High Aldosterone Research Articles

Factors Predicting Renal Outcomes in Hypertensive Emergencies With Severe Renal Impairment: A Single-Center Retrospective Study.

Hypertensive emergencies, characterized by elevated blood pressure (BP) and multiple organ damage, have poor prognosis. Patients occasionally show gradual improvement in renal function with appropriate antihypertensive treatment despite renal impairment. However, reports analyzing factors predicting prognosis in patients with hypertensive emergencies and severe renal impairment are limited. This retrospective study aimed to investigate clinical features and predictors of renal outcomes in such patients. Patients admitted to our hospital diagnosed with hypertensive emergency with severe renal impairment (serum creatinine [Cr] level > 2.5 mg/dL) between 2007 and 2021, were enrolled and divided into two groups: those who received renal replacement therapy (RRT) after 3 years (RRT group) and those who did not (non-RRT group); clinical characteristics and laboratory data were compared. Fifteen patients were enrolled, with a median age and serum Cr level of 48 years and 5.97 mg/dL, respectively. No significant between-group difference was observed in serum Cr levels or kidney size. However, the non-RRT group exhibited significantly higher levels of serum lactate dehydrogenase (LDH) levels and significantly lower platelet counts (PLT), suggesting development of microangiopathic hemolysis due to severe endothelial damage. Furthermore, the non-RRT group exhibited lower serum potassium levels than the RRT group, accompanied by high plasma renin activity and serum aldosterone levels, suggesting activation of the renin-angiotensin system (RAS). In the non-RRT group, serum Cr, LDH, potassium levels, and PLT improved significantly after treatment. Serum LDH, potassium levels, and PLT are useful predictors of renal prognosis in hypertensive emergencies with extremely poor renal function. In some cases, severe renal damage can be ameliorated by appropriate antihypertensive therapy. A positive response to treatment often signifies a favorable prognosis. Furthermore, early initiation of RAS inhibitors may be beneficial for lowering BP and providing renal protection.

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.

7859 Primary Hyperaldosteronism And Mild Autonomous Cortisol Secretion (MACS) In Adrenal Incidentaloma

Abstract Disclosure: K. Chanturishvili: None. Q. Gvazava: None. N. Zavrashvili: None. An adrenal incidentaloma is a mass lesion greater than 1 cm in diameter, discovered by radiologic examination, performed for another reason. Widespread use of imaging studies in everyday clinical practice has led to the increased rates of adrenal incidentalomas. Two main questions arise after discovering adrenal mass: is it malignant or benign, and is the mass hormonally active?We present a case of a 55 years old male, with a history of obesity (BMI 35).He had no significant past medical history and was not taking any medications.He presented to our clinic with an upper respiratory tract infection and shortness of breath. Chest CT was done to evaluate for possible pneumonia, where 46 x 30 cm adrenal incidentaloma with -5 HU was discovered.He was referred to our department for endocrine evaluation.Initial assessment revealed previously unknown hypertension with left ventricular hypertrophy. Laboratory workup revealed high aldosterone, suppressed renin, low normal ACTH and DHEA-S, positive 1-mg overnight dexamethasone suppression test (DST- 2.66 ug/dL) and 8-mg DST (2.26 ug/dL).Additionally, the metabolic panel showed prediabetes and hyperlipidemia.Diagnosis of adrenal macroadenoma with cortisol and aldosterone co-secretion was made.Unilateral adrenalectomy was planned. Possible postoperative adrenal insufficiency has been established. Recommendation for proper glucocorticoid coverage was given.In conclusion, evaluation of the functional status of adrenal tumors is essential to uncover hidden medical issues, as s well as to properly guide the patient for intra and postoperative management, avoiding the risks of adrenal insufficiency with proper glucocorticoid coverage. Surgical management of hormonally active adrenal incidentalomas, especially larger >2.4 cm, has potential benefit of improving and preventing metabolic abnormalities: hyperglycemia, dyslipidemia as well as comorbidities such as obesity, hypertension and osteoporosis. Presentation: 6/1/2024

Abstract P306: Aldosterone levels are associated with hypertension in post-menopausal women: the Study of Women’s Health Across the Nation

Introduction: Hypertension (HTN) is the leading cause of premature death in women. Apparent treatment-resistant hypertension (aTRH) is systolic blood pressure (SBP) ≥140 or diastolic BP (DBP) ≥90 mmHg despite treatment with ≥3 antihypertensive medications, or the use of ≥4 antihypertensive medications (irrespective of the BP level). aTRH occurs in approximately 17% of people with treated HTN. High aldosterone may elevate cardiovascular risk; despite causing sodium retention, aldosterone may paradoxically continue to be secreted even when dietary sodium intake is high. Little is known, however, about how aldosterone relates to BP and HTN in women, in whom significant increases in BP, carotid atherosclerosis, and arterial stiffness occur near the time of menopause. We examined the relationships of aldosterone with HTN and aTRH in a cohort of post-menopausal women. Methods: The Study of Women’s Health Across the Nation (SWAN) is a longitudinal cohort of women followed from midlife into late adulthood. This cross-sectional analysis included 999 women (30.3% of the cohort) free of congestive heart failure and with serum aldosterone measured during the 2015-2016 (15th follow-up) study visit. HTN was defined as SBP or DBP ≥140 or ≥90 mmHg, respectively, or use of antihypertensive medications. aTRH was defined as reported use of 4 or more concurrent antihypertensive medications at any visit, or 3 or more concurrent medications and SBP≥140 or DBP≥90 at two consecutive visits. Multivariable logistic regression related HTN or aTRH and aldosterone, adjusting for age, race/ethnicity, and body mass index. Results: In this cohort of women [mean age 66 years (standard deviation:2.7)], the prevalence of HTN and aTRH was 52% and 4.1%, respectively. Women with aTRH had higher median serum aldosterone [8.7 ng/dL, interquartile range (IQR) 5.0-11.7] versus those without (6.7 ng/dL, IQR 2.7-10.5). Each unit increase in aldosterone was associated with a 4% increased odds of HTN (95%CI 1.02,1.06; p<0.001). Similarly, the odds ratio for aTRH in the adjusted model was 1.04 (95%CI 0.99,1.08), although the association was not statistically significant (p=0.09). Conclusion: Aldosterone was positively associated with HTN and there was a non-statistically significant trend toward an association with aTRH in this cohort of post-menopausal women. Our findings suggest that aldosterone within an ostensibly “normal” range is associated with HTN in postmenopausal women.

Fast and reliable quantification of aldosterone, cortisol and cortisone via LC-MS/MS to study 11β-hydroxysteroid dehydrogenase activities in primary cell cultures

Cell culture experiments can support characterization of enzymatic activities in healthy and tumorous human tissues. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) enables simultaneous measurement of several steroids from a single sample, facilitating analysis of molecular pathways involved in steroid biosynthesis. We developed a reliable but fast method for quantification of cortisol, cortisone and aldosterone in cell culture supernatant. Validation, including investigation of matrix-matched calibration, was performed for two different cell types. Utility of the method was demonstrated in the study of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity under conditions of glucocorticoid and mineralocorticoid excess in different cell types. Aldosterone, cortisol and cortisone were extracted by liquid-liquid extraction (LLE) with methyl tert-butyl ether from 1 mL of cell culture supernatant. Steroids were separated on a Kinetex biphenyl column (50 ×2.1 mm, 2.6 µm) with gradient elution of water and methanol containing 2 mM ammonium format and analysed in multiple reaction monitoring mode after positive electrospray ionization. Application of the method included cell culture experiments with two different primary cell types, human coronary artery smooth muscle cells (HCSMC) and human coronary artery endothelial cells (EC). Cells were treated with different concentrations of cortisol, aldosterone and mifepristone, a glucocorticoid receptor antagonist and quantitative PCR was performed. The method exhibits high precision (CV ≤ 6 %) and accuracy (deviation from nominal concentration ≤ 6 %) for concentrations above the limit of quantification (LoQ) which is 0.11, 0.56 and 0.69 nmol/L for aldosterone, cortisone and cortisol, respectively. Calibration curves did not differ when prepared in media or solvent. The method enabled us to confirm activity of HSD11B2 and concentration dependent conversion of cortisol to cortisone in HCSMC (median conversion ratio at 140 nM cortisol = 1.46 %). In contrast we did not observe any HSD11B2 activity in EC. Neither addition of high aldosterone, nor addition of 1 µM mifepristone had impact on glucocorticoid concentrations. Quantitative PCR revealed expression of HSD11B1 and HSD11B2 in HCSMC but not in EC. We present a fast and reliable method for quantification of cortisol, cortisone and aldosterone in cell culture supernatants. The method enabled us to study HSD11B2 activity in two different cell types and will support future experiments investigating mechanisms of target organ damage in conditions of glucocorticoid and mineralocorticoid excess.

Sex-Specific Associations of Aldosterone and Renin with Body Composition: A Population-Based Cohort Study.

Renin-angiotensin-aldosterone system (RAAS) activation is closely linked to obesity; however, the sex-specific associations between RAAS activity and body composition among individuals without obesity are not well understood. To investigate the associations of aldosterone and renin with body composition according to sex in the general population. Population-based cohort study. Québec (Canada). Adults aged 40-69 years enrolled to CARTaGENE between 2009 and 2010 (N=3,687). Plasma aldosterone and renin concentrations. Body composition assessed via anthropometrics (waist circumference and waist-to-hip ratio), bioelectrical impedance (lean body mass, fat mass, and muscle mass), and cardiac magnetic resonance imaging (epicardial and pericardial adipose tissue volumes). The mean (SD) age and body mass index were 55 (8) years and 27.3 (4.8) kg/m2, respectively. Among males, higher aldosterone and renin were associated with increased waist circumference, increased waist-to-hip ratio, increased fat mass, decreased lean body mass, and decreased muscle mass (p<0.05). Aldosterone (p=0.02), but not renin (p=0.43), was associated with increased ectopic cardiac adiposity in males. In contrast, higher renin (p<0.05), but not aldosterone (p≥0.05), was associated with increased waist circumference, increased waist-to-hip ratio, and increased cardiac adiposity in females. Among females, higher renin and aldosterone were associated with increased fat mass (p<0.05) but were not associated with lean body mass or muscle mass (p≥0.05). All aforementioned associations were independent of body weight. Independent of body weight, increased RAAS activity is associated with unfavorable differences in body composition; however, the strength and pattern of association varies by sex.

Evaluation of aldosterone to direct renin ratio, low renin and related Phenotypes in Afro-Colombian patients with apparent treatment resistant hypertension

Apparent resistant hypertension (aTRH) is a significant public health issue. Once low adherence to antihypertensive treatment has been ruled out and true resistant hypertension is diagnosed, aldosterone-direct-renin-ratio (ADRR) aids in the screening of an aldosterone-producing adenoma (APA) and primary aldosteronism (PA). Once PA and other secondary causes have been ruled out, the values of aldosterone and renin allow patients to be classified into phenotypes such as low renin hypertension (LRH), Liddle’s-like (LLph), and primary hyperaldosteronism (PAph). These classifications could aid in the treatment decision-making process. However, optimal cut-off points for these classifications remain uncertain. This study aims to assess the prevalence of these phenotypes and the behavior of different cut-offs of the ADRR in an Afro-Colombian population with apparent resistant hypertension, as well to describe their sodium consumption. Afro-descendant individuals 18 years of age or older, diagnosed with resistant hypertension and attending to a primary care center in Colombia were recruited as volunteers. As part of the study, their plasma renin concentration (PRC) and plasma aldosterone concentration (PAC) were measured. The phenotypes were categorized into three groups based on multiple cut-off points from different authors: low renin and low aldosterone phenotype (LLph), low renin and high aldosterone phenotype (PAph), and high renin and high aldosterone phenotype, referred to as the renal phenotype (Rph). The prevalence of ADRR values exceeding the cut-off and phenotypes were calculated. A linear regression model was derived to assess the effect of sodium consumption with PAC, PRC and ADRR. A total of 88 patients with aTRH were included. Adherence to at least 3 antihypertensive medications was 62.5%. The median age was 56 years (IQR 48–60), 44% were female, and 20% had diabetes. The study found that the prevalence of ADRR values exceeding the cut-off ranged from 4.5 to 23%, while low-renin hypertension (LRH) varied from 15 to 74%, Rph was found in approximately 30 to 34% of patients, PAph in 30 to 51%, and the LLph in 15 to 41%, respectively, depending on the specific cut-off value by different authors. Notably, sodium consumption was associated with lower aldosterone (β − 0.15, 95% CI [− 0.27, − 0.03]) and renin concentrations (β − 0.75, 95% CI [− 1.5, − 0.02]), but ADRR showed no significant association with sodium consumption. There were no significant differences in prevalences between the groups taking < 3 vs ≥ 3 antihypertensive medications. Altered aldosterone-direct-renin-ratio, low renin hypertension, Liddle’s-like, and primary hyperaldosteronism are prevalent phenotypes in patients within Afro-Colombian patients with apparent treatment-Resistant hypertension.

Immune Mechanisms in Hypertension.

It is now apparent that immune mediators including complement, cytokines, and cells of the innate and adaptive immune system contribute not only to blood pressure elevation but also to the target organ damage that occurs in response to stimuli like high salt, aldosterone, angiotensin II, and sympathetic outflow. Alterations of vascular hemodynamic factors, including microvascular pulsatility and shear forces, lead to vascular release of mediators that affect myeloid cells to become potent antigen-presenting cells and promote T-cell activation. Research in the past 2 decades has defined specific biochemical and molecular pathways that are engaged by these stimuli and an emerging paradigm is these not only lead to immune activation, but that products of immune cells, including cytokines, reactive oxygen species, and metalloproteinases act on target cells to further raise blood pressure in a feed-forward fashion. In this review, we will discuss these molecular and pathophysiological events and discuss clinical interventions that might prove effective in quelling this inflammatory process in hypertension and related cardiovascular diseases.

Behcet's disease presenting as malignant hypertension induced by renovascular hypertension.

Hypertension is an uncommon manifestation of Behcet's disease, which is also an uncommon cause of renovascular hypertension. We herein report a case of malignant hypertension associated with unilateral renal artery stenosis due to vascular Behcet's disease. A 19-year-old man, who had no significant medical history, was referred to ophthalmology at our hospital because he was suspected to have uveitis and Vogt-Koyanagi-Harada syndrome. In addition to poor eyesight, he had been aware of a fever, loss of appetite, and weight loss for a month. He was admitted with markedly elevated blood pressure (222/140mmHg), hypertensive retinopathy, and acute kidney injury, who was diagnosed with malignant hypertension. Laboratory findings showed high plasma renin activity and plasma aldosterone concentration, hypokalemia, and elevated inflammatory response. Computed tomography showed an atrophic right kidney and a compensatorily enlarged left kidney. Renal computed tomography angiography revealed severe and diffuse stenosis of the right renal artery, and stenosis of the ostium of celiac artery. Since he was suspected to have uveitis and his inflammatory responses were elevated on admission, we listed Behcet's disease as a differential diagnosis. Medical interview and examination focusing on Behcet's disease revealed that the patient had recurrent oral aphthous lesions and folliculitis, and a positive pathergy test, which led to the patient being diagnosed with vascular Behcet's disease. After admission, his blood pressure was well controlled with multiple antihypertensive drugs including an angiotensin receptor/neprilysin inhibitor, and his oral aphthous lesions and skin lesion were improved with colchicine. When young men who are at a higher risk for vascular Behcet's disease show renovascular hypertension with an elevated inflammatory reaction, vascular Behcet's disease should be considered as a differential diagnosis.

The Association of Adiposity and RAAS With Incident Diabetes in African Americans: The Jackson Heart Study.

The renin-angiotensin-aldosterone system (RAAS) and adiposity measures are independently associated with the development of diabetes in African American adults. However, studies have not examined the combined interaction between RAAS and adiposity measures in relation to diabetes risk in African American adults. We examined the longitudinal association of combined RAAS and adiposity measures with incident diabetes among African American adults in the Jackson Heart Study. African American adults were assessed at baseline (2000-2004) and over 12 years of follow-up. RAAS, anthropometric (waist circumference [WC], body mass index), and adipokine (adiponectin, leptin, leptin to adiponectin ratio [LAR]) measures were collected at baseline. Aldosterone, WC, and LAR were chosen as the best predictor variables. The final model, adjusting for age, sex, education, occupation, systolic blood pressure, smoking, physical activity and RAAS-altering medications, incorporated these variables and their interactions (WC*aldosterone + LAR*aldosterone) to explore their impact on incident diabetes. Among 3219 participants without diabetes at baseline, there were 554 incident cases over a median follow-up period of 7.5 years. Aldosterone, WC, and LAR were positively associated with incident diabetes (all P < .05). A significant interaction was found between WC and aldosterone, with a greater association among individuals with lower WC. This interaction was significant in participants with prediabetes but not in those with normoglycemia. No significant interaction was found between log-LAR and aldosterone with risk of incident diabetes. Higher aldosterone in participants is associated with greater risk of diabetes, particularly among individuals with prediabetes and lower WC.

#1810 The association between circulating fibroblast growth factor 23 (FGF23) and serum aldosterone level in chronic kidney disease patients

Abstract Background and Aims Chronic kidney disease (CKD) remains a major health problem, till now, diagnosis of CKD depends on radiology and estimated glomerular filtration rate (eGFR). Therefore, there is an ultimate need for new sensitive prognostic and diagnostic biomarkers for diagnosis and progression of CKD. CKD is accompanied by increased levels of circulating fibroblast growth factor 23 (FGF23) and aldosterone levels. In the current study, we aim to evaluate the association between circulating FGF23 and serum aldosterone levels in CKD patients and to test the hypothesis that aldosterone may be a direct driving factor of increased FGF23 secretion in CKD patients. Method This cross section observational study was carried out at Kafr El Sheikh University Hospital's internal medicine department which enrolled 140 subjects that were divided into two groups: group I: 70 patients with various stages of newly diagnosed chronic kidney disease who did not receive renin-angiotensin-aldosterone system (RAAS) blocker yet (CKD stage 1 –5) &amp; group II: 70 apparently healthy subjects (of corresponding age and sex as a control group). We detected serum FGF-23 and Serum aldosterone using enzyme-linked immunosorbent assay (ELISA). Results A strong correlation was identified between FGF-23 and serum aldosterone in group I (p = &amp;lt; 0.001), there was remarkably stage dependent strong associations in CKD patients. High FGF-23 and serum aldosterone significantly independently increase risk of CKD by 1.15 and 1.043 folds respectively. The best cutoff of FGF-23 in prediction of kidney injury is ≥59.735 with area under curve 0.977, sensitivity 91.4%, specificity 90%, positive predictive value 90.1%, negative predictive value 91.3% and overall accuracy 90.7% (p &amp;lt; 0.001). The best cutoff of aldosterone in prediction of kidney injury is ≥117.59 with area under curve 0.978, sensitivity 92.9%, specificity 88.6%, positive predictive value 89%, negative predictive value 92.5% and overall accuracy 90.7% (p &amp;lt; 0.001). Conclusion FGF23 and aldosterone may be used as markers in CKD progression. aldosterone may be a direct driving factor of increased FGF23 secretion in CKD patients.

#1418 Phase II dose-selection, randomised, controlled trial of ASi BI 690517 with and without EMPA in CKD: subgroup analysis by T2D status

Abstract Background and Aims High aldosterone levels accelerate chronic kidney disease (CKD) progression. BI 690517 is a highly selective aldosterone synthase inhibitor (ASi) in clinical development for CKD treatment. ASi may reduce deleterious haemodynamic, inflammatory, and fibrotic actions of aldosterone. Coadministration of BI 690517 with a sodium-glucose cotransporter-2 inhibitor may also mitigate the risk of hyperkalaemia. This multinational, randomised, dose-finding, Phase II trial (NCT05182840) investigated the efficacy and safety of BI 690517, given either alone or in combination with empagliflozin (EMPA), in people who had CKD with or without type 2 diabetes (T2D) [1, 2]. Here, we present an analysis by T2D status (pooled for background randomizedon to EMPA or placebo [PBOEMPA]). Method Adults with CKD receiving a maximally tolerated dose of a renin-angiotensin system inhibitor were randomized (R1) 1:1 to an 8-week run-in to receive background EMPA 10 mg or PBOEMPA, then randomized again (R2) 1:1:1:1 to receive BI 690517 (3 mg, 10 mg, or 20 mg) or PBOASI for 14 weeks. The primary endpoint was the change from R2 baseline in urine albumin:creatinine ratio (UACR) in the first morning void of urine at Week 14. A secondary endpoint was UACR response (≥30% reduction from R2 baseline in UACR at Week 14). Changes in systolic blood pressure (SBP) and estimated glomerular filtration rate (eGFR) from R2 baseline to Week 14 were also assessed, as were safety outcomes. Results Of 586 people randomized at R2, 414 (70.6%) were reported to have T2D and 172 (29.4%) did not have T2D. Baseline demographics and clinical characteristics were mostly similar between these two groups [1]; however, those with T2D had higher mean BMI (30.6 vs 28.3 kg/m2), SBP (135.3 vs 130.2 mmHg) and eGFR (53.0 vs 49.4 mL/min/1.73 m2), and higher median UACR (444.7 vs 409.2 mg/g) than those without T2D. BI 690517 consistently reduced UACR versus PBOASI in people with and without T2D (p = 0.38, indicating no difference in treatment effect between these groups), with the largest reductions observed in the 10 mg and 20 mg dose groups; however, for the 3 mg dose group, UACR reduction was only observed in people with T2D (Figure). UACR response rates (≥30% reduction) were achieved in more than half of people with and without T2D in the BI 690517 10 mg and 20 mg dose groups, with the highest response rates in those also receiving EMPA (10 mg dose group: with T2D, 74.3%; without T2D, 64.0%). Decreases in SBP and small decreases in eGFR were also observed in people with and without T2D in response to BI 690517 10 mg and 20 mg, and were consistent with the observed changes in the overall population; however, for the 3 mg dose group, eGFR reduction was only observed in people with T2D. Adverse events leading to discontinuation in BI 690517 10 mg and 20 mg dose groups were more common among people with T2D than those without T2D who were receiving the same dose of BI 690517. Conclusion In people who had CKD, with or without T2D, BI 690517 dose-dependently reduced UACR, with high rates of UACR response suggestive of additive beneficial effects when given with EMPA.

Calcineurin inhibitor effects on kidney electrolyte handling and blood pressure: tacrolimus versus voclosporin.

Calcineurin inhibitors affect kidney electrolyte handling and blood pressure through an effect on the distal tubule. The second generation calcineurin inhibitor voclosporin causes hypomagnesemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally. Rats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric blood pressure recordings, and analysis of mRNA and protein levels of distal tubular transporters at day 28. Compared to vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at mRNA and/or protein level, including the sodium-chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium-calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium-chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased blood pressure, whereas voclosporin caused a gradual but persistent increase in blood pressure which was further characterized by high renin, normal aldosterone, and low endothelin-1. In contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two calcineurin inhibitors.

Association Between Plasma Aldosterone Concentration and Intraglomerular Hemodynamics in Primary Aldosteronism.

In primary aldosteronism (PA), aldosterone could affect glomerular hemodynamics by elevating renal vascular resistance and glomerular capillary pressure. However, the relationship between plasma aldosterone concentrations (PAC) and glomerular hemodynamics including efferent arteriolar resistance (Re), and afferent arteriolar resistance (Ra) in humans is still unclear. The aim of this study was to investigate the relationships of PAC with intraglomerular hemodynamic parameters in patients with PA. An observational study of glomerular hemodynamics was performed using simultaneous measurements of plasma clearance of para-aminohippurate and inulin (Cin; glomerular filtration rate (GFR)) in 17 patients with PA. Kidney function was evaluated by Cin, estimated GFR based on serum creatine (eGFRcre) and serum cystatin C (eGFRcys) and creatine clearance (Ccr). Intraglomerular hemodynamic parameters, including Re, Ra, and intraglomerular hydrostatic pressure (Pglo) were calculated using Gomez's formulae. In the 17 PA cases, PAC was significantly correlated with Cin (rho = 0.752, P = 0.001) and eGFRcys (rho = 0.567, P = 0.018), but was not correlated with eGFRcre and Ccr. PAC was also significantly correlated with Pglo, Re, and urinary protein/day (rho = 0.775, P = 0.0004, rho = 0.625, P = 0.009, and rho = 0.625, P = 0.007, respectively). Multivariable regression analysis showed that PAC was significantly associated with Cin and Re. In comparing aldosterone-producing adenoma (APA) and non-APA cases, Cin was significantly elevated in APA (P = 0.037), whereas eGFRcre, eGFRcys, and Ccr were not. Re tended to be higher in APA (P = 0.064). These results suggest high aldosterone causes glomerular hyperfiltration by constricting Re. Cin, but not eGFRcre and Ccr, may be useful for evaluating kidney function in PA.

Balancing sodium and potassium: Implication of mTORC2-mediated ENaC activation in DCT2 and early CNT for potassium balance in high dietary potassium

Background: The activity of the epithelial sodium ion channel, ENaC, and ENaC-dependent potassium (K+) secretion through ROMK are influenced by both aldosterone-dependent and independent mechanisms in response to dietary potassium (K+). While ENaC activity in the late connecting tubule (CNT) and cortical collecting duct (CCD) depends on aldosterone, it is aldosterone-independent in the late distal convoluted tubule (DCT2) and early CNT (eCNT). Aldosterone-stimulated ENaC activity relies on SGK1, transcriptionally upregulated by aldosterone and subsequently phosphorylated and activated by mTOR complex-2 (mTORC2). Recent evidence suggests that high potassium can rapidly activate mTORC2/SGK1 signaling to stimulate ENaC. In this study, we explore mTORC2’s role in K+ secretion and aldosterone-independent ENaC regulation. Methods: Rictor, a core component of mTORC2, was selectively knocked out (KO'd) in DCT2, CNT and CD by utilizing Calbindin as Cre-driver (CRKO mice) or late CNT and CD, by employing AQP2 as the Cre-driver (ARKO mice). Both wild-type (WT) and KO mice were subjected to a high potassium (HK) diet for short-term (4 hours) or medium-term (48 hours) periods, enabling the monitoring of both the early response and prolonged adaptation to the HK diet. Parameters assessed include urinary and blood electrolyte levels, renal transporter expression, activity and localization, and mTORC2 target phosphorylation. Results: On a normal K+ diet, both KO mice maintained Na+ and K+ balance but CRKO mice had elevated aldosterone levels. After short-term (4-hour) HK intake, CRKO mice had disrupted Na+ and K+ balance, reduced K+ excretion and hyperkalemia. In contrast, ARKO mice maintained Na+ and K+ balance with elevated aldosterone. On a prolonged HK diet (48 hours), CRKO mice had severe hyperkalemia, reduced GFR and significantly elevated aldosterone level. Immunofluorescence studies indicated markedly reduced apical localization of active ENaC in DCT2/eCNT of CRKO mice. Conversely, ENaC apical localization in the late CNT and CCD was mostly unaffected. Phosphorylation of mTORC2 targets involved in ENaC regulation, such as SGK1, and SGK1’s target, Nedd4-2, was also reduced in CRKO mice. ARKO mice maintained ion balance with normal K+ levels but significantly increased aldosterone levels and maintained ENaC apical localization in the late CNT and CCD. Conclusions: The data suggest that high aldosterone can compensate mTORC2 deficiency and maintain ENaC activity in the late CNT and CCD. However, mTORC2 activity is crucial for maintaining ENaC activity in the late DCT and early CNT (aldosterone-independent) and preserving potassium balance during high dietary potassium intake. National Institutes of Health (R01- DK56695), James Hilton Manning and Emma Austin Manning Foundation. 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.

ASSOCIATION OF SEVERE SLEEP APNOEA IN PRIMARY ALDOSTERONISM

Objective: It is well known that sleep apnoea and primary aldosteronism are related. However, it is unclear whether aldosterone excess contributes to the severity of sleep apnoea. We investigated factors correlated with sleep apnoea in patients with primary aldosteronism: the endocrine system, including aldosterone, cardiac function, renal function, and blood pressure. Design and method: We performed a 3% oxygen saturation index with a pulse oximeter in 50 patients (54% male, 49 ± 7.3 years) diagnosed with primary aldosteronism scheduled for adrenal vein sampling in 2017-2020. 3% oxygen saturation index results were classified as mild (less than 5), moderate (5-15), or severe(15 and above) sleep apnoea. In addition, we compared aldosterone (radioimmunoassay), renin activity, aldosterone/renin activity, brain natriuretic peptide, estimated glomerular filtration rate and blood pressure at the initial visit in the severe group and other groups. Results: The severe group did not have higher aldosterone than the mild (192.7 ± 114.7 vs 238.9 ± 128.8 pg/mL, P=0.640) and moderate (192.7 ± 114.7 vs 187.5 ± 85.5 pg/mL, P=0.995) groups, and the same results were obtained for renin activity and aldosterone/renin activity. In other parameters, estimated glomerular filtration rate was not significantly different between groups, but systolic blood pressure at the initial visit in the severe group was significantly higher than in the mild (175.3±25.7 vs 144.8±18.7 mmHg, P=0.003) and moderate (175.3±25.7 vs 143.0±18.5 mmHg, P=0.003) groups. Similarly, brain natriuretic peptide in the severe group was significantly higher than in the mild (53.5±90.0 vs 12.7±8.3 pg/mL, P=0.020) and moderate (53.5±90.0 vs 10.7±11.2, P=0.014) groups. Conclusions: Our results showed that aldosterone excess did not contribute to the severity of sleep apnoea. However, severe sleep apnoea was significantly associated with elevated systolic blood pressure and brain natriuretic peptide.

POLYCYSTIC OVARY SYNDROME (PCOS) AND ITS TREATMENT AS CAUSE OF SECONDARY ALDOSTERONISM: A DOG CHASING ITS TAIL

Objective: Polycystic Ovary Syndrome (PCOS) is a complex endocrine-metabolic disorder affecting about 7% of childbearing women. PCOS is characterized by anovulation, hyperandrogenism, insulin resistance and it is associated with an increased cardiovascular risk. PCOS patients may exhibit high blood pressure and signs of hydro-saline retention. Therefore, clinicians would be interested in performing hormonal screening for secondary hypertension. Design and method: We perform the aldosterone/direct renin concentration ratio as a screening test for primary aldosteronism (PA). The test was proceed after serum potassium correction and previous a wash-out period of interfering medications. The recumbent saline suppression test was performed with infusion of 2L NaCl 0.9% in 4 hours under standardized salt intake (9gr/24h). Aldosterone and direct renin were determined by chemiluminescent immunoassay technology (DiaSorin®). Results: A 33yrs old woman attended our renal outpatient clinic because of recurrent episodes of generalized swelling, diuresis contraction and fluid retention. The patient, known for PCOS, was treated with combined oral contraceptives and loop diuretics. She had no history of hypertension, but she repeatedly displayed very high aldosterone values. Clinical examination was unremarkable, in-office and home blood pressure values were normal. Laboratory data showed normal renal function and the absence of acid-base disorders; serum potassium was at lower limit of normal. A CT-scan showed normal adrenal glands. We performed a recumbent saline suppression test, previous a wash-out period of oral contraceptives (&gt; 6 weeks) and loop diuretics (&gt; 2 weeks). The results listed below are consistent with a baseline hyperaldosteronism with normal aldosterone adrenal response to volume expansion, excluding PA. Several years before, the same results were presented, without suspension of the oral contraceptives. Conclusions: In patients with PCOS the increased adrenal production of aldosterone is usually secondary and independent from the renin-aldosterone axis (direct stimulation of adrenal zona glomerulosa via testosterone). Other iatrogenic factors may affect the renin-aldosterone values, such us the use of oral contraceptives and diuretics. Therefore, a confirmatory test performed under standardized conditions is often required, in order to exclude primary versus secondary forms of hyperaldosteronism.

Contralateral Suppression in Adrenal Venous Sampling Predicts Clinical and Biochemical Outcome in Primary Aldosteronism.

The role of hormone parameters at adrenal venous sampling (AVS) in predicting clinical and biochemical outcomes remains controversial. To investigate the impact of hormone parameters at AVS under cosyntropin stimulation on lateralization and on complete biochemical and clinical outcomes. We retrospectively evaluated 150 sequential AVS under cosyntropin infusion. The bilateral successful cannulation rate was 83.3% (n = 140), 47.9% bilateral and 52.1% unilateral. The lateralization index, aldosterone/cortisol ratio (A/C) in the dominant adrenal vein (AV), and relative aldosterone secretion index (RASI = A/C in AV divided by A/C in inferior vena cava) were assessed. The contralateral suppression (CS) percentage was defined by (1 - nondominant RASI) * 100. A nondominant RASI <0.5 (CS >50%) had 86.84% sensitivity and 92.96% specificity to predict contralateral lateralization. An A/C ratio in dominant AV >5.9 (74.67% sensitivity and 80% specificity) and dominant RASI >4.7 (35.21% sensitivity and 88.06% specificity) had the worst performance to predict ipsilateral lateralization. Complete biochemical and clinical cure was significantly more frequent in the patients with CS >50% [98.41% vs 42.86% (P < .001) and 41.94% vs 0% (P < .001)]. CS correlated with high aldosterone at diagnosis (P < .001) and low postoperative aldosterone levels at 1 month (P = .019). Postoperative biochemical hypoaldosteronism was more frequent in patients with CS >50% (70% vs 16.67%, P = .014). In multivariable analysis, a CS >50% was associated with complete biochemical cure [odds ratio (OR) 125, 95% confidence interval (CI) 11.904-5000; P = .001] and hypertension remission (OR 12.19, 95% CI 2.074-250; P = .023). A CS >50% was an independent predictor of complete clinical and biochemical cure. Moreover, it can predict unilateral primary aldosteronism and postoperative biochemical hypoaldosteronism. Our findings underscore the usefulness of CS for clinical decision-making.

Dietary sodium alters aldosterone's effect on renal sodium transporter expression and distal convoluted tubule remodelling.

Aldosterone is responsible for maintaining volume and potassium homeostasis. Although high salt consumption should suppress aldosterone production, individuals with hyperaldosteronism lose this regulation, leading to a state of high aldosterone despite dietary sodium consumption. The present study examines the effects of elevated aldosterone, with or without high salt consumption, on the expression of key Na+ transporters and remodelling in the distal nephron. Epithelial sodium channel (ENaC) α-subunit expression was increased with aldosterone regardless of Na+ intake. However, ENaC β- and γ-subunits unexpectedly increased at both a transcript and protein level with aldosterone when high salt was present. Expression of total and phosphorylated Na+ Cl- cotransporter (NCC) significantly increased with aldosterone, in association with decreased blood [K+ ], but the addition of high salt markedly attenuated the aldosterone-dependent NCC increase, despite equally severe hypokalaemia. We hypothesized this was a result of differences in distal convoluted tubule length when salt was given with aldosterone. Imaging and measurement of the entire pNCC-positive tubule revealed that aldosterone alone caused a shortening of this segment, although the tubule had a larger cross-sectional diameter. This was not true when salt was given with aldosterone because the combination was associated with a lengthening of the tubule in addition to increased diameter, suggesting that differences in the pNCC-positive area are not responsible for differences in NCC expression. Together, our results suggest the actions of aldosterone, and the subsequent changes related to hypokalaemia, are altered in the presence of high dietary Na+ . KEY POINTS: Aldosterone regulates volume and potassium homeostasis through effects on transporters in the kidney; its production can be dysregulated, preventing its suppression by high dietary sodium intake. Here, we examined how chronic high sodium consumption affects aldosterone's regulation of sodium transporters in the distal nephron. Our results suggest that high sodium consumption with aldosterone is associated with increased expression of all three epithelial sodium channel subunits, rather than just the alpha subunit. Aldosterone and its associated decrease in blood [K+ ] lead to an increased expression of Na-Cl cotransporter (NCC); the addition of high sodium consumption with aldosterone partially attenuates this NCC expression, despite similarly low blood [K+ ]. Upstream kinase regulators and tubule remodelling do not explain these results.