentrations as wild-type mice. No calcium channels or transporters were upregulated to compensate for the loss of CaV3.2. The calcium oscillations observed were instead dependent on L-type voltage-gated calcium channels. Furthermore, we found that L-type channels can also partially compensate for an acute inhibition of CaV3.2 in wild-type mice. Only inhibition of both T- and L-type calcium channels abolished the increase of intracellular calcium caused by angiotensin II in wild-type. Our study demonstrates that T-type calcium channels are not strictly required to maintain glomerulosa calcium oscillations and aldosterone production. Pharmacological inhibition of T-type channels alone will likely not significantly impact aldosterone production in the long term.