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Systemic acid-base status is primarily determined by the interplay of net acid production (NEAP) arising from metabolism of ingested food stuffs, buffering of NEAP in tissues, generation of bicarbonate by the kidney, and capture of any bicarbonate filtered by the kidney. In chronic kidney disease (CKD), acid retention may occur when dietary acid production is not balanced by bicarbonate generation by the diseased kidney. Hormones including aldosterone, angiotensin II, endothelin, PTH, glucocorticoids, insulin, thyroid hormone, and growth hormone can affect acid-base balance in different ways. The levels of some hormones such as aldosterone, angiotensin II and endothelin are increased with acid accumulation and contribute to an adaptive increase in renal acid excretion and bicarbonate generation. However, the persistent elevated levels of these hormones can damage the kidney and accelerate progression of CKD. Measures to slow the progression of CKD have included administration of medications which inhibit the production or action of deleterious hormones. However, since metabolic acidosis accompanying CKD stimulates the secretion of several of these hormones, treatment of CKD should also include administration of base to correct the metabolic acidosis.

BACKGROUND: Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed. OBJECTIVES: To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan. ANIMALS: Dogs with pCKD (n = 36) and healthy controls (n = 20). METHODS: Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models. RESULTS: Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P

Aim Methods Results Conclusion Increasing the dietary intake of K+ in the setting of a high salt intake promotes renal Na+ excretion even though K+ concurrently enhances the secretion of aldosterone, the most effective stimulus for renal Na+ reabsorption. Here, we questioned whether in the high salt state a mechanism exists, which attenuates the aldosterone response to prevent renal Na+ reabsorption after high K+ intake.Mice were fed diets containing varying amounts of Na+ combined with KCl or KCitrate. Murine cortical connecting duct (mCCDcl1) cells were cultured in media containing normal or high [Cl−]. The response to aldosterone was analyzed by high‐resolution imaging and by biochemical approaches.The canonical cellular response to aldosterone, encompassing translocation of the mineralocorticoid receptor (MR) and activation of the epithelial Na+ channel ENaC was repressed in Na+‐replete mice fed a high KCl diet, even though plasma aldosterone concentrations were increased. The response to aldosterone was restored in Na+‐replete mice when the extracellular [Cl−] increase was prevented by feeding a high KCitrate diet. In mCCDcl1 cells, an elevated extracellular [Cl−] was sufficient to disrupt the aldosterone‐induced MR translocation.These findings indicate a pivotal role for extracellular [Cl−] in modulating renal aldosterone signaling to adapt MR activation by a high K+ intake to the NaCl balance. An impairment of [Cl−]‐mediated aldosterone resistance may contribute to excessive MR activation by aldosterone in the presence of a high salt intake characteristic of the Western diet, resulting in an inappropriate salt reabsorption and its downstream detrimental effects. [ABSTRACT FROM AUTHOR]

Background: Hypertensive 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. Methods: We 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. Results: Among 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]). Conclusion: In 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. [ABSTRACT FROM AUTHOR]

Key Clinical Message: 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. [ABSTRACT FROM AUTHOR]

Aldosterone is a mineralocorticoid hormone involved in controlling electrolyte balance, blood pressure, and cellular signaling. It plays a pivotal role in cardiovascular and metabolic physiology. Excess aldosterone activates mineralocorticoid receptors, leading to subsequent inflammatory responses, increased oxidative stress, and tissue remodeling. Various mechanisms have been reported to link aldosterone with cardiovascular and metabolic diseases. However, mitochondria, responsible for energy generation through oxidative phosphorylation, have received less attention regarding their potential role in aldosterone-related pathogenesis. Excess aldosterone leads to mitochondrial dysfunction, and this may play a role in the development of cardiovascular and metabolic diseases. Aldosterone has the potential to affect mitochondrial structure, function, and dynamic processes, such as mitochondrial fusion and fission. In addition, aldosterone has been associated with the suppression of mitochondrial DNA, mitochondria-specific proteins, and ATP production in the myocardium through mineralocorticoid receptor, nicotinamide adenine dinucleotide phosphate oxidase, and reactive oxygen species pathways. In this review, we explore the mechanisms underlying aldosterone-induced cardiovascular and metabolic mitochondrial dysfunction, including mineralocorticoid receptor activation and subsequent inflammatory responses, as well as increased oxidative stress. Furthermore, we review potential therapeutic targets aimed at restoring mitochondrial function in the context of aldosterone-associated pathologies. Understanding these mechanisms is vital, as it offers insights into novel therapeutic strategies to mitigate the impact of aldosterone-induced mitochondrial dysfunction, thereby potentially improving the outcomes of individuals affected by cardiovascular and metabolic disorders. [ABSTRACT FROM AUTHOR]

Vertebrates exhibit a left–right asymmetry from the central structures to the peripheral paired endocrine organs. However, the asymmetries in paired endocrine glands and the pathological consequences of such asymmetries remain largely unknown. The adrenal gland constitutes a pair of peripheral end organs in the neuroendocrine system, responsible for producing steroid hormones under stimuli. In the present study, the lateralized asymmetry of left and right adrenal glands in leptin receptor-deficit db/db mice was investigated. First, a morphological and histological examination showed that adrenal mass and adrenal cortex volume in db/db mice were significantly higher than in non-diabetic control mice. Then, adrenal transcriptomic and serum metabolomic analyses were performed. Adrenal steroid profiling showed that the levels of corticosterone and aldosterone in the right adrenal gland of db/db mice were two times higher than in the left one. The expression of multiple genes related to adrenal regeneration and innervation in db/db mice was reduced in contrast to the increased steroid hormone secretion. Furthermore, an examination of morphogens in asymmetric adrenal development revealed a significant differential expression of Shh and its receptor gene Ptch1. In conclusion, the present study has provided evidence that a superior steroidogenesis exists in the right adrenal gland of db/db mice and suggested that Shh signaling may play an important role in asymmetric adrenal responses in type 2 diabetes and its complications. [ABSTRACT FROM AUTHOR]

Accurate measurements of renin and aldosterone levels play an important role in primary aldosteronism screening, which is of great importance in the management and categorization of hypertension. The objective of this study is to investigate the current status of plasma renin and aldosterone measurements in China, which is achieved by analyzing the results of 526 clinical laboratories nationwide for three pooled fresh plasma samples derived from more than 2,000 patients. Renin and aldosterone in three pooled plasma samples were measured four times in 526 laboratories employing various measurement systems. The inter- and intra-laboratory %CV were calculated and compared. To determine the source of the substantial inter-laboratory %CV, laboratories were categorized according to the measurement systems they are using, and both the inter- and intra-measurement-system %CV were calculated and compared. Regarding renin, the majority of laboratories use four primary commercial immunoassays. However, for aldosterone, in addition to commercial immunoassays, laboratory-developed liquid chromatography-tandem mass spectrometry (LC-MS) methods are also used by laboratories. The median values of intra-laboratory %CVs, intra-measurement-system %CVs, inter-laboratory %CVs, and inter-measurement systems %CVs varied between 1.6 and 2.6 %, 4.6 and 14.9 %, 8.3 and 25.7 %, and 10.0 and 34.4 % for renin, respectively. For aldosterone, these values ranged from 1.4 to 2.2 %, 2.5–14.7 %, 9.9–31.0 %, and 10.0–35.5 %, respectively. The precision within laboratories and measurement systems for plasma renin and aldosterone measurements is satisfactory. However, the comparability between laboratories using different measurement systems remains lacking, indicating the long way to achieve standardization and harmonization for these two analytes. [ABSTRACT FROM AUTHOR]

It is unknown whether liver surgery leads to increased RAAS activity and anti-diuretic hormone (ADH) levels and subsequent fluid accumulation. Furthermore, it is unknown whether the peri-operative fluid strategy changes this effect. This is a pre-planned post hoc analysis of a randomised controlled trial which compared restrictive (n = 20) versus liberal fluid strategy (n = 20) in patients undergoing liver surgery. Primary outcomes for the current study were the difference in hormone levels after anaesthesia induction and after liver resection. Fluid overload was defined as a ≥10% increase in weight. Renin activity (6 [2.1–15.5] vs. 12 [4.6–33.5]) and ADH levels (6.0 [1.7–16.3] vs. 3.8 [1.6–14.7]) did not differ significantly before and after resection. However, aldosterone levels were significantly higher after resection (0.30 [0.17–0.49] vs. 0.69 [0.31–1.21]). Renin activity and aldosterone levels did not differ between the groups. ADH was significantly higher in the restrictive strategy group (1.6 [1.1–2.1] vs 5.9 [3.8–16.0]). No differences in hormone levels were found in patients with and without fluid overload. Aldosterone levels increased after liver surgery but renin activity and ADH levels did not. ADH levels were higher in the restrictive group. Development of post-operative fluid overload was not associated with RAAS activity or ADH levels. [ABSTRACT FROM AUTHOR]

BACKGROUND: Diagnosis of primary aldosteronism (PA) is complicated by the need to withdraw antihypertensive medications that interfere with test results, particularly renin. This study examined whether machine learning-based steroid-probability scores offer a renin measurement-independent approach for testing less prone to interference than the aldosterone-to-renin ratio (ARR). METHODS: This prospective multicenter cohort study involved the use of plasma steroidomics and the ARR in 839 patients tested for PA, including 190 with and 578 without PA (71 indeterminate). Receiver operating characteristic curves for steroid-probability scores and the ARR were examined with and without interfering medications. Impacts of individual medications on plasma aldosterone, 18-oxocortisol, 18-hydroxycortisol, steroid-probability scores, renin, and ARRs were examined by multivariable and paired analyses in patients with and without PA. RESULTS: Receiver operating characteristic curves indicated a significant impact of interfering antihypertensive medications on the diagnostic performance of the ARR and minimal impact on steroid-probability scores. Mineralocorticoid receptor antagonists increased plasma aldosterone, 18-oxocortisol, and 18-hydroxycortisol in patients without PA and resulted in false-positive test results for steroid-probability scores and false-negative results for the ARR. Diuretics increased aldosterone, 18-oxocortisol, and steroid-probability scores in patients without PA, whereas angiotensin-converting enzyme inhibitors decreased aldosterone, steroid-probability scores, and ARRs. Beta-adrenoceptor blockers, dihydropyridine calcium channel blockers, and angiotensin receptor blockers had negligible impact on mineralocorticoids and steroid-probability scores. CONCLUSIONS: Among antihypertensive drugs that impact plasma aldosterone, 18-oxocortisol, and 18-hydroxycortisol, mineralocorticoid receptor antagonists stood out as a cause of false-positive results for derived steroid-probability scores. Other antihypertensives have minimal or no impact, an advantage for use of steroid-probability scores over the ARR when those medications cannot be withdrawn. [ABSTRACT FROM AUTHOR]

Aims Methods Conclusion Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT‐HFpEF) is a unique pragmatic registry‐based randomized controlled trial.SPIRRIT‐HFpEF is a multicentre, prospective, randomized, open‐label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N‐terminal pro‐B‐type natriuretic peptide >300 ng/L (in sinus rhythm) or >750 ng/L (in atrial fibrillation), with pre‐specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event‐driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients.SPIRRIT‐HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry‐based trials in heart failure and other chronic conditions. [ABSTRACT FROM AUTHOR]

Background: Hypocholesterolemia hallmarks critical illness though the underlying pathophysiology is incompletely understood. As low circulating cholesterol levels could partly be due to an increased conversion to cortisol/corticosterone, we hypothesized that glucocorticoid treatment, via reduced de novo adrenal cortisol/corticosterone synthesis, might improve cholesterol availability and as such affect adrenal gland and skeletal muscle function. Methods: In a matched set of prolonged critically ill patients (n = 324) included in the EPaNIC RCT, a secondary analysis was performed to assess the association between glucocorticoid treatment and plasma cholesterol from ICU admission to day five. Next, in a mouse model of cecal ligation and puncture-induced sepsis, septic mice were randomized to receive either hydrocortisone (1.2 mg/day) (n = 17) or placebo (n = 15) for 5 days, as compared with healthy mice (n = 18). Plasma corticosterone, cholesterol, and adrenocortical and myofiber cholesterol were quantified. Adrenal structure and steroidogenic capacity were evaluated. Muscle force and markers of atrophy, fibrosis and regeneration were quantified. In a consecutive mouse study with identical design (n = 24), whole body composition was assessed by EchoMRI to investigate impact on lean mass, fat mass, total and free water. Results: In human patients, glucocorticoid treatment was associated with higher plasma HDL- and LDL-cholesterol from respectively ICU day two and day three, up to day five (P < 0.05). Plasma corticosterone was no longer elevated in hydrocortisone-treated septic mice compared to placebo, whereas the sepsis-induced reduction in plasma HDL- and LDL-cholesterol and in adrenocortical cholesterol was attenuated (P < 0.05), but without improving the adrenocortical ACTH-induced CORT response and with increased adrenocortical inflammation and apoptosis (P < 0.05). Total body mass was further decreased in hydrocortisone-treated septic mice (P < 0.01) compared to placebo, with no additional effect on muscle mass, force or myofiber size. The sepsis-induced rise in markers of muscle atrophy and fibrosis was unaffected by hydrocortisone treatment, whereas markers of muscle regeneration were suppressed compared to placebo (P < 0.05). An increased loss of lean body mass and total and free water was observed in hydrocortisone-treated septic mice compared to placebo (P < 0.05). Conclusions: Glucocorticoid treatment partially attenuated critical illness-induced hypocholesterolemia, but at a cost of impaired adrenal function, suppressed muscle regeneration and exacerbated loss of body mass. [ABSTRACT FROM AUTHOR]

AIM: To explore the mechanisms behind the inhibition of lymphangiogenesis in pregnant rats with obstructive nephropathy and assess the protective effects on kidney function. METHODS: Forty nulliparous female Wi-star rats were randomly assigned to four groups: sham operation, sham operation + pregnancy, model, and Esaxerenone groups, with 10 rats in each group. Renal injury was induced in the model and Esaxerenone groups via unilateral ureteral obstruction (UUO). The other two groups underwent ureteral dissociation without ligation. Nine weeks post-UUO, female rats in the sham operation+pregnancy, model, and Esaxerenone groups were mated with male rats (2:1 ratio) to establish a rat model of obstructive nephropathy during pregnancy. Starting the day after UUO, rats in the Esaxerenone group received Esaxerenone at 1 mg⋅kg-1⋅d-1. On the 18th day of pregnancy, 24-hour urine was collected using metabolic cages. The following day, the rats were sacrificed, serum samples collected, and the contralateral kidney removed. Blood urea nitrogen (BUN) was measured using standard biochemical methods, and endogenous creatinine clearance rate (Ccr) was calculated. Kidney tissue pathology was assessed using HE, Masson, and Sirius red staining. Serum aldosterone levels were determined via ELISA. Immunohistochemistry, real-time PCR, and Western blot were employed to assess mineralo-corticoid receptor (MR) activation, lymphangiogenesis, signaling pathways, and fibrosis-related markers. RESULTS: Renal function tests revealed increased BUN levels and decreased Ccr in the model group (P<0. 01). Pathological examination showed dilated renal tubules, significant collagen deposition, and inflammatory cell infiltration in the model group. ELISA results indicated a significant increase in serum aldosterone levels in the model group (P<0. 01). Immunohisto-chemistry showed enhanced nuclear translocation of MR in the kidneys of the model group post-activation. Western blot and real-time PCR demonstrated a marked increase in neutrophil gelatinase-associated lipocalin (NGAL) expression in the model group (P<0. 01). Additionally, the expression of vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR3 was significantly elevated in the renal tubulointerstitium of the model group, as shown by both immunohistochemistry and real-time PCR (P < 0. 01). The PI3K/Akt signaling pathway was activated in the model group, with significantly increased phosphorylation levels observed primarily in renal tubular epithelial and interstitial cells (P<0. 01). Collagen type III (Col III) expression, primarily in the renal tubulointerstitium, was also significantly upregulated in the model group, consistent with real-time PCR results (P<0. 01). Esaxerenone treatment improved renal function, reduced pathological damage, inhibited aldosterone secretion, and downregulated the expression of MR, NGAL, VEGF-C, VEGFR3, phosphorylated PI3K, phosphorylated Akt, and Col III (P<0. 01). CONCLUSION: Esaxerenone mitigates aldosterone-induced MR activation, modulates the PI3K/Akt signaling pathway, reduces lymphangiogenesis in the contralateral kidney of pregnant rats with obstructive nephropathy, decreases collagen deposition, and delays the progression of renal interstitial fibrosis. [ABSTRACT FROM AUTHOR]

Apparent bilateral adrenal suppression (ABAS), where aldosterone/cortisol ratios in both adrenal veins are lower than in the inferior vena cava, yields uninterpretable adrenal venous sampling (AVS) results and is poorly understood. A 57-year-old male with hypertension and spontaneous hypokalemia was admitted to our hospital. Confirmatory tests established a diagnosis of primary aldosteronism (PA). Initial AVS indicated ABAS, but unilateral PA remained possible due to elevated aldosterone, low renin, hypokalemia, and a right adrenal nodule (8 × 7 mm) on computed tomography. Subsequently, a second, super-selective AVS identified tributaries from areas of aldosterone hypersecretion, enabling accurate localization of unilateral PA. ABAS may occur due to anatomical factors such as dilution by tributaries from nonaldosterone-producing adenoma (APA) areas with suppressed aldosterone production. Super-selective AVS proves beneficial in diagnosing unilateral PA concealed within ABAS by pinpointing tributaries from APA regions. [ABSTRACT FROM AUTHOR]

Epithelial Na+ channels (ENaCs) are activated by proteolysis of the α and γ subunits at specific sites flanking embedded inhibitory tracts. To examine the role of α subunit proteolysis in channel activation in vivo, we generated mice lacking the distal furin cleavage site in the α subunit (αF2M mice). On a normal Na+ control diet, no differences in ENaC protein abundance in kidney or distal colon were noted between wild‐type (WT) and αF2M mice. Patch‐clamp analyses revealed similar levels of ENaC activity in kidney tubules, while no physiologically relevant differences in blood chemistry or aldosterone levels were detected. Male αF2M mice did exhibit diminished ENaC activity in the distal colon, as measured by amiloride‐sensitive short‐circuit current (ISC). Following dietary Na+ restriction, WT and αF2M mice had similar natriuretic and colonic ISC responses to amiloride. However, single‐channel activity was significantly lower in kidney tubules from Na+‐restricted αF2M mice compared with WT littermates. ENaC α and γ subunit expression in kidney and distal colon were also enhanced in Na+‐restricted αF2Mvs. WT mice, in association with higher aldosterone levels. These data provide evidence that disrupting α subunit proteolysis impairs ENaC activity in vivo, requiring compensation in response to Na+ restriction. Key points: The epithelial Na+ channel (ENaC) is activated by proteolytic cleavage in vitro, but key questions regarding the role of ENaC proteolysis in terms of whole‐animal physiology remain to be addressed.We studied the in vivo importance of this mechanism by generating a mouse model with a genetic disruption to a key cleavage site in the ENaC's α subunit (αF2M mice).We found that αF2M mice did not exhibit a physiologically relevant phenotype under normal dietary conditions, but have impaired ENaC activation (channel open probability) in the kidney during salt restriction.ENaC function at the organ level was preserved in salt‐restricted αF2M mice, but this was associated with higher aldosterone levels and increased expression of ENaC subunits, suggesting compensation was required to maintain homeostasis.These results provide the first evidence that ENaC α subunit proteolysis is a key regulator of channel activity in vivo. [ABSTRACT FROM AUTHOR]

Context Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production. Objective To investigate the contributions of renin-independent aldosteronism and ACTH-mediated aldosteronism in individuals with a low-renin phenotype representing the entire continuum of blood pressure. Design/Participants Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure. Setting 4 international centers. Interventions/Main Outcome Measures The saline suppression test (SST) to quantify the magnitude of renin-independent aldosteronism; dexamethasone suppression and ACTH-stimulation tests to quantify the magnitude of ACTH-mediated aldosteronism; adrenal venous sampling to determine lateralization. Results There was a continuum of nonsuppressible and renin-independent aldosterone production following SST that paralleled the magnitude of the blood pressure continuum and transcended conventional diagnostic thresholds. In parallel, there was a full continuum of ACTH-mediated aldosteronism wherein post-SST aldosterone levels were strongly correlated with ACTH-stimulated aldosterone production (r = 0.75, P <.0001) and nonsuppressible aldosterone production postdexamethasone (r = 0.40, P <.0001). Beyond participants who met the criteria for primary aldosteronism (post-SST aldosterone of ≥10 ng/dL or ≥277 pmol/L), the continuum of nonsuppressible and renin-independent aldosterone production persisted below this diagnostic threshold, wherein 15% still had lateralizing aldosteronism amenable to surgical adrenalectomy and the remainder were treated with mineralocorticoid receptor antagonists. Conclusion In the context of a low-renin phenotype, there is a continuum of primary aldosteronism and dysregulated aldosterone production that is prominently influenced by ACTH. A large proportion of individuals with low renin may benefit from aldosterone-directed therapy. [ABSTRACT FROM AUTHOR]

Background: Adrenal vein sampling (AVS), integral to identifying surgically remediable unilateral primary aldosteronism (PA), is technically challenging and subject to fluctuations in cortisol and aldosterone secretion. Intra‐procedural adrenocorticotropic hormone (ACTH), conventionally administered as a 250‐μg bolus and/or 50 μg per hour infusion, increases cortisol and aldosterone secretion and can improve AVS success, but may cause discordant lateralisation compared to unstimulated AVS. Aims: To assess if AVS performed with ultra‐low dose ACTH infusion causes discordant lateralisation. Methods: Here, we describe our preliminary experience using an ultra‐low dose ACTH infusion AVS protocol. We retrospectively reviewed the results of consecutive AVS procedures (n = 37) performed with and without ultra‐low dose ACTH (1‐μg bolus followed by 1.25 μg per hour infusion). Results: Bilateral AV cannulation was successful in 70% of procedures pre‐ACTH and 89% post‐ACTH (p < 0.01). Sixty‐nine percent of studies lateralised pre‐ACTH and 55% post‐ACTH, improving to 79% when both groups were combined. Lateralisation was discordant in 11 cases, including eight in which lateralisation was present only on basal sampling, and three in which lateralisation occurred only with ACTH stimulation. Discussion: Overall, the decrease in lateralisation rates with ACTH was higher than previously reported for some protocols utilising conventional doses of ACTH. Our results suggest that AVS performed with ultra‐low dose ACTH can cause discordant lateralisation similar to AVS performed with conventional doses of ACTH. Conclusion: Prospective studies directly comparing low and conventional dose ACTH AVS protocols and long‐term patient outcomes are needed to help define the optimal ACTH dose for accurate PA subtyping. [ABSTRACT FROM AUTHOR]

Background Mammalian target of rapamycin (mTOR) inhibitors suppress adrenal cortical carcinoma cell proliferation and cortisol production; the relationship between mTOR and aldosterone production has not been examined. Methods HAC15 cells were incubated with an mTOR activator and several inhibitors including AZD8055 (AZD) in the presence and absence of angiotensin II (AngII). The expression of rapamycin-sensitive adapter protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (Rictor), adaptor proteins of mTOR complex 1 and 2, respectively, were studied in the HAC15 cells and deleted by CRISPR/gRNA. Results The mTOR inhibitors decreased aldosterone induced by AngII. Inhibition of mTOR by AZD significantly suppressed AngII-induced aldosterone and cortisol formation in a dose-dependent manner, whereas the mTOR activator MHY had no effect. AZD did not alter forskolin-induced aldosterone production showing that it is specific to the AngII signaling pathway. AngII-mediated ERK and mTOR activation were suppressed by AZD, along with a concomitant dose-dependent reduction of AngII-induced steroidogenic enzymes including steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase-type 2, CYP17A1, and aldosterone synthase protein. Furthermore, mTOR components ribosomal protein S6 kinase (P70S6K) and protein kinase B phosphorylation levels were decreased by AZD. As mTOR exerts its main effects by forming complexes with adaptor proteins Raptor and Rictor, the roles of these individual complexes were studied. We found an increase in the phosphorylation of Raptor and Rictor by AngII and that their CRISPR/gRNA-mediated knockdown significantly attenuated AngII-induced aldosterone and cortisol production. Conclusion mTOR signaling has a critical role in transducing the AngII signal initiating aldosterone and cortisol synthesis in HAC15 cells and that inhibition of mTOR could be a therapeutic option for conditions associated with excessive renin–angiotensin system-mediated steroid synthesis. [ABSTRACT FROM AUTHOR]

Abstract Background Hypertensive 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. Methods We 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. Results Among 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]). Conclusion In 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.

Abstract Background Naturally occurring hypoadrenocorticism is an uncommon endocrine disorder in dogs but has significant morbidity and mortality. Some dogs present with apparent glucocorticoid deficiency alone as evidenced by eunatraemia and eukalaemia. Few studies have compared dogs with hypoadrenocorticism with or without electrolyte disturbances and there are no large case series of affected dogs from Ireland. Methods Retrospective observational study. Results Ninety-two cases diagnosed with hypoadrenocorticism subdivided into those with supportive electrolyte disturbances (Group 1; n = 72) and those without (Group 2; n = 20). Dogs in Group 1 were significantly (p = 0.001) younger (4.0 (3.0–6.0) years) than dogs in Group 2 (6.0 (4.75–8.25) years). Dogs in Group 1 presented significantly more commonly with vomiting (Group 1: 52/71 (73.2%), Group 2: 6/20 (30.0%); p

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) is common liver disease often found and occurs in community. Prevalence of liver disease (NAFLD) has risen rapidly along with an increase obesity incidence in women. Inflammation condition in obese condition causing an increase in IL-6, Platelets Count (PLTC), and Aldosterone level increased risk of developing NAFLD. Aim: To analyze differences IL-6, PLTC, and Aldosterone level between Obese and Non-Obese Women. Methods: This study was an observational cross-sectional analytical study that conducted in November-January 2021 at Diponegoro National Hospital (RSND) Semarang. Inclusion criteria for respondents in this study were being middle-aged women (30-49 years), healthy, and willing to take part in this study. Total respondent in this study was 60 people then divided into two groups that is Obese and Non-Obese Group. The degree of fatty liver was examined using the ultrasound method. Platelet count (PLTC) were measured by Indico Blood Analyzer. Meanwhile IL-6 and Aldosterone level analyzed by the enzyme-linked immunosorbent assay (ELISA) method. Fatty liver was diagnosed by abdominal ultrasound. Data were analyzed using SPSS 18.0 that including normality, different tests, and regression tests. Result: Incidence of fatty liver in the obese group was significantly different from the non-obese group (p

Aldosterone is a kind of steroid hormone produced by the zona glomerulosa (ZG) cells of the adrenal cortex which plays a crucial regulatory role in fluid-electrolyte balance and blood pressure stability. Aldosterone biosynthesis is a calcium-dependent process, and ion channels play a key role in this process. Primary aldosteronism is closely related to mutations in ion channels. Recent studies have highlighted an intriguing relationship between the unique rosette structure of ZG cells and their electrical excitability. Elucidating the connection between rosettes and ZG cell electrical excitability as well as aldosterone secretion leads to a deeper understanding of the mechanisms regulating aldosterone secretion and may provide new insights into the pathogenesis of primary aldosteronism.

Shuaiwei Song,1– 5,&ast; Xintian Cai,1– 5,&ast; Junli Hu,1– 5 Qing Zhu,1– 5 Di Shen,1– 5 Huimin Ma,1– 5 Yingying Zhang,1– 5 Rui Ma,1– 5 Wenbo Yang,1– 5 Jing Hong,1– 5 Delian Zhang,1– 5 Nanfang Li1– 5 1Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, 830001, People’s Republic of China; 2Xinjiang Hypertension Institute, Urumqi, Xinjiang, 830001, People’s Republic of China; 3NHC Key Laboratory of Hypertension Clinical Research, Urumqi, Xinjiang, 830001, People’s Republic of China; 4Key Laboratory of Xinjiang Uygur Autonomous Region ”Hypertension Research Laboratory”, Urumqi, Xinjiang, 830001, People’s Republic of China; 5Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang, 830001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, 830001, People’s Republic of China, Tel +86 8,564,818, Email lnanfang2016@sina.comObjective: While the role of aldosterone in bone metabolism is well established, the specific effects of the widely used aldosterone antagonist, spironolactone, on bone health are not fully understood. This study aimed to investigate the effects of spironolactone on osteoporosis and future fracture risk in middle-aged and elderly hypertensive patients, revealing its potential benefits for bone health.Methods: Propensity score matching was employed in this study to create matched groups of spironolactone users and non-users at a 1:4 ratio. We investigated the association between spironolactone use and the risk of osteoporosis using multivariate logistic regression analysis. Furthermore, we conducted multivariate linear regression analysis to explore the relationship between cumulative dosage and the FRAX score. Subgroup analysis was also performed to assess the effects under different stratification conditions.Results: In both pre-match and post-match analyses, multivariable logistic regression revealed a significant reduction in the risk of osteoporosis in the spironolactone usage group (pre-match: odds ratios [OR] 0.406, 95% confidence interval [CI], 0.280– 0.588; post-match: OR 0.385, 95% CI, 0.259– 0.571). Furthermore, post-match multivariable linear regression demonstrated a clear negative correlation between cumulative spironolactone dosage and the FRAX score. Subgroup analyses consistently supported these findings.Conclusion: This study offers evidence supporting the significant positive impact of the antihypertensive drug spironolactone on bone health, resulting in a substantial reduction in the risk of osteoporosis and future fractures in hypertensive patients. Future research should consider conducting large-scale, multicenter, randomized controlled trials to further investigate the long-term effects of spironolactone on bone health in hypertensive patients.Keywords: hypertensive, spironolactone, aldosterone, osteoporosis, FRAX score

Hypertension affects one-third of the adult population worldwide, with primary aldosteronism (PA) accounting for at least 5-10% of these cases. The aldosterone synthase enzyme (CYP11B2) plays a pivotal role in PA manifestation, as increased expression of CYP11B2 leads to excess aldosterone synthesis. Physiological expression of CYP11B2 in humans is normally limited to cells of the adrenal zona glomerulosa under tight homeostatic regulation. In PA, however, there are CYP11B2-positive lesions in the adrenal cortex that autonomously secrete aldosterone, highlighting the dysregulation of adrenal cortex zonation and function as a key aspect of PA pathogenesis. Thus, this review aims to summarize the development of the adrenal glands, the key regulators of adrenal cortex homeostasis, and the dysregulation of this homeostasis. It also discusses the development of CYP11B2 inhibitors for therapeutic use in patients with hypertension, as well as the current knowledge of the effects of CYP11B2 inhibition on adrenal cortex homeostasis and cell fate. Understanding the control of adrenal cell fate may offer valuable insights into both the pathogenesis of PA and the development of alternative treatment approaches for PA. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is associated with alterations in neuroendocrine function, primarily the hypothalamic–pituitary–adrenal axis, including lower expression of the glucocorticoid receptor (GR) and its target genes in peripheral blood mononuclear cells (PBMC) or full blood. We previously found reduced mineralocorticoid receptor (MR) expression in MS patients' peripheral blood. MS is being treated with a widening variety of disease-modifying treatments (DMT), some of which have similar efficacy but different mechanisms of action; body-fluid biomarkers to support the choice of the optimal initial DMT and/or to indicate an unsatisfactory response before clinical activity are unavailable. Using cell culture of volunteers' PBMCs and subsequent gene expression analysis (microarray and qPCR validation), we identified the mRNA expression of OTUD1 to represent MR signaling. The MR and MR target gene expression levels were then measured in full blood samples. In 119 MS (or CIS) patients, the expression of both MR and OTUD1 was lower than in 42 controls. The expression pattern was related to treatment, with the MR expression being particularly low in patients treated with fingolimod. While MR signaling may be involved in the therapeutic effects of some disease-modifying treatments, MR and OTUD1 expression can complement the neuroendocrine assessment of MS disease course. If confirmed, such assessment may support clinical decision-making. [ABSTRACT FROM AUTHOR]

Background Extracellular calcium critically regulates physiologic aldosterone production. Moreover, abnormal calcium flux and signaling are involved in the pathogenesis of the majority of primary aldosteronism cases. Methods We investigated the influence of the saline suppression test (SST) on calcium homeostasis in prospectively recruited participants (n = 86). Results During SST, 100% of participants had decreases in serum calcium, with 48% developing frank hypocalcemia. Serum calcium declined from 2.30 ± 0.08 mmol/L to 2.13 ± 0.08 mmol/L (P <.001) with parallel increases in parathyroid hormone from 6.06 ± 2.39 pmol/L to 8.13 ± 2.42 pmol/L (P <.001). In contrast, serum potassium and bicarbonate did not change, whereas eGFR increased and serum glucose decreased (P <.001). Lower body surface area (translating to greater effective circulating volume expansion during SST) was associated with greater reductions in (β =.33, P =.001), and absolutely lower, serum calcium levels (β =.25, P =.001). When evaluating clinically-relevant diagnostic thresholds, participants with post-SST aldosterone levels <138 pmol/L had lower post-SST calcium and 25-hydroxyvitamin D levels (P <.05), and higher post-SST parathyroid hormone levels (P <.05) compared with those with post-SST aldosterone levels >277 pmol/L. Conclusion SST uniformly decreases serum calcium, which is likely to be due to the combination of variable dilution, increased renal clearance, and vitamin D status. These acute reductions in bioavailable calcium are associated with lower post-SST aldosterone. Given the critical role of extracellular calcium in regulating aldosterone production, these findings warrant renewed inquiry into the validity of SST interpretations for excluding primary aldosteronism. [ABSTRACT FROM AUTHOR]

The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT1A receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission. [ABSTRACT FROM AUTHOR]

Background: Vascular smooth muscle cell (VSMC) injury caused by the inflammatory response plays a key role in cardiovascular disease (CVD), and the vasoprotective effects of mineralocorticoid receptor blockers (MRBs) support the role of mineralocorticoid receptor (MR) activation. Methods: C57BL/6 mice and VSMCs isolated from rats were treated with aldosterone and esaxerenone. Caspase-1, GSDMD-N, IL-1β, and NR3C2 expression and DNA damage in aortic VSMCs were detected using immunohistochemistry, Western blotting, and TUNEL staining. Mitochondrial changes were detected by transmission electron microscopy (TEM). Reactive oxygen species (ROS), MitoTracker, JC-I, mitochondrial respiratory chain complexes I–V, and NR3C2 were detected using immunofluorescence and flow cytometry. Pyroptosis was detected with scanning electron microscopy (SEM). Results: After aldosterone treatment, the number of TUNEL-positive cells increased significantly, and the expression of caspase-1, GSDMD-N, and IL-1β increased. TEM revealed mitochondrial damage, and SEM revealed specific pyroptotic changes, such as cell membrane pore changes and cytoplasmic extravasation. Increased ROS levels and nuclear translocation of NR3C2 were also observed. These pyroptosis-related changes were reversed by esaxerenone. Conclusions: Aldosterone activates the MR and mediates mitochondrial damage, thereby inducing pyroptosis in VSMCs via the NLRP3/caspase-1 pathway. Esaxerenone inhibits MR activation and reduces mitochondrial damage and oxidative stress, thereby inhibiting pyroptosis. [ABSTRACT FROM AUTHOR]

Introduction: Our objective was to investigate the association between the presence of placental anastomoses and intertwin differences in renin‐angiotensin‐aldosterone activation in monochorionic twins using amniotic fluid aldosterone (AF‐ALD) levels. In addition, this study also examined the association between AF‐ALD and the ALD levels in the umbilical cord blood (UCB‐ALD) in monochorionic twins. Material and Methods: This prospective study included monochorionic diamniotic (MD) twin pregnancies that were not complicated by twin‐to‐twin transfusion syndrome (TTTS) at delivery. Amniotic fluid and umbilical cord vein blood samples were collected from each twin at delivery, and the ALD levels were measured subsequently. The MD twins were divided into two groups: those with placental anastomoses and those without anastomoses owing to fetoscopic laser surgery. The differences in the AF‐ALD levels between the larger and smaller twins were analyzed. Results: The AF‐ALD levels showed a strong and significant positive correlation with UCB‐ALD levels in 131 MD twins (r = 0.804, p < 0.001). Intertwin differences were examined in 41 and 28 pairs of MD twins with and without placental anastomoses, respectively. The AF‐ALD levels in the smaller twins were significantly higher than those in the larger twins among the pairs of MD twins with placental anastomoses (p = 0.003); however, no statistically significant intertwin differences were observed among the twins without placental anastomoses (p > 0.05). Conclusions: The AF‐ALD levels reflect the UCB‐ALD levels in MD twins. The presence of placental anastomoses led to intertwin discordance in the ALD levels in MD twins even uncomplicated with TTTS. It was considered that monochorionic twins have this clinical background, and it leads to the development of TTTS. [ABSTRACT FROM AUTHOR]

Primary aldosteronism (PA) is the most common cause of endocrine arterial hypertension, and the suggested screening test for case detection is the aldosterone-to-renin ratio (ARR) or aldosterone-to-direct renin ratio (ADRR) based on radio-immunoassay (RIA) and chemiluminescence assay (CLIA), respectively. The objective of our study was to evaluate the reliability of CLIA for aldosterone and renin measurement and the diagnostic performance of ADRR. A prospective cohort of 1110 patients referred to a single laboratory medicine center underwent measurement of aldosterone and direct renin concentration (DRC) by CLIA and measurement of aldosterone and plasma renin activity (PRA) by RIA. Of 1110 patients, 640 obtained a final diagnosis of hypertension, and 90 of these patients were diagnosed with PA. Overall, between-method correlation was highly significant for aldosterone concentrations (R = 0.945, p < 0.001) and less strong but significant for DRC/PRA (R = 0.422, p < 0.001). Among hypertensive patients, in PA cases, the areas under the receiver operator characteristics (ROC) curves were 0.928 (95% confidence interval 0.904–0.954) for ADRR and 0.943 (95% confidence interval 0.920–0.966) for ARR and were comparable and not significantly different. The highest accuracy was obtained with an ADRR cut-off of 25 (ng/L)/(mIU/L), displaying a sensitivity of 91% and a specificity of 85%. The chemiluminescence assay for aldosterone and DRC is a reliable method for PA diagnosis compared to the classical RIA method. [ABSTRACT FROM AUTHOR]

Activation of the renin–angiotensin–aldosterone system (RAAS) plays an important pathophysiological role in hypertension. Increased mRNA levels of the angiotensinogen angiotensin-converting enzyme, angiotensin type 1 receptor gene, Agtr1a, and the aldosterone synthase gene, CYP11B2, have been reported in the heart, blood vessels, and kidneys in salt-sensitive hypertension. However, the mechanism of gene regulation in each component of the RAAS in cardiovascular and renal tissues is unclear. Epigenetic mechanisms, which are important for regulating gene expression, include DNA methylation, histone post-translational modifications, and microRNA (miRNA) regulation. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in visceral adipose tissue and the heart of salt-sensitive hypertensive rats. Several miRNAs influence AGT expression and are associated with cardiovascular diseases. Expression of both ACE and ACE2 genes is regulated by DNA methylation, histone modifications, and miRNAs. Expression of both angiotensinogen and CYP11B2 is reversibly regulated by epigenetic modifications and is related to salt-sensitive hypertension. The mineralocorticoid receptor (MR) exists in cardiovascular and renal tissues, in which many miRNAs influence expression and contribute to the pathogenesis of hypertension. Expression of the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene is also regulated by methylation and miRNAs. Epigenetic regulation of renal and vascular HSD11B2 is an important pathogenetic mechanism for salt-sensitive hypertension. [ABSTRACT FROM AUTHOR]

Background: New evidence links elevated blood aldosterone levels to endothelial dysfunction which causes insulin resistance and kidney damage in diabetics. In this study, we aimed to measure serum aldosterone levels and assess the severity of renal injury in different stages of diabetic nephropathy. Methods: The 52 participants in this case-control study were classified according to albuminuria and ACR, and they all had type 2 diabetes mellitus (T2DM): Group (A): 13 healthy individuals as control, Group (B): 13 controlled patients with T2DM with normoalbuminuria and normal albumin/create ratio =30mg/gm, Group (C): 13 patients with T2DM with microalbuminuria and albumin/create ratio 30-300mg/g, and Group (D): 13 patients with T2DM with macroalbuminuria and albumin/create ratio =300mg/g. Serum aldosterone and serum renin were assessed. Results: Serum aldosterone and renin differed significantly between the four groups (p<0.001). In the microalbuminuria diabetic group, a statistically significant strong negative correlation was found between s. aldosterone and high-density lipoprotein (HDL) (p= 0.025), and a statistically significant strong positive correlation was found between s. aldosterone and Alb/Cr ratio & s. renin (p=.0.037, 0.007 respectively). In the macroalbuminuria diabetic group, a statistically significant strong negative correlation was found between s. aldosterone and all of the Alb/Cr ratios, as well as total leucocytic count (TLC) (p=0.009, 0.029 respectively), and a statistically significant strong positive correlation was found between s. aldosterone, HDL, and K (p=0.042, 0.013, respectively). Post hoc analysis of S. Aldosterone showed that there was a statistically significant difference between the four studied groups (P<0.001), and as regards S. renin there was a statistically significant difference between Group A vs Group D (p= P3,0.015), Group B vs Group D (p=0.001), and Group C vs Group D (p<00.001). Conclusion: serum aldosterone level could have a significant role in the progression of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β‐hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone‐dependent, uncontrolled hypertension, including treatment‐resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374‐fold selectivity for CYP11B2 vs. CYP11B1. A first‐in‐human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single‐ and multiple‐dose administration, lorundrostat plasma levels peaked 1–3 h after administration with a t1/2 of 10–12 h. Plasma aldosterone decreased up to 40% with single 100‐mg to 200‐mg doses and up to 70% with single 400 to 800‐mg doses. Plasma aldosterone returned to baseline within 16 h after single 100‐mg doses and multiple once‐daily 120‐mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose‐ and exposure‐dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin‐stimulated cortisol production and only a modest increase in mean serum potassium. [ABSTRACT FROM AUTHOR]

Few studies have investigated the hemodynamic mechanism whereby primary hyperaldosteronism causes hypertension. The traditional view holds that hyperaldosteronism initiates hypertension by amplifying salt-dependent increases in cardiac output (CO) by promoting increases in sodium retention and blood volume. Systemic vascular resistance (SVR) is said to increase only as a secondary consequence of the increased CO and blood pressure. Recently, we investigated the primary hemodynamic mechanism whereby hyperaldosteronism promotes salt sensitivity and initiation of salt-dependent hypertension. In unilaterally nephrectomized male Sprague-Dawley rats given infusions of aldosterone or vehicle, we found that aldosterone promoted salt sensitivity and initiation of salt-dependent hypertension by amplifying salt-induced increases in SVR while decreasing CO. In addition, we validated mathematical models of human integrative physiology, derived from Guyton’s classic 1972 model - Quantitative Cardiovascular Physiology-2005 and HumMod-3.0.4. Neither model accurately predicted the usual changes in sodium balance, CO, and SVR that normally occur in response to clinically realistic increases in salt intake. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models. Together these findings challenge the traditional view of the hemodynamic mechanisms that cause salt-sensitive hypertension in primary aldosteronism. [ABSTRACT FROM AUTHOR]

The physiology of fluid balance in humans should be understood and applied in clinical practice. Fluid balance, when managed accurately and safely, can prevent significant morbidity and mortality. Anaesthesia and critical care patients are often fasted and under physiological stress. Therefore, homeostatic regulation of fluid balance is impaired. A disturbance in normal fluid balance induces a physiological 'stress' response via metabolic, neuroendocrine and immune-mediated systems. Critically unwell patients may suffer morbidity secondary to high-volume fluid losses or oedema. There are three fluid compartments discussed in relation to human fluid balance. The intracellular space is surrounded by extracellular fluid, separated by a water permeable cell membrane. Extracellular fluid (ECF) compartment volume and electrolyte concentration, majorly sodium, must be tightly regulated to avoid osmosis and cell damage. The renal system maintains ECF volume by regulating sodium and osmotic concentration by retaining or excreting water. [ABSTRACT FROM AUTHOR]

Pseudohypoaldosteronism type 1 (PHA1) has two genetically distinct variants, including renal and systemic forms. Systemic PHA type I (PHA1B) has varying degrees of clinical presentation and results from mutations in genes encoding subunits of the epithelial sodium channel (ENaC) including the alpha, beta, and gamma subunits. To date, about 45 variants of PHA1B have been identified. We report a boy with PHA1B, who presented with vomiting, lethargy, and poor feeding due to salt wasting six days after birth. The patient had electrolyte imbalances. A novel SCNN1A (sodium channel epithelial subunit alpha) gene mutation, NM_001038.6:c.1497G>C, with an autosomal recessive pattern, was identified by whole exosome sequencing. This variant was inherited as a homozygote from both heterozygous parents. PHA should be considered in neonates with hyponatremia and hyperkalemia. This case report presents a patient with a novel mutation in SCNN1A that has not been previously reported. Long-term follow-up of identified patients to understand the underlying phenotype-–genotype link is necessary. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of primary aldosteronism (PA) is comprehensive, which includes case-detection testing, case confirmation followed by subtype classification. In certain instances, such as in the setting of spontaneous hypokalemia, suppressed renin activity (PRA) plus plasma aldosterone concentration (PAC) of > 15 ng/dL, one may not proceed with confirmatory tests. However, the quality of evidence behind this approach is very low. This study sought to evaluate the proposed "simplified confirmatory pathway" that can spare confirmatory testing for primary aldosteronism by evaluating the diagnostic performances of the various pre-specified PAC thresholds in combination with findings of suppressed renin and spontaneous hypokalemia. Methods: This is a multi-center, retrospective diagnostic accuracy cohort-selected cross-sectional study. A total of 133 participants aged 18 years and above underwent saline infusion test between January 2010 to March 2024. The outcome measures comprise of the diagnostic performances of the different index test combinations (baseline PAC, baseline PRA and presence of spontaneous hypokalemia): sensitivity, specificity, negative predictive value, positive predictive value, positive likelihood ratio, negative likelihood ratio, and diagnostic accuracy. Data analysis was performed using SPSS 29.0.1.0 & MedCalc 20.218. Results: Of the 133 patients who underwent saline infusion test, 88 (66.17%) were diagnosed with PA. A PAC of > 25 ng/dL plus PRA < 1.0 ng/dL/hr with spontaneous hypokalemia showed the highest specificity at 100% (95% CI 90.51%, 100.00%) and positive predictive value at 100% (85.18 – 100.00%). The minimum acceptable combination criteria were determined to be a PAC of > 20 ng/dL plus PRA < 0.6 ng/dL/hr, and presence of spontaneous hypokalemia. It has high specificity (94.59%; 95% CI 81.81%, 99.34%), positive predictive value (93.55%, 95% CI 78.49%, 98.29%), and moderate positive likelihood ratio (LR+) (6.39, 95% CI 1.61, 25.38) Conclusion: A hypertensive patient with spontaneous hypokalemia and screening findings of PAC > 20 ng/dL and suppressed PRA of < 0.6 ng/ml/hr, may be classified as "overt primary aldosteronism confirmed" and may not need to proceed with dynamic confirmatory testing. Protocol registration number: SRCTN34186253 [ABSTRACT FROM AUTHOR]

Kidney disease frequently coexists with cardiovascular (CV) diseases, and this dual presence significantly amplifies the risk of adverse clinical outcomes. Shared pathophysiological mechanisms and common CV risk factors contribute to the increased expression of mineralocorticoid receptors, which in turn can drive the progression of chronic CV–kidney disorders. The steroidal mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have demonstrated efficacy in improving patient outcomes in cases of heart failure with reduced ejection fraction or after a myocardial infarction, but have limited value in patients with chronic kidney disease. The non-steroidal MRA finerenone has now established itself as a foundational guideline-recommended therapy in patients with diabetic kidney disease. To date, these pharmacological agents have been developed in distinct patient populations. The consequences of their distinct pharmacological profiles necessitate further consideration. They have not undergone testing across the entire spectrum of cardiorenal scenarios, and the evidence base is currently being complemented with ongoing trials. In this review, we aim to synthesize the existing body of evidence and chart the future trajectory for the use of spironolactone, eplerenone and finerenone in improving clinical outcomes across the diverse spectrum of cardiorenal diseases. By consolidating the current state of knowledge, we seek to provide valuable insights for informed decision making in the management of patients with these complex and interconnected conditions. [ABSTRACT FROM AUTHOR]

Renin‐secreting tumours are rare causes of secondary hypertension and hypokalaemia. They are usually surgically curable, hence proper diagnostic work‐up and tumour localisation is essential. In this paper, we present three Swedish patients recently diagnosed with renin secreting tumours, two with reninomas and one with an extrarenal renin‐producing tumour, to illustrate diagnostic challenges. We also discuss the biochemical work‐up, the pros and cons of different imaging techniques (computer tomography [CT], magnetic resonance imaging and [18F]fluorodeoxyglucose‐positron emission tomography‐CT), as well as how renal vein sampling (RVC) may contribute to localisation of the tumour. [ABSTRACT FROM AUTHOR]

The majority of disorders that cause renal potassium wasting present with abnormalities in adrenal hormone secretion. While these findings frequently lead patients to seek endocrine evaluation, clinicians often struggle to accurately diagnose these conditions, delaying treatment and adversely impacting patient care. At the same time, growing insight into the genetic and molecular basis of these disorders continues to improve their diagnosis and management. In this review, we outline a practical integrated approach to the evaluation of renal hypokalemia syndromes that are seen in endocrine practice while highlighting recent advances in understanding of the genetics and pathophysiology behind them. [ABSTRACT FROM AUTHOR]

Primary aldosteronism, characterized by the dysregulated production of aldosterone from 1 or both adrenal glands, is the most common endocrine cause of hypertension. It confers a high risk of cardiovascular, renal, and metabolic complications that can be ameliorated with targeted medical therapy or surgery. Diagnosis can be achieved with a positive screening test (elevated aldosterone to renin ratio) followed by confirmatory testing (saline, captopril, fludrocortisone, or oral salt challenges) and subtyping (adrenal imaging and adrenal vein sampling). However, the diagnostic pathway may be complicated by interfering medications, intraindividual variations, and concurrent autonomous cortisol secretion. Furthermore, once diagnosed, careful follow-up is needed to ensure that treatment targets are reached and adverse effects, or even recurrence, are promptly addressed. These challenges will be illustrated in a series of case studies drawn from our endocrine hypertension clinic. We will offer guidance on strategies to facilitate an accurate and timely diagnosis of primary aldosteronism together with a discussion of treatment targets which should be achieved for optimal patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Tetrandrine (Tet) is the main pharmacological component of Stephania tetrandra S. Moore, which is a well-documented traditional Chinese medicine known for its diuretic and antihypertensive properties. Unraveling the specific targets and mechanisms of Tet involved in inducing diuresis and mitigating hypertension can provide valuable insights into its therapeutic effects. This study aimed to explore the diuretic and antihypertensive targets and mechanisms of Tet using chemical biology coupled with activity analyses in vivo and in vitro. Methods: The diuretic effects of Tet were evaluated using a water-loaded mouse model. The direct target proteins for the diuretic and antihypertensive effects of Tet were determined using chemical biology. Furthermore, the molecular mechanism of Tet binding to target proteins was analyzed using a multidisciplinary approach based on the structure and function of the proteins. Finally, the effects of the Tet-targeted protein on downstream signaling pathways and blood pressure were evaluated in hypertensive model rats. Results: Tet exhibited significant antihypertensive and potassium-preserving diuretic effects. The mechanism underlying these effects involves the modulation of the enzyme activity by covalent binding of Tet to Cys423 of CYP11A1. This interaction alters the stability of heme within CYP11A1, subsequently impeding electron transfer and inhibiting aldosterone biosynthesis. Discussion: This study not only revealed the mechanism of the diuretic and antihypertensive effects of Tet but also discovered a novel covalent inhibitor of CYP11A1. These findings contribute significantly to our understanding of the therapeutic potential of Tet and provide a foundation for future research in the development of targeted treatments for hypertension. [ABSTRACT FROM AUTHOR]

Background. Ouabain, a Na+, K+‐ATPase inhibitor, is elevated in hypertensive patients. Evidence suggests ouabain contributes to hypertension mainly through activation of the sympathetic nervous system (SNS). Renal nerves play a vital role in the regulation of SNS activity, so we hypothesize that renal denervation may attenuate the development of ouabain‐induced hypertension. Methods and Results. Forty Sprague‐Dawley rats were divided into following groups (n = 10 each): control group (sham surgery plus intraperitoneal saline injection), RDN group (renal denervation (RDN) plus intraperitoneal saline injection), ouabain group (sham surgery plus intraperitoneal ouabain injection), and ouabain + RDN group (RDN plus intraperitoneal ouabain injection). After eight weeks, compared with the control group, rats in the ouabain group exhibited elevated blood pressure (P < 0.05), increased plasma epinephrine, norepinephrine, angiotensin II, and aldosterone levels (P < 0.05). These indexes could be significantly ameliorated by RDN. RDN also reduced the thickening of aortic tunica media and downregulated the expression of proliferating cell nuclear antigen (PCNA) in the thoracic aorta induced by ouabain. Masson staining and echocardiography showed that myocardial fibrosis and increased left ventricular mass in the ouabain group could be attenuated by RDN. Conclusions. The present study reveals that renal nerves play an important role in the development of ouabain‐induced hypertension. RDN could inhibit the pressor effect and the myocardial remodeling induced by ouabain potentially via inhibiting catecholamine release and vascular smooth muscle cell proliferation. Clinical studies are needed to explore whether RDN may exhibit better antihypertensive effects on hypertensive patients with high plasma ouabain levels as compared to those with normal plasma ouabain levels. [ABSTRACT FROM AUTHOR]

Aldosterone is a steroid hormone that is important for maintaining the volume and ionic composition of extracellular fluids and is produced in the zona glomerulosa of the adrenal cortex. The basic mechanisms controlling aldosterone secretion are known. However, more detailed studies on the regulation of aldosterone secretion often fail due to the lack of suitable models: although secretion can be studied in cultured adrenocortical cells under defined conditions, the differentiation status of the cells is difficult to control and the complex anatomy of the adrenal cortex is lost. In living animals, the physiological context is intact, but the influences are manifold and the examination conditions cannot be sufficiently controlled. One method that closes the gap between cell models and studies in living animals is the isolated perfused adrenal gland. In the past, this method has provided important data on the pathophysiology of adrenal glands from larger animals, but the technique was not used in mice. Here, we developed a method for isolation and perfusion of the mouse adrenal gland to study aldosterone secretion. This technique preserves the complex anatomical and functional context of the mouse adrenal cortex, to ensure defined experimental conditions and to minimize extra-adrenal influences. Initial series of experiments with the ex vivo perfused mouse adrenal gland show that this model offers the possibility for unique insights into pathophysiological regulatory principles and is suitable for the use of genetically modified mouse models. [ABSTRACT FROM AUTHOR]

Aim: This Phase I study evaluated the safety and early efficacy of an aldosterone synthase inhibitor (BI 690517) in people with diabetes and albuminuric chronic kidney disease. Methods: Double‐blind, placebo‐controlled study (NCT03165240) at 40 sites across Europe. Eligible participants [estimated glomerular filtration rate ≥20 and <75 ml/min/1.73 m2; urine albumin/creatinine ratio (UACR) ≥200 and <3500 mg/g] were randomized 6:1 to receive once‐daily oral BI 690517 3, 10 or 40 mg, or eplerenone 25‐50 mg, or placebo, for 28 days. The primary endpoint was the proportion of participants with drug‐related adverse events (AEs). Secondary endpoints included changes from baseline in the UACR. Results: Fifty‐eight participants were randomized and treated from 27 November 2017 to 16 April 2020 (BI 690517: 3 mg, n = 18; 10 mg, n = 13; 40 mg, n = 14; eplerenone, n = 4; placebo, n = 9) for 28 days. Eight (13.8%) participants experienced drug‐related AEs [BI 690517: 3 mg (two of 18); 10 mg (four of 13); 40 mg (two of 14)], most frequently constipation [10 mg (one of 13); 40 mg (one of 14)] and hyperkalaemia [3 mg (one of 18); 10 mg (one of 13)]. Most AEs were mild to moderate; one participant experienced severe hyperkalaemia (serum potassium 6.9 mmol/L; BI 690517 10 mg). UACR responses [≥20% decrease from baseline (first morning void urine) after 28 days] were observed for 80.0% receiving BI 690517 40 mg (eight of 10) versus 37.5% receiving placebo (three of eight). Aldosterone levels were suppressed by BI 690517, but not eplerenone or placebo. Conclusions: BI 690517 was generally well tolerated, reduced plasma aldosterone and may decrease albuminuria in participants with diabetes and albuminuric chronic kidney disease. [ABSTRACT FROM AUTHOR]

Aldosterone is a kind of steroid hormone produced by the zona glomerulosa (ZG) cells of the adrenal cortex which plays a crucial regulatory role in fluid-electrolyte balance and blood pressure stability. Aldosterone biosynthesis is a calcium-dependent process, and ion channels play a key role in this process. Primary aldosteronism is closely related to mutations in ion channels. Recent studies have highlighted an intriguing relationship between the unique rosette structure of ZG cells and their electrical excitability. Elucidating the connection between rosettes and ZG cell electrical excitability as well as aldosterone secretion leads to a deeper understanding of the mechanisms regulating aldosterone secretion and may provide new insights into the pathogenesis of primary aldosteronism. [ABSTRACT FROM AUTHOR]

Introduction: 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. Objective: 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. Method: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]