Low Renin Research Articles

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.

6568 A Novel Case of Liddle Syndrome in Siblings: Insights into a Rare Genetic Mutation

Abstract Disclosure: A.B. Humrickhouse: None. M. Peltsverger: None. Introduction: Liddle syndrome (LS) is an inherited form of hypertension caused by a mutation in the epithelialsodium channel (ENaC). This condition is characterized by hypertension (HTN), hypokalemia,hyporeninemia, and metabolic alkalosis, although clinical presentation can vary. Asymptomaticearly-onset HTN is common, and if left undiagnosed, it can lead to advanced renal disease,cardiovascular complications, stroke, and even sudden death. Treatment typically involves theadministration of ENaC blockers such as amiloride and triamterene. We present a novel case ofLS in two siblings resulting from a missense mutation in the SCNN1B gene. Case Presentation: The patient is a 24-year-old Hispanic female who presented for evaluation of poorly controlledHTN and severe hypokalemia of 2.9 mmol/L during the first trimester of pregnancy. She wasdiagnosed with HTN at age eighteen. The family history was notable for resistant HTN in herfather and younger brother. Biochemical evaluation revealed normal plasma-free metanephrinesand 24-hour urine-free cortisol. Low plasma renin activity (0.530 ng/mL/hr) and aldosterone(<1.0 ng/dL) were detected on multiple tests. The urine-free cortisol-to-cortisone ratio was <0.5,excluding the diagnosis of apparent mineralocorticoid excess syndrome. The diagnosis of LS wasconfirmed by genetic analysis, which identified a novel heterozygous mutation, c.1859 A>G(Tyr620Cys), in the SCNN1B gene, which had not been reported in the literature to date. Thesame mutation was identified in her brother. The patient was treated with a high dose ofamiloride (15 mg daily), which controlled her HTN and hypokalemia throughout her pregnancy. Discussion: LS is an autosomal dominant disorder with genetic heterogeneity. It is characterized by HTN,low plasma aldosterone and renin activity, and increased potassium excretion. This leads tohypokalemia and metabolic alkalosis. LS is caused by germline mutations found in theSCNN1A, SCNN1B, and SCNN1G genes, which encode the alpha, beta, and gamma subunits ofthe ENaC channel. These mutations lead to enhanced sodium reabsorption in the kidneys,independent of aldosterone. Our patient was diagnosed with hypertension at the age of 18.However, the diagnosis of LS was not made until six years later when she presented during herfirst trimester of pregnancy. Treatment with amiloride effectively controlled her hypertension andhypokalemia, which allowed her to deliver a healthy child. Amiloride was also prescribed for thepatient's brother. A combination of biochemical analysis and genetic testing enables a betterunderstanding of the various clinical presentations, ensuring appropriate treatment andprevention of end-organ damage. Genetic counseling is essential for families affected by LS. Presentation: 6/1/2024

5042 The Prevalence of Primary Aldosteronism in Incidentally Discovered Adrenocortical Adenomas Irrespective of Blood Pressure: A Prospective Cohort Study

Abstract Disclosure: T. Uslar: None. A. Burnier: None. B. Sanfuentes: None. P. Böhm: None. M. Orellana: None. F.J. Guarda: None. R.I. Olmos: None. Á. Huete: None. N. Mertens: None. C. Besa: None. A. Majerson: None. J. Cartes: None. C.E. Fardella: None. F. Allende: None. S. Solari: None. A. Vaidya: Consulting Fee; Self; Corcept Therapeutics, HRA Pharmaceuticals. R. Baudrand: None. Background: Incidental adrenocortical adenomas are commonly found on imaging. Guidelines recommend screening for primary aldosteronism (PA) only when adrenocortical adenomas are accompanied by hypertension or unexplained hypokalemia. Objective: To prospectively evaluate the prevalence of PA in consecutive patients with incidentally discovered adrenocortical adenomas. Design: Prospective, longitudinal, single-center study. Methods: 254 consecutive patients with incidentally discovered adrenocortical adenomas were studied, without any evidence of autonomous cortisol secretion, excluded via 1mg dexamethasone suppression test. A structured protocol was followed, which involved measurement of plasma aldosterone (PAC), 24h-urinary aldosterone and sodium, plasma renin activity (PRA) and/or direct renin (DRC). Samples were collected in the morning, in a seated posture, after withdrawing interfering medications. Possible PA was defined across a continuum by having a low renin (DRC <10 uIU/mL or PRA < 1ng/mL/hr) in addition to one of the following 3 criteria reflecting the severity of PA: 1) overt PA: aldosterone/renin ratio (ARR) >30, PA >15 ng/dL, and/or 24h urinary aldosterone >10 ug/24h; 2) moderate PA: ARR 20-30 and PAC 10-15 ng/dL; 3) mild PA: ARR <20 and PAC 5-10ng/dL. Adjusted linear regressions were performed. Patients were followed longitudinally to evaluate treatment outcomes with paired T-test. Results: Among patients with incidentally discovered adrenocortical adenomas, 35% (n=89/254) had possible PA. Overt, moderate, and mild PA were identified in 10%, 12%, and 13% of the overall sample, respectively. Notably, one in five of these individuals (20%) were normotensive. There were trends across the 3 phenotypes of PA indicating a continuum of severity, including: systolic blood pressure (152 ±19, 144 ±13, 142 ±16 mmHg, p-trend=0.02), resistant hypertension (56%, 38%, 33% p-trend=0.034), daily defined dose of antihypertensives (DDD) (2.9 ±1.8, 2.1 ±1.5, 1.0 ±0.8 p-trend=0.001), higher PAC (30.7 ±29.4, 10.3 ± 2.7, 7.9 ±2.5ng/dL p-trend<0.001) and urinary aldosterone (18.2 ±12, 5.6 ±3.6, 5.5 ±3.9 ug/24h p-trend<0.001). In longitudinal treatment follow-up (mean 28-months), 83% had a favorable response to treatment (84% medical, 16% adrenalectomy). After treatment, there was a decrease in SBP of -31.3 ±23 mmHg in overt PA, -13.2 ±19 mmHg in moderate PA, and -9.4 ±18 mmHg in mild PA (p<0.001 in all groups). Similar trends were observed for DDD, with a significant increase in renin in all groups. Conclusions: Overt PA, as well as a continuum of PA, was frequently seen in up to 35% of incidentally discovered adrenocortical adenomas. These findings underscore the importance of screening for PA in all patients with adrenocortical adenomas, irrespective of blood pressure and/or hypokalemia. Presentation: 6/1/2024

7787 Primary Aldosteronism Medical Treatment Outcomes (PAMO): An International Consensus on Outcome Assessment Criteria and Multicentre Study

Abstract Disclosure: J. Yang: None. J. Burrello: None. J. Goi: None. T.A. Williams: None. W.F. Young: Consulting Fee; Self; Arena Pharmaceuticals, Inc.. Other; Self; Crinetics Pharmaceuticals. P.J. Fuller: None. P. Investigators: None. Primary aldosteronism (PA) is the most common endocrine cause of hypertension. Mineralocorticoid receptor antagonists, at adequate doses, lower blood pressure and cardiovascular risk in patients with PA. However, there is a lack of a standardized approach to medical therapy and subsequent outcomes assessment. We aimed to: 1) establish criteria for assessing outcomes of targeted medical treatment of PA, and 2) evaluate outcomes using these criteria across an international cohort. A panel of 31 PA experts from 31 centres across four continents used the Delphi method, including three rounds of online questionnaires, to reach consensus. Clinical data were then collected from consecutive patients with PA who started targeted medical treatment between 2016 and 2021 at the participating centres. Consensus was reached for six outcomes, including complete, partial, or absent biochemical response, and complete, partial, or absent clinical response. “Complete biochemical response” was defined as “correction of hypokalemia without potassium supplementation, and normalization of plasma renin activity or concentration”; while “absent biochemical response” was defined as “persistent hypokalemia and/or persistently suppressed or low plasma renin activity or concentration without change from baseline”. “Complete clinical response” was defined as “normal blood pressure without additional antihypertensive medications”; while “absent clinical response” was defined as “the same or increased blood pressure compared to before targeted treatment with same or more antihypertensive medications, not counting targeted therapy”. Of 1483 patients (mean age 52y, 48% female) from 28 centers, 232 (16%) had a complete clinical response, and 719 (49%) had a complete biochemical response at the most recent follow-up (median 29 months after treatment initiation). Compared to those with partial or absent clinical response, patients with complete clinical response had a significantly higher proportion of women and lower proportion with diabetes, stroke or left ventricular hypertrophy. They also had a significantly shorter duration of hypertension, lower BMI, higher eGFR and lower defined daily dose of antihypertensives at baseline. In contrast, these differences were not observed in those with a complete, partial or absent biochemical response. The defined daily dose of targeted therapy did not differ across the various response categories. In conclusion, we have established an international expert consensus for standardized criteria to evaluate the response to targeted medical treatment of PA, facilitate comparisons of outcome data and guide clinicians who manage PA. In a retrospective international cohort, less than half of medically-treated patients reached the established biochemical treatment targets. Further work is needed to increase the rate of complete response. Presentation: 6/3/2024

Baseline characteristics of the first 302 patients included for acute malignant hypertension crisis in the prospective multidisciplinary HAMA cohort.

Malignant hypertension has not disappeared and remains the most severe form of hypertension. More than 100 years after its description, many points remain unanswered. Mechanisms, definitions, and optimal treatment are still controversial. In 2019, we decided to launch a prospective multicentre multidisciplinary cohort in France to try to fill these gaps. This study aimed to describe the baseline characteristics of the first 302 included patients and compared these data to already published cohorts. We included patients with severe hypertension associated with severe hypertensive retinopathy and patients filling the HYP MOD (HYPertension MultiOrgan Damage) definition from a broad range of departments (cardiology, nephrology, neurology intensive care unit, emergency department, internal medicine). We collected clinical, biological, imaging, and target organ damage data at admission, along with social and demographic data. We also recorded diagnostic and therapeutic management, adverse events during hospitalization, and characteristics at discharge. We enrolled 302 patients in 32 months (105/year) among 40 centres and different specialties. They mainly included young men (68%, mean age 48.7 ± 14.5 years). Target organ damage involved the eye in 86.7% of patients, kidney in 58.6%, heart in 50%, brain in 32.8%, and Thrombotic Microangiopathy stigmata in 15.6%. Patients with severe retinopathy shared characteristics similar to those included in the most important cohorts already published. We also reported several additional subgroups of interest: one-third of our patients were less than 40 years old, one-third were of non-European origin, 14.3% were included through the multiorgan damage definition, without fundus severe injuries, 22.8% were treated without the use of IV therapy, 40.9% had normal or low renin level, and almost all patients were not on antihypertensive therapy at the time of the enrolment. These preliminary findings already challenge long-standing dogma, raise numerous questions, and provide a solid basis to address them in ancillary studies of the cohort.

Relationship Between Renin, Aldosterone, Aldosterone-to-Renin Ratio and Arterial Stiffness and Left Ventricular Mass Index in Young Adults.

Primary aldosteronism, characterized by renin-independent aldosterone production, is associated with adverse cardiovascular remodeling and outcomes. Elevated cardiovascular risk is observed even in subclinical forms of primary aldosteronism according to studies conducted primarily in middle-aged and elderly populations. This study aimed to assess whether early changes in primary aldosteronism biomarkers during young adulthood are associated with arterial stiffness and left ventricular mass index (LVMI) before the onset of overt disease. The Raine Study is a longitudinal, population-based cohort study in Western Australia that enrolled women during pregnancy. We analyzed the data from the offspring of these women at 17 (2006-2009) and 27 (2016-2018) years of age. Participants with elevated high-sensitivity C-reactive protein (>10 mg/L) and female participants who were on oral contraception were excluded. Pulse wave velocity and aortic augmentation index were measured by SphygmoCor Pulse Wave System at both ages, and aortic distensibility and LVMI were measured by cardiac magnetic resonance imaging at 27 years. Multivariable linear regression was used to examine the relationship between plasma renin, aldosterone, or aldosterone-to-renin ratio and arterial stiffness and LVMI. Mediation analysis was used to test the role of systolic blood pressure. This study included 859 participants at 17 (38.0% female) and 758 participants at 27 (33.2% female) years of age. Females had lower renin concentration at both 17 (20.7 mU/L versus 25.7 mU/L; P<0.001) and 27 (12.0 mU/L versus 15.4 mU/L; P<0.001) years of age; hence, the aldosterone-to-renin ratio was significantly higher at both 17 (18.2 versus 13.5; P<0.001) and 27 (21.0 versus 15.6; P<0.001) years of age in females compared with males. At 27 years of age, a significant association was detected between aldosterone and LVMI in males (β=0.009 [95% CI, 0.001-0.017]; P=0.027) and between aldosterone-to-renin ratio and LVMI in females (β=0.098 [95% CI, 0.001-0.196]; P=0.050) independently of systolic blood pressure and other confounders. No association was found between primary aldosteronism biomarkers and measures of arterial stiffness (pulse wave velocity, aortic augmentation index, and aortic distensibility) at either age. Aldosterone concentration and aldosterone-to-renin ratio were positively associated with the LVMI in young males and females, respectively, independently of systolic blood pressure. Long-term follow-up is required to determine whether the relationship persists over time, and clinical trials are needed to assess the cardiovascular benefits of early interventions to block aldosterone.

Abstract 19: Effect of the endothelin receptor antagonist aprocitentan on plasma endothelin, renin and aldosterone concentrations in patients with resistant hypertension. A biomarker analysis of the PRECISION study.

Hypothesis: Dual endothelin (ET) ET A /ET B receptor antagonist aprocitentan significantly reduced blood pressure in patients with resistant hypertension, who were still hypertensive despite standard background anti-hypertensive drugs including a diuretic, an ARB and a CCB (PRECISION trial, NCT03541174). The effect of aprocitentan in this population, characterized with low renin and elevated aldosterone levels, was assessed on a panel of plasma biomarkers: ET-1, CT-proET-1 (a stable peptide and biomarker for ET-1 production), renin, aldosterone. Methods: From the 730 randomized patients in PRECISION, ET-1 (n=700), CT-proET-1 (n=100, randomly selected), immunoreactive renin (n=679) and aldosterone (n=703) were measured in plasma samples collected at randomization (baseline) and after 4 weeks for either placebo, aprocitentan 12.5 or 25 mg. Results: Four-week placebo treatment had no effect on the studied biomarkers compared to baseline. Treatment with aprocitentan 12.5 and 25 mg increased plasma ET-1 by +34% and +53% and CT-proET-1 by +38% and +47% vs. baseline respectively. Aprocitentan had no effect on renin levels (p&gt;0.05) while decreasing plasma aldosterone by -17% and -24% at the 12.5 and 25 mg dose respectively. Importantly, the reduction in aldosterone did not result in a change in kalemia (see Table ). Conclusions: Aprocitentan caused reactive dose-dependent increases in plasma CT-proET-1 and ET-1, resulting from effective ET receptor blockade. The increase in CT-proET-1 may indicate a compensatory increase in ET-1 de novo synthesis, while the increase in ET-1 may reflect a reduced clearance due to blockade of ET B and increased production. The decrease of aldosterone by aprocitentan confirms the secretagogue role of ET-1 on aldosterone production by adrenal cortical cells via both ET A and ET B receptors This decrease of aldosterone was observed on top of the known decrease induced by an ARB but did not induce hyperkalemia nor aggravation of renal function.

Abstract P428: Angiotensin II vascular abnormalities in 32.5% of 3322 patients with essential hypertension(EH): Use of angiotensin II analogue, saralasin.

Introduction: Renin-AII abnormalities in EH were documented by infusing saralasin , the AII analogue:patients with a abnormal fall in mean BP(&lt;=-8mmHg) indicating a “angiotensinogenic” component to their hypertension and those with a abnormal rise in mean BP(&gt;=8mmHg) indicating, as previously reported, an increased AII vascular sensitivity. Methods: Pa tients tested for secondary HBP in a 1-day BP study with recumbent BP by Arteriosonde, infusion of Lasix, recumbent for 1 hr, stand for 2 hours, measure renin(ng/ml/hr), recumbent for 1/2 hr, infusion of saralasin for 1/2 hr, infusion of 2 l of 0.9%NS over 4 hr and measurement of plasma aldosterone and cortisol. Patients with secondary causes of hypertension, those age&lt;18, those with renal insufficiency, vascular abnormalities (eg diabetes, ASHD) were excluded. Data is now stored using excel 365. Linear regression was calculated using GraphPad Prism version 10.0.0 for Windows, www.graphpad.com. Results: 3691 adults(mean age = 43.4±0.2, 46.3% female) with EH of whom 3322 received saralasin: “Angiotensinogenic” HBP occurred in 12.9% of EH and they were younger[p=.0012,t=3.2]than the EH group, and had a high renin(nl:1.7-6.6). The saralasin-induced fall in BP was -15.6±.6/-13.0±.3. Saralasin increased the % of SBP that was &lt;=130 from 28.1% to 54.7%. Saralasin induced an abnormal BP rise in 19.6% of patients who were older with low renin. There was a significant linear correlation with log 10 of renin for 3322 patients with EH for Δ Mean BP with saralasin[ΔMBP = -9.3*(log renin) + 4.3] (p&lt;.0001,f=1056, r=-.50). Results were similar in 1463 patients on no BP meds. [ΔMBP=-9.5*(log renin) +4.46](p&lt;0.0001,f=470,r=-.50). 12.5% were "angiotensinogenic", 16.7% pressor responders. Conclusions: EH has a significant “angiotensingenic” component (12.9%) and increased AII vascular sensitivity(19.6%), both of which may contribute to their HBP. table: three saralasin groups(BP fall, rise,no Δ) as in abstract(data are mean+se) Change in mean BP to ------------ #(%) -------- initial BP ------- post lasix BP ---- saralasin BP -- Age(yr) - renin i nfusion of saralasin (1)&lt;= -8 mmHg ---- 430(12.9%) -- 160±2*/99±1* --- 147±1*/96±1* ---- 132±1*/83±1* --- 41.1±.7* ---8.1±.4* (2)&gt;=+8 mmHg---- 651(19.6%) -- 170±1 &amp; /103+1 &amp; - 142±1 &amp; /90±1 ns1 160±1 &amp; /101±1 &amp; - 50.2±.5 &amp; --- 1.5±.1 &amp; (3)&gt;8,&lt;-8 mmHg-2241(67.5%) - 155±1 @ /98±1 ! --- 137±1 @ / 90±1 @ - 138±1 @ /90±1 @ - 41.3±.9 ns2 - 3.4±.1 @ ___________________________________________ *p&lt;.00001(1v2), &amp; p&lt;.0001(2v3), @ p&lt;.0001(1v3), ! p=ns(1v3), ns1 (2v3), ns2 (1v3)

Glycyrrhizic acid induced acquired apparent mineralocorticoid excess syndrome with a hyperadrenergic state: a case report

BackgroundSyndrome of apparent mineralocorticoid excess (AME) is characterized by excessive MR stimulation despite low levels of aldosterone. 11Beta-hydroxysteroid dehydrogenase-2 (11βDSH-2) inactivates cortisol to cortisone, preventing cortisol-induced MR activation. Genetic defects in 11βDSH-2 cause AME through accumulation of cortisol in the distal nephron, leading to MR activation induced hypertension, hypokalemia and metabolic alkalosis. Acquired AME can occur due to the ingestion of glycyrrhizic acid, found in licorice root, which inhibits 11βDSH-2 and has additional effects on cortisol homeostasis through inhibition of 11βDSH-1.Case reportWe present a case of acquired AME with a hyperadrenergic symptoms induced by ingestion of Advanced Liver Support, a nutritional supplement produced by Advanced BioNutritionals(R), in a 65-year-old Caucasian female who presented with accelerated hypertension, hypokalemia, metabolic alkalosis and adrenergic symptoms. Cessation of the licorice-containing supplement resulted in complete resolution of the patient's hypertension, symptoms and abnormal lab values. To our knowledge this is the first reported case of AME from this supplement, and the first to describe accompanying hyperadrenergic symptoms.ConclusionsGlycyrrhizic acid is increasingly being found in unregulated nutritional supplements and has the potential to induce a reversable syndrome of AME. Acquired AME should be suspected in individuals who present with hypertension along with hypokalemia, metabolic alkalosis and low plasma renin and serum aldosterone levels.

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.

A Randomized trial assessing Efficacy and safety of Mineralocorticoid receptor Antagonist therapy compared to Standard antihypertensive Therapy in hypErtension with low Renin (REMASTER): rationale and study design

Low-renin hypertension affects 1 in 4 people with hypertension, but the optimal management of this condition is not known. We hypothesize that a large proportion of people with low-renin hypertension is mediated by excess mineralocorticoid receptor (MR) activation and that targeted treatment with an MR antagonist (MRA) will be beneficial. This randomized, single-blinded, titration-to-effect aims to investigate whether targeted treatment in low-renin hypertension with MRA is better compared to standard antihypertensives in terms of blood pressure control and end-organ protection. Adults with hypertension, who are treatment naïve or are receiving up to two antihypertensive agents and have a low direct renin concentration <10 mU/L will be included. Participants with severe hypertension, a secondary cause of hypertension, pregnant, breastfeeding, with moderate-severe cardiovascular and chronic kidney disease, or on medications that confound interpretation of the plasma direct renin or aldosterone concentrations will be excluded. Eligible participants will be randomized 1:1 to either MRA therapy (spironolactone) or standard anti-hypertensive therapy (perindopril+/− amlodipine) for 48 weeks. Anti-hypertensives will be up-titrated every 12 weeks until target blood pressure is achieved. The primary objective will be to determine the total defined daily dose of antihypertensives required to achieve the target blood pressure and change in mean clinic systolic blood pressure at week 48. Current hypertension guidelines do not have specific recommendations for the choice of anti-hypertensive medications for people with low-renin hypertension. The results of this trial could guide future hypertension guidelines.

Quality of life, neuro-humoral status and physical performance in adolescents with sinus tachycardia

The variety of causes, conditions and prognosis of sinus tachycardia (ST) had determined the study examining the quality of life, neurohumoral status as well as ST course in 17-year-old adolescents compared to their peers without heart rhythm disorders. The aim was to study neurohumoral status, quality of life and physical performance in adolescents of both sexes, aged 17 years with diagnosed ST during preventive examination using 24-hour ECG monitoring. Materials and methods. In the open prospective study, 165 adolescents (74 boys and 91 girls) with a mean age of 17.5 ± 0.5 years were enrolled. 24-hour ECG monitoring showed increased heart rate &gt;90 bpm in 12 boys and 19 girls considered themselves healthy. All the children were examined according to a program including 24-hour blood pressure monitoring, heart rate variability, serum concentrations of the main hormones, endothelin and copeptin. Health-related quality of life was measured by the SF-36 questionnaire. A physical work capacity test (PWC170) on a bicycle ergometer was evaluated in an 8-month physical rehabilitation program. Results. Adolescents of both sexes with ST were hypersympathicotonic with humoral dysregulation of the sinoatrial node, grade I arterial hypertension, elevated blood levels of estradiol and osteocalcin and low renin in females. ST in adolescents was associated with reduced physical performance, the restoration of which was accompanied by ST termination. Conclusions. The examination of the 165 adolescents with the mean age of 17.5 years who considered themselves healthy has revealed 12 (16.6 %) males and 19 (22.9 %) females with ST and mean 24-hour heart rate &gt;90 bpm. The children have been clinically diagnosed with inappropriate ST based on international classification, that were inadequate to healthy state. ST was accompanied by hypersympathicotonic type of sinoatrial node humoral dysregulation, grade I arterial hypertension in boys, abnormal pubertal development in girls with elevated blood levels of total estradiol and osteocalcin and low free renin levels, lowered levels of quality of life on role functioning of the SF-36 questionnaire. Adolescents with ST had lower performance in the PWC170 tests. The completion of the 8-week physical rehabilitation program via stationary cycling exercises has resulted in improved physical performance based on the PWC170 test from baseline levels of 8.6 ± 1.9 kgm/min per kg body weight to 12.8 ± 2.1 kgm /min per kg in girls (p = 0.08) and from 13.2 ± 1.5 kgm/min to 15.9 ± 1.6 kgm/min per kg body weight in boys (p &gt; 0.1), that was accompanied by ST termination.

Prevalence and Characteristics of Low-renin Hypertension in a Primary Care Population.

Low-renin hypertension is an underrecognized subtype of hypertension with specific treatment options. This study aims to identify the prevalence in primary care and to compare patient characteristics to those with normal-renin hypertension and primary aldosteronism (PA). In a cohort study, patients with treatment-naïve hypertension were screened for PA with plasma aldosterone and direct renin concentrations. Patients with an elevated aldosterone-to-renin ratio [≥70 pmol/mU (≥2.5 ng/dL:mU/L)] underwent confirmatory testing. All screened patients were then classified as having (1) normal-renin hypertension, (2) low-renin hypertension (direct renin concentration <10mU/L (plasma renin activity ∼<1 ng/mL/hour) and not meeting the criteria for PA), or (3) confirmed PA. Of the 261 patients, 69 (26.4%) had low-renin hypertension, 136 (51.9%) had normal renin hypertension, and 47 (18.0%) had PA. Patients with low-renin hypertension were older and more likely to be female compared to normal-renin hypertension (57.1 ± 12.8 years vs 51.8 ± 14.0 years, P < .05 and 68.1% vs 49.3%, P < .05, respectively) but similar to PA (53.5 ± 11.5 years and 55.3%). However, in an adjusted binomial logistic regression, there was no association between increasing age or sex and low-renin hypertension. The median aldosterone concentration was lower compared to patients with normal-renin hypertension and PA: 279 pmol/L (216-355) vs 320 pmol/L (231-472), P < .05 and 419 pmol/L (360-530), P < .001. At least a quarter of treatment-naïve hypertensive patients in primary care had a low direct renin concentration but did not meet the criteria for PA. Patient characteristics were similar, aside from a lower aldosterone concentration compared to patients with normal-renin hypertension and PA. Further research is needed to understand the underlying pathophysiology of low-renin hypertension and the optimal first-line treatment.

#357 Sex differences in the aldosterone-renin system must be taken into account during screening for primary aldosteronism

Abstract Background and Aims Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Patients with PA are at higher risk for cardiovascular and renal complications than those with essential hypertension. Screening for PA is rarely considered in the assessment of a hypertensive patient, in part because of difficulties in the diagnostic process. Nevertheless, identification of PA is crucial to guide patients towards optimal management, either by mineralocorticoid receptor blockade or by unilateral adrenalectomy, with the latter offering potential cure for patients with aldosterone-producing adenomas (APAs). Numerous studies show inadequate diagnostic accuracy of the aldosterone:renin ratio (ARR) for screening for PA, particularly in females, who have higher ARR variability and lower renin compared to males. Women have a higher risk of false-positive screening results leading to unnecessary confirmatory tests. Use of oral contraception (OC) or hormone replacement therapy (HRT) may also confound the ARR. The aim of this study was to develop improved screening tools for PA, including adjustments for sex-specific differences. Method PROSALDO is a multicenter prospective cohort study designed to test new diagnostic procedures for patients with suspected PA. Medication that interfere with the renin-angiotensin-aldosterone system are withdrawn before laboratory measurements. For screening, the routine ARR is calculated along with additional probability scores based on a peripheral venous steroid hormone profile (PVSP). The latter allows for identification of potentially false-negative ARR results. After a positive screening result of the ARR and/or a high probability score based on the PVSP, PA is confirmed or excluded with a saline infusion test (SIT). PA confirmation is followed by adrenal venous sampling (AVS) to identify patients with unilateral PA. We compared aldosterone, renin and ARR levels between females and males with and without PA. Renin- and sex dependent formulas for aldosterone screening cut-offs were derived from the study population. Logistic regression and the corresponding receiver operating characteristic (ROC) curves were used to determine and compare diagnostic accuracies. Results PA was confirmed in 159 (24.5%) of 649 (328 (50.5%) females and 321 (49.5%) males). Lateralization was shown in 58 out of 117 patients who underwent AVS. In hypertensive patients without PA, ARR was higher in females vs. males (26.4 vs. 11.7 pmol/mU, P &amp;lt; 0.0001), mainly due to a lower renin (9.2 vs. 16.2 mU/L, P &amp;lt; 0.0001). Furthermore, ARRs in patients with vs. without PA showed more overlap in females compared to males. Areas under ROC curves (AUROCs) for the ARR were 0.857 (CI 95%: 0.797-0.902) vs. 0.912 (CI 95%: 0.876-0.938) for females and males respectively. Using liquid chromatography mass spectrometry measurements (LC-MS/MS) of aldosterone, an ARR cut-off of 21.75 pmol/L yielded a sensitivity of 93% with only 45% specificity in females, while for males, a specificity of 66% was obtained for a sensitivity of 97.7%. This meant for females having a higher risk of false-positive screening results (OR 2.36 (CI 95%: 1.65-3.41)), even after excluding patients on OC or HRT (OR 2.17 (CI 95%: 1.5-3.17)). We derived a renin- and sex-dependent formula for the calculation of aldosterone cut-offs, which improved diagnostic accuracy for both males and females (ΔAUROC = 0.05 and 0.045, P &amp;lt; 0.0001 and 0.02 respectively): for a diagnostic sensitivity of 94-95%, specificity was improved to 61% in females and 82% in males. Conclusion Lower renin in females without PA leads to higher ARRs and thus a higher risk of false-positive screening results. Higher overlap of the ARR between females with and without PA compared to their male counterparts weakens utility of the ARR for discrimination of patients with and without PA. Sex- and renin-specific aldosterone cut-offs for screening for PA offer improved diagnostic accuracy. Diagnostic accuracy remains however superior in males, which highlights the need for further optimization of diagnostic procedures specifically in women.

Dietary effects on blood pressure control in primary aldosteronism using a cardiorenal model

Primary aldosteronism (PA) is associated with hypertension (HTN), and these patients have significant lowering of blood pressure (BP) and improved hypokalemia when moving to a DASH dietary intervention (≤65 mEq/day Na+ and ≥120 mEq/day K+). However, current guidelines for PA treatment briefly recommend lowering Na+ intake and make no specific mention of supplementing K+ intake or using DASH in PA. Additionally, high levels of aldosterone increase the risk of developing cardiovascular and chronic kidney disease. However, the impact of DASH diet on hyperkalemia risk and the extent of BP reduction in PA patients with renal dysfunction are unknown. Because continuous monitoring of cardiovascular, neural, and hormonal changes during PA and its treatment cannot be achieved experimentally, we used the mathematical model of human physiology, HumMod, to test the responses to a DASH diet during PA. We hypothesized that both low Na+ and high K+ (DASH) have additive benefits on natriuresis and BP control during PA. We added known renal physiological effects of K+ in HumMod using data from David Young’s work in dogs and further validated the model’s response to changes in Na+ intake based off of chronic salt sensitivity experiments in PA patients. Starting from baseline conditions with normal Na+/K+ intake (150 and 40 mmol/day, respectively), we simulated an aldosterone secreting tumor to gradually increase plasma aldosterone to 20 ng/dL over 3 years. Baseline PA was associated with hypertension (149/85 mmHg), very low endogenous renin and aldosterone secretion, hypokalemia (2.6 mmol/L K+), and tumor aldosterone secretion of 360 μg/day. We simulated a chronic change in dietary intake: 1) Low Na+ diet- Na+ intake fixed at 65 mmol/day with normal K+ intake, 2) High K+ diet - 120 mmol/day K+ intake with normal Na+ intake, or 3) DASH diet- Low Na+ intake and high K+ intake. Lowering Na+ intake without or with high K+ intake (DASH) were associated with lower systolic BP over the first 4 weeks and persisted for 2 years despite continued activation of the renin-angiotensin system and increasing tumor aldosterone secretion. Simulating mineralocorticoid blockade (MCB) was associated with reductions in systolic BP (-17 mmHg), decrease in left ventricular mass, and correction of hypokalemia (~4.0 mmol/L), but BP still remained uncontrolled (134/81 mmHg), partly due to the compensatory increase in renin secretion. Adding DASH to MCB therapy completely normalized BP without inducing hyperkalemia (4.8 mmol/L). Simulating chronic kidney disease by reducing nephron number in the model amplified BP sensitivity to changes in both Na+ and K+ but increased plasma K+ near the hyperkalemic range. These current simulations may help better understand the sequence of physiological events in PA and yield new insights into its diagnosis and management in patients with different baseline renal function. The physiological effects of the DASH diet desperately need to be tested in patients with PA with various baseline renal function as our simulations suggest beneficial effects beyond current treatment guidelines. Supported by the National Institute on Minority Health and Health Disparities (R00 MD014738). 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.

EARLY RESULTS OF THE PROSPECTIVE MULTIDISCIPLINARY HAMA COHORT: DESCRIPTION OF THE FIRST 302 PATIENTS, COMPARISON WITH ALREADY PUBLISHED COHORT AND NOVEL INSIGHTS

Objective: Malignant hypertension has not disappeared and remains the most severe form of hypertension. More than 100 years after its description, many points remain unanswered. Mechanisms, definition and optimal treatment are still discussed. In 2019 we decided to launch a prospective multicenter multidisciplinary cohort in France try filling these gaps. Thjs study aims to describe the baseline characteristics of the first 302 included patients and compare these data to already published cohorts. Design and method: We included patient with severe hypertension and severe hypertensive retinopathy and patients filling the HYP MOD definition from a broad range of department (cardiology, nephrology, neurology intensive care unit, emergency department, internal medicine). We collected clinical data at admission, biological, imaging and target organ damage along with social and demographic data. We also recorded diagnostic and therapeutic management, adverse events during hospitalization and characteristics at discharge. Results: We recruited 302 patients in 32 month (105 / year) among 40 centres and different specialities. They are mostly young men (68%, mean age 48.7 +/- 14.5 years), with several interesting subgroups. Around one third of our patients were less than 40 years old, one third were from non-European origin, 13.6% were included through the multiorgan damage definition, without fundus severe injuries. Target organ damage involves the eye in 86% of patients, kidney in 54%, heart in 56%, brain in 33% and Thrombotic Microangiopathy in 13%. Our patients with severe retinopathy are very similar with those included in the most important cohorts already published. Interestingly, 22.8% of patients were treated without use of IV therapy, most patients were untreated or showed poor observance of treatments and a significant proportion had normal or low renin level. Conclusions: These preliminary findings already challenge long standing dogma, raise many questions and provide a strong basis to address them in ancillary studies of the cohort.

Testing for Primary Hyperaldosteronism in Resistant Essential Hypertensive Patients

Background: Hypertension is a common condition that affects many people all over the world. It could be associated with several complications especially in cases of resistant hypertension. Many clinical practice guidelines recommend screening for primary aldosteronism especially in persons with resistant hypertension owing to the worse prognosis when compared with blood pressure-matched essential hypertension. Objective: The study aimed to screen for primary aldosteronism in high-risk hypertensive Egyptian patients, and to determine the challenges faced in the diagnosis. Material and methods: 50 high-risk hypertensive patients were recruited from the Outpatient Endocrinology Clinic out of 200 hypertensive patients in the period from February 2019 and April 2021. Creatinine, Glycosylated hemoglobin (HBA1c), lipid profile, potassium level, sodium level, Plasma Aldosterone Concentration (PAC), Active Renin Concentration (ARC), and aldosterone/ Renin Ratio (ARR) were assessed in all patients. Results: A series of 50 hypertensive patients screened for PA (26 females and 24 males) with a mean age of 41.88±11.91 SD. We found that 41(82%) patients were receiving antihypertensive medications and 9(18%) patients didn’t receive treatment for hypertension previously. 9(18%) patients kept on no treatment, 6(12%) patients were kept on the same anti-hypertensive medications, and 35(70%) of them were shifted to other anti-hypertensive drugs. 4 patients out of total 50 patients had a positive ARR (&gt;46), while 13(26%) patients out of total 50 hypertensive patients had low renin levels. There was a statistically significant relation between serum Aldosterone/ Renin Ratio (ARR) and serum Potassium (K) with P-value=0.001 (Figure 4), also a statistically significant relation between serum aldosterone/ renin ratio (ARR) and (systolic blood pressure, diastolic blood pressure) with P-value=0.001 was found. Conclusion: We recommend routine screening for PA in high-risk hypertensive patients that could offer targeted treatment before adverse cardiovascular consequences develop.

Low Cortisone as a Novel Predictor of the Low-Renin Phenotype.

To evaluate low cortisone as a predictor of low renin activity and its association with parameters of kidney and vascular damage. A cross-sectional study was carried out in 206 adult subjects. The subjects were classified according to low plasma renin activity (<1 ng/mL × hours) and low cortisone (<25th percentile). Plasma renin activity was associated with aldosterone (r = 0.36; P < .001) and cortisone (r = 0.22; P = .001). A binary logistic regression analysis showed that serum cortisone per ug/dL increase predicted the low-renin phenotype (OR 0.4, 95% CI 0.21-0.78). The receiver operating characteristic curves for cortisone showed an area under the curve of 0.6 to discriminate subjects with low renin activity from controls. The low-cortisone subjects showed higher albuminuria and PAI-1 and lower sodium excretion. The association study also showed that urinary cortisone was correlated with blood pressure and serum potassium (P < .05). This is the first study showing that low cortisone is a predictor of a low-renin condition. Low cortisone also predicted surrogate markers of vascular and renal damage. Since the aldosterone to renin ratio is used in the screening of PA, low cortisone values should be considered additionally to avoid false positives in the aldosterone-renin ratio calculation.

Low renin forms of monogenic hypertension: review of the evidence

&lt;b&gt;Background:&lt;/b&gt; Monogenic hypertension syndromes result from a single genetic mutation and present with severe, refractory hypertension, distinct laboratory abnormalities, and a positive family history. These syndromes are often unrecognized or misdiagnosed as essential hypertension, thus preventing proper treatment. The rise of molecular genetics has brought these conditions to the limelight, and physicians must be kept abreast of the latest in this field. This paper aims to educate doctors to recognize and institute appropriate management early to prevent end-organ damage.&lt;br /&gt; &lt;b&gt;Discussion: &lt;/b&gt;These syndromes all affect sodium transport in the distal nephron of the kidneys. However, they are divided based on the location of the primary disorder, i.e., the adrenal glands or the distal nephron and discussed in that manner. Tables provide an overview of the different syndromes and provide essential information in a snapshot.&lt;br /&gt; &lt;b&gt;Conclusion:&lt;/b&gt; The widespread availability of genetic testing facilities will aid in the earlier diagnosis of these conditions to prevent morbidity.

Novel co-occurrence of hypophosphatemic rickets with 46XY DSD (disorder of sex development) due to a CYP17A1 variant

17-α-hydroxylase deficiency causes a rare type of congenital adrenal hyperplasia (CAH). X-linked hypophosphatemic rickets (XLH) is a rare disorder caused by inactivating mutations in the PHEX gene. We report a novel co-occurrence of XLH with 46XY disorder of sex development due to 17-α-hydroxylase deficiency. A young child reared as a girl, presented as a toddler with genu varus, low phosphorus, normal calcium, and parathormone, and was treated as hypophosphatemic rickets. In early childhood, due to short stature and hypertension, the child was investigated for Turner syndrome. Ultrasound revealed intra-abdominal gonads and an absent uterus. The karyotype was 46XY. Investigations revealed low serum cortisol, renin, normal 17-hydroxyprogesterone, and aldosterone. A year later, a bilateral orchidectomy was performed. Two years later, she was referred to us for further management. Adrenocorticotrophic hormone (ACTH), cortisol, renin, deoxycorticosterone, and clinical exome were advised. She was lost to follow-up for 3 years. On follow-up in early adolescence, she was pre-pubertal; biochemical findings of hypophosphatemic rickets, elevated ACTH, low cortisol, and low normal aldosterone were noted. Clinical exome revealed variants in the CYP17A1 gene (homozygous) causing CAH (17-α-hydroxylase) and PHEX (hemizygous) gene causing XLH. Treatment with hydrocortisone, phosphate, cholecalciferol, and calcitriol was commenced. Hypertension is now well-controlled, but genu varus persists and may require surgical correction.