Renin Activity Research Articles

Comparative Analysis of Liquid Chromatography-Tandem Mass Spectrometry and Radioimmunoassay in Determining Plasma Aldosterone Concentration and Plasma Renin Activity for Primary Aldosteronism Screening.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) accurately measures plasma aldosterone concentration (PAC), but its correlation with radioimmunoassay (RIA), equivalent RIA levels, and optimal cutoff for PAC and aldosterone-to-renin ratio (ARR) in primary aldosteronism (PA) screening have not been determined in a Korean population. Our study of 127 patients who underwent diagnostic testing for PA showed that the LC-MS/MS and RIA methods have good correlation, with a mean bias of 29.3% for PAC. An LC-MS/MS PAC level of 11.7 ng/dL was equivalent to an RIA PAC level of 15 ng/dL. Receiver operating characteristic curve analysis showed that an LC-MS/MS PAC level of 10.3 ng/dL and LC-MS/MS ARR level of 20.0 provided sensitivity of 73.1% with a specificity of 57.3% and sensitivity of 92.3% with a specificity of 14.7%, respectively. When the LC-MS/MS method is used for PA screening, an adjustment of cutoff values is necessary.

Antihypertensive effects and changes in extracellular water content by mineralocorticoid receptor antagonists in patients with primary aldosteronism.

In primary aldosteronism (PA), non-suppressible excessive aldosterone secretion due to dietary salt intake significantly contributes to hypertension and cardiovascular complications. Blocking the overactivation of mineralocorticoid receptors (MRs) with mineralocorticoid receptor antagonists (MRAs) is a cornerstone for the medical treatment of PA. However, the role of MRAs in controlling hypertension remains unclear. This study aimed to explore the relationship between changes in body composition parameters (determined by bioelectrical impedance analysis), blood pressure (BP) levels, serum potassium (K+) levels and Study 36-Item Short-Form Health Survey (SF-36) scores after MRA treatment in 50 patients with PA. Treatment with MRAs significantly decreased the systolic BP (SBP) and diastolic BP (DBP) levels and extracellular water (ECW) volume, while it increased the serum K+ levels, active renin concentrations (ARCs), and scores on several SF-36-based quality of life (QOL) subscales. ECW change (ΔECW) and serum K+ change were not significantly associated with changes in SBP and DBP levels. ΔECW showed a significant inverse correlation with ΔARC, suggesting that ARC increases with decreasing ECW volume due to renal MR activity blockade and that ARC is a highly sensitive indicator of ECW volume. In the stratified analysis of patients with PA, ECW volume was significantly decreased in those aged ≥60 years and those with a body mass index of ≥25 kg/m2. In conclusion, MRA treatment showed antihypertensive, biochemical, and QOL improvement effects in patients with PA. The antihypertensive effect may not be related to the decrease in ECW volume due to renal MR activity blockade. Evaluation of ECW using BIA in patients with PA treated with MRAs. Abbreviations: ARC, active renin concentration; BIA, bioelectrical impedance analysis; BMI, body mass index; BP, blood pressure; ECW, extracellular water; K+, serum potassium; MRA, mineralocorticoid receptor antagonist; PA, primary aldosteronism; QOL; quality of life; Δ, parameter changes after MRA treatment.

Molecular Imaging of Renin Activity using Fluorogenic Nanoprobes for Precision Antihypertensive Therapy

AbstractLife‐threatening hypertension remains inadequately controlled in clinics due to its heterogeneous renin levels. Rapid stratification of hypertension through renin analysis is crucial for effective personalized treatment, yet an ultrasensitive detection approach is currently lacking. Here, we report activatable renin nanoprobes (ARNs) for non‐invasive and ultrasensitive profiling of renin activity and guiding antihypertensive treatment decision through near‐infrared fluorescence (NIRF) in vivo imaging and in vitro urinalysis. ARNs are intrinsically non‐fluorescent due to NIRF reporter connected to a gold nanocluster through a renin‐responsive peptide. In hyperreninemia mouse models, ARNs specifically react with renin to liberate the renal clearable NIRF reporter for accurate renin detection that outperforms the gold standard radioimmunoassay. Such specific and sensitive detection also enables imaging‐based high‐throughput screening of antihypertensive drugs. In hypertensive rat models, ARNs enable ultrasensitive detection of both plasma and urinary renin, facilitating renin‐guided precision treatment and significantly improving hypertension control rate (90 % versus 58 %). Our nanoprobe platform holds great potential for assisting clinicians in rapidly and accurately classifying hypertensive patients and improving outcomes through tailored treatment selection.

The effect of spironolactone versus eplerenone on blood pressure targets in resistant hypertension patients

Abstract Objective to evaluate different effects on blood pressure (BP) control in two treatment options spironolactone (SPIR) versus eplerenone (EPL) as an add-on therapy in resistant hypertensive (RAH) patients. Design and methods: We studied 208 patients with true RAH confirmed by the office and ambulatory BP monitoring (ABPM) despite the use of 3 antihypertensive medications including a calcium channel blocker, a blocker of the renin-angiotensin system, and a thiazide diuretic with maximally tolerated doses for at least 3 months. Patients were randomized into 2 groups throughout 12 weeks of once-daily treatment with SPIR (25–50 mg) or EPL (25-50 mg) in addition to their baseline triple-combination and then rotated with drugs. BP was measured in the office and by ABPM. Changes in laboratory tests were also studied. The predictive values of plasma aldosterone, active renin concentration (ARC), aldosterone-renin ratio (ARR), and serum potassium were analyzed to determine the antihypertensive response. Results There were no significant differences in the reduction of average office BP, average systolic 24-h, daytime, and nighttime BP by SPIR and EPL. SPIR reduced average diastolic 24-h BP by 7.3 mm Hg, diastolic daytime BP by 7.2 mm Hg, and diastolic nighttime BP by 7.5 mm Hg compared with a reduction of 5.6 mm Hg (P = 0.01), 5.6 mm Hg (P = 0.03) and 4.2 mm Hg (P = 0.0001) with EPL, respectively. Overall, 40.7 % RAH patients achieved targets of clinical BP and 24-h ABPM levels on SPIR and 33.3 % on EPL (Р = 0.002). After 12 weeks of treatment mean plasma potassium concentrations increased by 7.1 (P = 0.0001) on SPIR and by 5.0 % (Р = 0.0001) on EPL, but eGFR did not significantly change on the two drugs. Plasma aldosterone (β = 0.498, Р = 0.02) and ARC (β= -0.374, Р = 0.04) were predictors of the BP-lowering effect of SPIR and plasma aldosterone (β = 0.453, Р = 0.04) was a predictor of reduction BP for EPL in multivariate modeling. Breast pain or tenderness, changes in sex drive, and irregular menstrual cycles or spotting were more often by SPIR than by EPL (5.2 % vs 1.9 %, respectively, P = 0.04). Conclusions The greater antihypertensive effect of SPIR is related to aldosterone status, ARS level in resistant hypertension. EPL may be recommended for RAH patients who have high serum potassium levels that cannot tolerate spironolactone and for people with systolic resistant hypertension.

Evaluating the effects of adrenalectomy and mineralocorticoid receptor antagonist on cardiac remodeling and diastolic function in patients with aldosterone-producing adenoma.

Cardiac remodeling and diastolic dysfunction in patients with aldosterone-producing adenomas (APA) can be improved after adrenalectomy. However, the effect of mineralocorticoid receptor antagonist (MRA) treatment remains unclear. The aim of this study is to evaluate the effect of MRA on cardiac remodeling and diastolic dysfunction in patients with PA. We prospectively enrolled patients with APA from 1993 to 2023, who either received medical treatment with MRAs or underwent adrenalectomy. Biochemical characteristics and echocardiographic findings were collected at baseline and one year after treatment. Propensity score matching was conducted based on baseline biochemical characteristics, left ventricular mass index (LVMI), and diastolic function. A total of 467 APA patients were enrolled in the study. After propensity score matching, 159 patients who underwent adrenalectomy were matched with 159 patients who received MRAs. After therapy, patients who received MRAs showed significant improvement in diastolic function after one year of treatment but not LVMI. Compared to the MRA group, the adrenalectomy group had greater improvement in systolic blood pressure, plasma aldosterone concentration, plasma renin activity, aldosterone-to-renin ratio, and LVMI. In multivariable regression analysis, pretreatment echocardiographic values were significantly associated with changes in both LVMI and E/e', while the treatment strategy showed a significant association with changes in LVMI. Thus, one year after therapy, both adrenalectomy and MRA are effective in improving diastolic function in patients with APA. However, adrenalectomy is more effective than MRA treatment in reversing cardiac remodeling in patients with APA.

Primary and "Pre-Primary" Aldosteronism in Resistant Hypertension: A Practical, Pragmatic, and Prudent Approach in Resource-Limited Milieu.

Introduction Primary aldosteronism (PA), once considered rare, is now recognized as the most common cause of secondary hypertension, accounting for almost a quarter of resistant hypertension (RH) cases. Despite this, PA remains underdiagnosed, with an extremely low percentage of RH patients undergoing screening. Methods In a specialty diabetes-endocrinology clinic, the aldosterone:renin ratio (ARR) was assessed in 115 consecutive RH patients (ages 21-93 years; 47% male; 87% with type 2 diabetes). Fasting blood samples were drawn in a standing position after 30 minutes of walking. Adrenal imaging (CT/MRI) was performed for those with an ARR >20. Results ARR values ranged from 0.4 to 227 (ARR <10 (35%); 11-20 (19%), 21-40 (25%), and >40 (21%)), with corresponding stepwise decreasing plasma renin activity (PRA) (P= 1E-6) and increasing serum aldosterone (SA) (P= 8E-7). Increasing ARR tended to be associated with an increase in serum creatinine (R= 0.23; P= 0.03) and a decrease in estimated glomerular filtration rate (eGFR) (R= -0.24; P= 0.02) and an increase in urine albumin: creatinine ratio. The ARR> 40 group displayed the highest serum creatinine, lowest eGFR, higher urine albumin: creatinine ratio, highest serum sodium, lowest serum potassium, and highest (44%) abnormal adrenal imaging (bilateral hyperplasia diffuse/nodular; solitary adenoma), reflecting a later stage of the pathological spectrum. PA treatment with mineralocorticoid receptor antagonists (MRAs) had a salutary effect. Conclusions Our observations further reinforce that PA is not a binary condition, but exists as a spectrum disorder responsive to MRAs, even in patients with mildly elevated or normal aldosterone levels. Early disease detection/recognition ("renin-independent aldosterone production") can be facilitated by marking "pre-primary" aldosteronism (ARR 11-20), followed by monitoring progression (periodic rescreening) and optimizing treatment, with hopeful mitigation of end-organ damage in RH.

Respiratory failure and rhabdomyolysis caused by severe hypokalemia in a young female with hypertension: a rare critical condition in primary aldosteronism

BackgroundThe two classic manifestations of primary aldosteronism are hypertension and hypokalemia. However, acute respiratory failure due to hypokalemia in primary hyperaldosteronism is rare.Case presentationThe patient was a 27-year-old female who presented with drowsiness and weakness in all extremities. She had been diagnosed with hypertension three years prior, with irregular follow-up, and had a history of preeclampsia one year later. She exhibited high blood pressure and severe hypokalemia (2 mEq/L), leading to respiratory depression and impending respiratory arrest. Consequently, the patient was intubated and transferred to the intensive care unit (ICU). She also developed rhabdomyolysis. Blood pressure tests, including hormonal tests (aldosterone: 13.2 ng/dL, plasma renin activity: 0.32 ng/mL/h), were conducted. Due to the high aldosterone-renin ratio, an abdominopelvic computed tomography (CT) scan was performed. The CT scan revealed a 14 × 12 mm round mass with a washout value above 60%, consistent with an adrenal adenoma, leading to a diagnosis of primary aldosteronism. The patient was discharged after stabilization, and one and a half months after ICU admission, a laparoscopic left adrenalectomy was successfully performed without post-operative complications. Histopathology showed encapsulated hypertrophy of the adrenal cortex with a predominance of large clear cells, confirming the diagnosis of adrenal adenoma. At the most recent follow-up, the patient had normal potassium levels, was normotensive without any medications, and exhibited no alarming signs or symptoms.ConclusionRespiratory depression to the extent of impending respiratory failure and rhabdomyolysis as a result of hypokalemia in primary aldosteronism are extremely rare. In this patient, who developed respiratory depression due to resistant hypokalemia, timely investigation of secondary causes and diagnosis of adrenal adenoma were crucial. The surgery provided definitive treatment for the patient’s blood pressure and prevented the recurrence of life-threatening complications.

Alterations in the Renin-Angiotensin System in Experimental Septic Shock.

To analyze dynamic changes in the renin-angiotensin system (RAS) during septic shock, focusing on angiotensin-converting enzyme (ACE) activity and the balance between angiotensin peptides, using a mass spectrometry method. Experimental septic shock model induced by peritonitis in swine. Experimental Laboratory, Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles. Forty time points from eight mechanically ventilated pigs. Septic shock was induced using intraperitoneal instillation of autologous feces, followed by standardized fluid resuscitation, norepinephrine infusion, antibiotic administration, and peritoneal lavage. The induction of sepsis resulted in a significant increase in plasma renin activity and levels of angiotensin I and II, with a significant decrease in ACE activity observed from 4 hours post-resuscitation and a notable rise in the angiotensin I/angiotensin II ratio at 12 hours. Additionally, a shift toward the angiotensin-(1-7) axis was observed, evidenced by an increased angiotensin-(1-7)/angiotensin II ratio. The study highlighted dynamic shifts in the RAS during septic shock, characterized by reduced circulating ACE activity, elevated angiotensin I/II ratio, and a shift toward the angiotensin-(1-7) axis. These findings suggest an adaptive response within the RAS, potentially offering new insights into sepsis management and therapeutic targets.

Placenta may exert fetal protection against maternal high salt diet intake via renin-angiotensin-aldosterone system

ObjectiveThis study investigated the effects of high compared to normal dietary salt intake on fetoplacental vascular function, activity of renin-angiotensin-aldosterone system (RAAS), placental pro- and anti-angiogenic factors and biomarkers of placental remodeling and oxidative stress during healthy uncomplicated pregnancy. Materials and methodsBased on their 24-h sodium excretion pregnant women (37–40 weeks’ gestation) were categorized into three groups: normal salt (NS, <5.75 g/day, N = 12), high salt (HS, 5.75–10.25 g/day, N = 36), and very high salt (VHS, >10.25 g/day, N = 17). Pulsatility (PI) and resistive index of middle cerebral artery (MCA) and umbilical artery, plasma renin activity (PRA), serum aldosterone, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) concentrations, as well as placental vascular endothelial growth factor C (VEGF-C), oxidative/antioxidative stress markers (TBARS/FRAP) and matrix metalloproteinase 9 (MMP-9) concentration were measured. ResultsPI MCA was significantly decreased in HS/VHS groups compared to NS group. HS/VHS intake did not suppress PRA and aldosterone concentration. Serum PlGF concentration was significantly increased while sFlt-1 concentration and sFlt-1/PlGF ratio were significantly decreased in VHS group compared to NS group. MMP-9, VEGF-C concentration, TBARS and FRAP in placental tissue were similar between study groups. ConclusionsHS/VHS diet does not suppress RAAS during pregnancy; however, it is associated with decreased PI MCA, a significantly decreased sFlt-1/PlGF ratio and unchanged biomarkers of placental remodeling or oxidative stress in healthy pregnant women, suggesting the presence of a possible protective or compensatory mechanism aimed at preserving placental function and pregnancy outcome itself in terms of maternal HS intake.

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(&amp;lt;1.0 ng/dL) were detected on multiple tests. The urine-free cortisol-to-cortisone ratio was &amp;lt;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&amp;gt;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

6657 A rare case of a composite pheochromocytoma and ganglioneuroma in a 47-year-old male

Abstract Disclosure: C. Ekladios: None. M.J. Levine: None. Introduction: Pheochromocytoma is a rare tumor that originates from adrenal chromaffin cells. It remains a diagnostic challenge due to its diverse clinical manifestations. We present a case of pheochromocytoma, shedding light on its atypical presentation and diagnostic complexity.Case reportA 47-year-old male was referred to our clinic with a recent diagnosis of pheochromocytoma. Patient started having symptoms approximately two months prior to referral to our office. He initially presented to the emergency department (ED) with generalized weakness for three days, accompanied by feelings of “rushing of blood to the head” and a “rush of blood in the arms” every time he laid down. Symptoms would last for a few seconds and resolve without intervention. Vitals signs and physical examination (PE) were within normal limits. He had basic laboratory studies including BMP and CBC without any abnormalities. He was discharged home with instructions to follow-up outpatient. He returned to the ED two days after with a chief complaint of left sided chest pain associated with palpitations, pain was non-persistent, lasting a few seconds. On presentation his blood pressure was 142/89 mmHg, Pulse: 66 bpm, Temperature: 98.4 °F, and oxygen Saturation 100%. On PE, he had clear bilateral air entry and regular heart rate with no murmurs noted, EKG demonstrated no ischemic changes. Chest Xray showed no evidence of cardiopulmonary disease. A CTA revealed no pulmonary embolism, pleural effusion, or pneumothorax. However, a large heterogeneous adrenal mass was partially visualized, measuring 8.3 cm anteroposteriorly concerning for adrenal cortical carcinoma. His labs were pertinent for Metanephrine level of 0.52 nmol/L (nl:0-0.49) and Normetanephrine of 4.22 nmol/L (nl:0-0.89). Aldosterone level is 16.2 ng/dL and Renin activity was 0.1ng/mL. An abdominal CT scan confirmed a left adrenal mass measuring approximately 9.2 x 8.8 cm transaxially and 9.9 cm craniocaudal. He was seen in our office after discharge, at that time he was still experiencing tingling in both lower extremities that sometimes would wake him up from sleep. His blood pressure at the office was 125/83 mm Hg. In preparation for the surgery, we started treatment with Prazosin, followed by addition of Metoprolol succinate. Further work-up included a dexamethasone suppression test that ruled out Cushing’s syndrome and a negative RET proto-oncogene, ruling out MEN 2. Patient underwent laparoscopic left adrenalectomy without complications. Pathology results interestingly showed a composite pheochromocytoma and ganglioneuroma constituting 5 % of the mass volume, Ki-67 proliferative index was less than 1% for the pheochromocytoma and overall findings were consistent with a benign tumor.ConclusionOur case report emphasizes the necessity of a high index of suspicion for diagnosing pheochromocytoma in the absence of the classic symptoms. Presentation: 6/2/2024

12293 Dynamic Clinical Evolution: Why Patients Require Long-Term Follow-up Over Time

Abstract Disclosure: A. Attre: None. A. Syeda: None. A. Khan: None. B. Esayag-Tendler: None. Dynamic Clinical Evolution: Why Patients Require Long-Term Follow-up Over Time Introduction Primary Hyperaldosteronism (PHA) is an increasingly recognized cause of secondary hypertension amenable to specific therapy. We describe a case of PHA with change in management trajectory over time. Case A 48-year-old woman was diagnosed with PHA in 2009 based on an aldosterone level of 42.7 ng/dL, plasma renin activity of &amp;lt;0.1 ng/mL/hr, and a low potassium of 3.4 mmol/L. At that time, simultaneous adrenal venous sampling (AVS) had revealed a bilateral etiology of aldosterone excess. Original imaging with CT scan had shown fullness on both adrenal glands, and she was treated with 50mg daily spironolactone. Follow-up with CT scan in 2018 revealed similar imaging phenotype. When she established care with us in 2020, the abdomen MRI revealed a 2.5 cm x 1.9 cm right adrenal nodule. In addition, the blood pressure readings were noted to be high despite increasing doses of spironolactone to 150mg. Her laboratory results revealed aldosterone 151 ng/dL [&amp;lt; 31 ng/dL], cortisol 0.8 µg/dL, plasma renin activity 0.8 ng/mL/hr [0.2 ng/mL/hr - 1.6 ng/mL/hr], ACTH 12.5 pg/mL [7.2 pg/mL - 63.3 pg/mL], normal plasma metanephrine and a normal thyroid panel. A decision was made to repeat AVS in 2023 following Dr. Doppman’s protocol. The patient’s spironolactone was held before AVS and the plasma renin activity before the procedure was 0.4-0.8 ng/mL/hr. Results: Repeat AVS in 2023 showed mean pre-ACTH right to left lateralization index (LI) of 29.9 and mean post-ACTH LI of 9.7 (cutoff &amp;gt;4). This is concordant with the right adrenal nodule noted on imaging. The selectivity index confirmed adequate adrenal venous sampling data. Analysis of our findings confirmed right adrenal excess and left adrenal suppression compared to the IVC results. This patient underwent a laparoscopic right adrenalectomy in 2023. This patient's aldosterone levels were measured two days postoperatively and were found to be 4.2 ng/dL, showing immediate improvement. Six months postoperatively, our patient’s home and clinic blood pressures are in 120s/60s mmHg range without any medications. The aldosterone remains less than 6 ng/dL and the plasma renin activity is no longer low. Her potassium remains around 4.9 mmol/L. Discussion Based on current literature, surgical treatment is preferred when there is a confirmed unilateral cause of PHA. Adrenalectomy is recommended in patients with confirmed unilateral hyperaldosteronism especially when they do not achieve clinical and biochemical goals (renin plasma activity &amp;gt;1 ng/mL/hr, resolution of hypokalemia and optimal BP control) despite the use of MRA at appropriate doses. Suppressed renin is known to be associated with increased cardiovascular morbidity. This case serves as an important example of the need to follow patients long-term because PHA is a dynamic clinical entity that affects quality of life. Presentation: 6/3/2024

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

8659 Aldosterone-Secreting Adrenocortical Carcinoma: A Rare Cause Of Primary Hyperaldosteronism Associated With Dismal Outcome

Abstract Disclosure: S. Beeby: None. C.H. Huzita: None. F.Q. Aratani: None. L.S. Motomia: None. F. Coelho: None. M. Polo: None. C.R. Victor: None. A.O. Hoff: None. J. Chambo: None. V. Srougi: None. F. Ledesma: None. A. Latronico: None. M.Q. Almeida: None. B.B. Mendonca: None. M.C. Fragoso: None. Background: Adrenocortical carcinoma (ACC) is a rare and one of the most aggressive solid tumors, with an incidence of 1-2 cases per million. In adults, hormonal excess is usually manifested by ACTH-independent Cushing's syndrome or mixed endocrine syndrome due to cortisol and androgen production. Isolated aldosterone secretion is an extremely rare condition, with an estimated 2.5% of patients with ACC. We aimed to describe two patients with aldosterone-secreting ACC with poor outcomes. Case 1 - A 34-year-old male who was diagnosed with hypertension at 29 years of age, associated with hypokalemia needing intravenous potassium replacement therapy. Diagnosis of primary hyperaldosteronism was established with aldosterone levels of 72 ng/dL (RR &amp;lt; 23.1 ng/dL) and renin activity of 1.1 ng/mL/h (RR 0.3 to 5.8 ng/mL/h. An abdominal CT scan identified a tumor mass of 9.5 x 8.0 x 4.5 cm. He underwent a left adrenalectomy and histological and immunohistochemistry data suggested an adrenocortical carcinoma (modified Weiss score 5/7, Ki67 40%). Initial staging was ENSAT III and a Helsinki score of 48. There was transient improvement, however recent laboratory studies showed an increase in aldosterone (66,9 ng/dL) accompanied by new episodes of hypokalemia. CT scans on follow-up showed recurrence of disease, with the presence of nodules on the surgical site and abdominal wall. He received 3 lines of systemic chemotherapy and mitotane and underwent 2 other surgical procedures to treat the metastatic lesions. Currently, overall survival is 3 years. Case 2 - A 44-year-old female incidentally found a right adrenal mass (6.6 x 6.4 cm) on MRI during the investigation of elevated liver enzymes and abdominal pain. Laboratory studies showed hypokalemia, with potassium levels of 2 mEq/L (RR 3.5-5 mEq/L), aldosterone levels of 243 ng/dL (RR &amp;lt; 23.1 ng/dL), and renin of 12.2 uUI/mL (RR 4.4 - 46.1 uUI/mL). She underwent right adrenalectomy and histology and immunohistochemistry data showed a modified Weiss 7/7 and Ki67 of 80%. The patient had a germline pathogenic variant of TP53 (p.R337H). Initial staging was ENSAT III and a Helsinki score of 88. She received adjuvant mitotane and systemic chemotherapy. Even so, follow-up imaging showed hepatic metastatic disease, with an elevated aldosterone production surpassing 1000 ng/dL. The patient's overall survival was 2 years and she passed away during surgical procedure for resection of liver metastases. Discussion: ACC is a rare and aggressive tumor, and isolated aldosterone production by such tumors is extremely rare. We presented two cases with poor prognostic features and in which despite adjuvant mitotane and systemic chemotherapy there was disease progression. Due to the rarity of this condition, data on patient outcomes is limited, and further understanding of the molecular signature of these tumors could bring new insights on the tumorigenesis process. Presentation: 6/3/2024

7764 A Case of Primary Hyperaldosteronism With Negative Imaging Findings -Diagnostic Approach and Outcome in a Decade

Abstract Disclosure: U.D. Gupta: None. M. Al-Ghuraibawi: None. R. Abdulhussein: None. K. Panigrahi: None. Z. Deribe: None. Distinguishing between the various subtypes of primary hyperaldosteronism (PHA) poses a clinical challenge. Nevertheless, it is notable that primary hyperaldosteronism is a prominent contributor to secondary hypertension, accounting for less than 1% of cases. The triad of hypertension, hypokalemia, and metabolic alkalosis demands screening for PHA. While bilateral adrenal hyperplasia and aldosterone-producing adenomas (APA) are common, rarer forms like unilateral adrenal hyperplasia and glucocorticoid-responsive aldosteronism can also occur. In our case, a 61-year-old patient has been diagnosed and treated for primary hyperaldosteronism for last 10-years. Presently, the patient is undergoing management for blood pressure with a medication regimen comprising Amiloride, Nifedipine, Minoxidil, Atenolol, and Eplerenone over the past decade. No abnormal findings were observed in the computed tomography or magnetic resonance imaging of the adrenal gland, and adrenal venous sampling test results were non-conclusive. The patient has exhibited favorable outcomes with medications, also subsequent imaging has not revealed the presence of an adrenal mass. This case is presented as unique due to its atypical presentation, characterized by the absence of anatomical lesions in the adrenal gland and non-conclusive sampling test results. Nevertheless, the patient responded positively to treatment, supported by the diagnostic significance of preliminary lab tests for primary hyperaldosteronism (aldosterone level: 20.5; plasma renin activity: 0.19, initially aldosterone levels were 17 and 7 before and after saline infusion). Notably, literature acknowledges that the aldosterone-producing adenomas (APAs) can be very small, sometimes &amp;lt;3 mm in diameter, and lesions &amp;lt;1 cm may be overlooked on CT scans. The limitation of adrenal venous sampling (AVS) is the challenge in obtaining good sample due to technical difficulties and variations in local expertise, success rates in AVS may vary. This case exemplifies the diagnostic complexities encountered in primary hyperaldosteronism cases, where imaging and adrenal venous sampling, though frequently recommended, may pose challenges. In conclusion, we share insights from this case and its treatment outcome. Clinically, a thorough assessment of symptoms, along with laboratory results, is crucial for diagnosis and treatment and further categorization may be challenging without imaging and adrenal venous sampling. Presentation: 6/3/2024

9296 A Novel LC-MS/MS Salivary Fludrocortisone Method With Potential for Monitoring in Adrenal Insufficiency Patients

Abstract Disclosure: M. Dolan: None. D. Marshall: None. J. Hawley: None. N. Reisch: None. B.G. Keevil: None. Fludrocortisone (FC) is a fluorinated exogenous mineralocorticoid used to treat conditions associated with adrenal insufficiency including Addison’s disease and classic congenital adrenal hyperplasia (CAH). The mineralocorticoid action of FC allows the drug to compensate for aldosterone deficiency, thus helping to maintain blood pressure and other homeostatic mechanisms. Optimising FC replacement is vital as under-replacement can cause dizziness and hypotension, whereas over-replacement can lead to cardiometabolic disturbances. Treatment in classic CAH patients, who are typically diagnosed as new-borns, is even more complex as the requirement for mineralocorticoid replacement decreases with age. Endocrine Society guidelines recommend that FC monitoring should involve the clinical assessment of symptoms, which can be non-specific, and regular blood pressure measurements. Plasma renin activity (PRA) should be measured if clinical changes occur, aiming towards the upper end of the reference range. The utility of PRA is debated due to methodological issues and the inherent variability of the analyte itself, which may not always represent FC replacement status. Therefore, investigation into alternative biochemical markers of FC replacement is required. Here we aimed to facilitate this by developing an LC-MS/MS method for the measurement of salivary FC. Method: A salivary FC LC-MS/MS assay has been developed and validated for use according to FDA and EMA guidelines. Passive drool samples from 10 clinical trial patients with classic CAH were collected on two separate occasions at select time points throughout the day (0800, 1200, 1600, 2000 and 2300h). In most patients the 0800h sample was taken pre-FC dose. Once in the laboratory the patient samples were extracted and analysed using the FC method to produce a FC concentration day curve. Results: The method analysis time was 2.1 minutes, with a mean recovery of 102% and limit of quantification of 5 pmol/L (2.1 pg/mL). No analytical interference was identified. Analysis of patient samples using the method showed the presence of FC allowing the production of day curves. In most patients, the pre-dose sample contained no FC, with the subsequent samples showing a peak FC concentration corresponding to the Cmax. After this the FC concentration gradually tapered off throughout the remainder of the day. Conclusions: We have developed a novel assay for the measurement of salivary FC, which may allow the calculation of the area under the curve. As an optimal FC dose has yet to be determined this method may facilitate more in-depth pharmacokinetic studies into FC metabolism and blood pressure control. Thereby identifying patients that are fast metabolisers or poor absorbers of the medication, enabling a non-invasive strategy to optimise patient care. Presentation: 6/1/2024

6606 Connshing Syndrome: An Uncommon Presentation Of Bilateral Adrenal Mass

Abstract Disclosure: C.S. Botero Suarez: None. N. Meda: None. K. Lamar: None. S.K. Suryanarayanan: None. Introduction: Mild autonomous hypersecretion of cortisol in the underlying setting of hyperaldosteronism has been described before and coined the term Connshing Syndrome. Even though it was described in 1979, recently W. Arlt et al in 2017 revived interest in the topic of Connshing Syndrome represents a distinct entity among PA (primary hyperaldosteronisms). We present a case of bilateral adrenal mass associated with mild autonomous hypersecretion of cortisol as well as the development of primary aldosteronism. Case Description: A 62-year-old male with a medical history of hyperlipidemia, hypertension, spontaneous hypokalemia, and T2DM was referred to the clinic due to concerns for hyperaldosteronism. Exam was unremarkable for signs of hypercortisolism. Blood pressure in the clinic was 143/88 mmHg, pulse 81 bpm, weight 105.4 Kg (231.8 lbs.), and a BMI of 28 kg/m2. A non-contrast abdominal CT performed, showed a 2.9 x.1.4 cm right adrenal lipid-rich adenoma with -3.7 HU, as well as a left adrenal lipid-rich adenoma of 1.8 x 1.3 x cm and -7.7 HU. A hormonal workup showed normal plasma metanephrines, an aldosterone of 39 ng/dL, plasma renin activity 0.16 ng/mL/h, and aldosterone/PRA ratio of 243. The patient underwent 1 mg dexamethasone suppression test which resulted in an ACTH &amp;lt;5 pg/mL, dexamethasone level of 288 ng/dL, and cortisol of 1.9 mcg/dL. AVS with Cosyntropin was performed (see Table 1). Right sided adrenalectomy is being considered but the identification of possible lateralization of cortisol is being considered. Discussion: Surgical management is usually preferred treatment modality for both unilateral PA and MACS, but identification of lateralization of both cortisol and aldosterone can be difficult. Although identifying lateralization of aldosterone with Cosyntropin-stimulated AVS is well understood, lateralization of cortisol production is not well understood. Johnson et. all have suggested the use of adrenal venous sampling with dexamethasone suppression as well as measurement of epinephrine levels to identify the source of hypercortisolism. They demonstrated identification of cortisol lateralization with adrenal vein sampling with specificity of 95 – 100% for unilateral disease utilizing a AV/IVC cortisol ratio &amp;gt; 9 and a cortisol lateralization ratio (CLR) of &amp;gt; 2.3. Although our case had a Cosyntropin-stimulated AVS showing clear lateralization of aldosterone production to the right adrenal, the lateralization of cortisol production is yet unknown and AVS with dexamethasone suppression is being considered. Although the treatment considerations are traditionally utilizing the guidelines for both PA and Cushing Syndrome guidelines respectively, very little is known when there are divergence of autonomous secretion amongst the bilateral adrenal masses and more studies are needed to clarify the long-term treatment considerations. 1 Presentation: 6/3/2024

8295 Development of Type 1 Diabetes and Primary Adrenal Insufficiency Secondary to Immunotherapy Treatment for Chordoma in a Patient With Hypopituitarism

Abstract Disclosure: P. Kesavan Chary: None. J.M. Silverstein: None. Background: Cranio-cervical chordomas are rare locally aggressive, invasive, and slow-growing bone neoplasms. Treatment involves a combination of excision and radiation therapy, and sometimes immunotherapy for recurrent disease. Endocrine-related toxicities from immune checkpoint inhibitors are well recognized and include autoimmune thyroid disease, hypophysitis, and less commonly, type 1 diabetes mellitus (T1DM) and primary adrenal insufficiency (PAI). We present a case of a patient with hypopituitarism secondary to a recurrent and aggressive skull base chordoma with leptomeningeal spread who developed T1DM and PAI after treatment with nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody. Diagnosis of PAI was delayed because patient was on hydrocortisone replacement for secondary adrenal insufficiency. Case Report: A 38 year old male with history of primary hypothyroidism underwent endoscopic endonasal transsphenoidal resection and adjuvant proton beam radiation therapy for a sellar chordoma after presenting with diplopia. Testing was consistent with hypopituitarism and the patient was started on hydrocortisone, levothyroxine, and testosterone replacement. Due to recurrent disease and leptomeningeal spread, he subsequently underwent three additional surgeries and two courses of gamma knife radiosurgery. Five months after starting systemic therapy with nivolumab, the patient developed insulin dependent diabetes presumed to be T1DM secondary to immunotherapy. He was continued on nivolumab, and six months into treatment developed hyperkalemia and hyponatremia requiring inpatient admission. He was treated with diuretics and fluid restriction initially without improvement in his electrolyte abnormalities although he remained relatively asymptomatic. Laboratory evaluation showed a renin activity of 66 ng/mL/H and aldosterone &amp;lt; 4.0 ng/dL (&amp;lt;= 21) with sodium of 128 mmol/L (135-145) and potassium 5.8 mml/L (3.3-4.9). Due to suspicion for PAI secondary to checkpoint-inhibitor induced adrenalitis, 21-hydroxylase antibody was checked and was positive. It was felt that the patient had not had other signs or symptoms classic for PAI such as nausea and/or vomiting because he had already been on glucocorticoid replacement for his hypopituitarism. Ultimately, the patient was started on fludrocortisone, with resolution of his hyponatremia and hyperkalemia. Conclusion: Adrenal insufficiency from immunotherapy is most commonly caused by hypophysitis. T1DM and PAI due to adrenalitis are less common. In patients on steroid replacement for hypopituitarism, the development of electrolyte abnormalities with or without symptoms in a patient on immunotherapy should raise the suspicion for rarer endocrine side effects such as primary adrenal insufficiency. Presentation: 6/3/2024

6966 A Rhythmic Life-Threatening Enigma Unveiled: KCNH2 Mutation-Associated Torsades de Points Unmasking Primary Hyperaldosteronism in Cardiological Realm

Abstract Disclosure: S. Dejprapasorn: None. N. Nopparatana: None. S. Soonthornpun: None. R. Leelawattana: None. N. Kietsiriroje: None. S. Limumpornpetch: None. T. Nilmoje: None. W. Lohawijarn: None. T. Wongsuttipakorn: None. P. Choochuen: None. P. Limumpornpetch: None. Introduction: Primary hyperaldosteronism (PA) is characterized by hypertension and hypokalemia. However, its ability to masquerade life-threatening Torsades de Pointes makes it an unusual and dismissed diagnosis, revealing the link between PA and serious arrythmia. Clinical Case A 30-year-old female experienced three episodes of palpitations, followed by syncope. Upon admission, her blood pressure was 147/87 mmHg. ECG showed prolonged QT intervals with potassium level was 2.6 mmol/L (3.5-5.0 mmol/L). Continuous cardiac monitoring captured Torsades de Pointes. Despite potassium replacement, long QT still persisted. Pathogenic variant, c.2592+1G&amp;gt;A, within KCNH2 was discovered. Aldosterone concentration showed 69.65 ng/dL (9.70-62.60 ng/dL) and plasma renin activity was 0.12 ng/mL/h (1.50-5.70 ng/mL/h). Aldosterone-to-renin ratio was 580. Aldosterone post 4-h saline infusion test was 31.71 ng/dL which were consistent with PA. Adrenal unenhanced CT scan identified bilateral adrenal nodules (right 1.3 cm, left 1.1 cm). After receiving a cardioverter-defibrillator and spironolactone, the patient has had no palpitations, and their potassium level has remained normal. Clinical lessons: PA rarely presents ventricular arrhythmia. KCNH2 mutation may link between long QT syndrome (LQTS) and PA arises. LQTS type 2 is attributable to KCNH2 mutations, impacting potassium channel subunits crucial for adjusting currents during sympathetic activation. This is essential for shortening the QT interval with increasing heart rate. KCNH2 mutations disrupt this process, prolonging the QT interval and heightening the risk of arrhythmias. Aldosterone synthesis relies on calcium signaling triggered by potassium currents. Adrenal cortex hosts approximately 90 potassium channels genes, including KCNJ5 and KCNH2. Mutations in gene can disrupt the calcium signaling cascade, leading to excessive aldosterone production. While KCNJ5 mutation is well-documented in PA, the potential correlation between KCNH2 mutations and a similar mechanism remains unexplored in clinical reports to date. This case highlights the importance of a thorough comprehension of genetic cause contributing to pathogenesis of PA with complex clinical presentations. Presentation: 6/1/2024

6661 Critical Limb Ischemia - An Unusual Presentation Of A Pheochromocytoma

Abstract Disclosure: S. Hassan: None. Background: Pheochromocytomas can lead to vasoconstriction and its various clinical manifestations due to excess catecholamine release. Critical limb ischemia as a clinical manifestation of pheochromocytoma has been reported sparsely. Clinical Case: A 43 year old female with a past medical history of type 2 diabetes mellitus, Turner syndrome, and hypertension presented to the emergency department with acute on chronic left leg pain. She underwent workup with a CT angiography of the abdomen with runoff for evaluation of her vessels, which revealed an occlusion of her left superficial femoral artery with chronic stenosis of the right femoral system. Multiple unsuccessful attempts were made at revascularization of her left lower extremity, including femoropopliteal bypass, with eventual left above knee amputation, multiple fasciotomies, and angiogram and stenting of multiple vessels. The patient was on a combined OCP (norethindrone-ethinyl estradiol) for hormone replacement for Turner syndrome for the past 30 years, and did not have a personal or family history of clotting disorders. She underwent a hypercoagulable workup which was negative. Echocardiogram was negative for thrombi and was otherwise unremarkable. Incidentally discovered on her initial CT angiography was a heterogeneously enhancing right adrenal mass, which was further delineated on a dedicated CT of the adrenals, which showed a 3.7 cm right adrenal mass with pre-contrast Hounsfield units measuring 46. Biochemical workup revealed a normal plasma renin activity and aldosterone, plasma metanephrine elevated to 5.20 nmol/L (range 0.00 – 0.49 nmol/L), plasma normetanephrine elevated to 4.95 nmol/L (range 0.00 – 0.89 nmol/L), 24 hour urine metanephrine elevated to 3830 ug/d (range 36-229 ug/d), and 24 hour urine normetanephrine 1733 ug/d (range 95 – 650 ug/d). She reports a diagnosis of hypertension at age 36, with no secondary workup pursued; she had suboptimal control on three separate medications, lisinopril, metoprolol, and hydrochlorothiazide. Her blood pressure and heart rate were noted to be labile during her aforementioned surgery. Alpha blockade with doxazosin was started based on her significantly elevated plasma and urine metanephrines and normetanephrines, with improvement in her blood pressure control. She was not found to have a definitive cause of her critical limb ischemia; she was noted to have atherosclerosis in the vessels of her lower extremities, and her chronic oral contraceptive use may also have played a role. However, OCPs are often reported to cause venous rather than arterial thrombi. Therefore, it can be inferred that the catecholamine excess from her presumed pheochromocytoma caused vasoconstriction which may have played a role in the development of her critical limb ischemia. Conclusion: Catecholamine excess that is resultant from a pheochromocytoma may manifest as critical limb ischemia. Presentation: 6/1/2024