Bilateral Primary Aldosteronism Research Articles

Machine learning-based differentiation of uni- and bilateral primary aldosteronism using circulating microRNA combinations

Machine learning-based differentiation of uni- and bilateral primary aldosteronism using circulating microRNA combinations

Prediction of endogenous mineralocorticoid receptor activity by depressor effects of mineralocorticoid receptor antagonists in patients with primary aldosteronism.

Patients with primary aldosteronism have an increased risk of developing cardiovascular disease. The response to mineralocorticoid receptor antagonists varies among individuals, indicating diverse mineralocorticoid receptor activities in these patients. This study explored the factors linked to the efficacy of blood pressure reduction through mineralocorticoid receptor antagonists in patients with primary aldosteronism. We examined the relationship between the reduction in blood pressure and patient characteristics in a group of 41 patients with primary aldosteronism (24 males, mean age 55 ± 13 years, including 34 patients diagnosed with bilateral primary aldosteronism) before and after undergoing treatment with mineralocorticoid receptor antagonists. Significant reductions in office blood pressure were observed 3 and 6 months after treatment initiation. Single correlation analyses showed that the urinary chloride-to-potassium ratio displayed the strongest positive association with blood pressure reduction, surpassing plasma aldosterone concentration, plasma renin activity, and urinary sodium-to-potassium ratio, at 3 and 6 months. Multiple correlation analyses revealed a consistent and independent positive correlation between the urinary chloride-to-potassium ratio and blood pressure reduction at 3 and 6 months. The optimal threshold for the urinary chloride-to-potassium ratio with respect to its ability to lower blood pressure, was determined as 3.18. These results imply that the urinary chloride-to-potassium ratio may be independently associated with the effectiveness of blood pressure reduction facilitated by mineralocorticoid receptor antagonists. Moreover, it could potentially serve as a valuable predictor of the effectiveness of these agents and function as an indicator of endogenous mineralocorticoid receptor activity in patients with primary aldosteronism.

Clinical prediction model for primary aldosteronism subtyping and special focus on adrenal volumetric assessment.

Our aim was to develop a prediction model based on a simple score with clinical, laboratory, and imaging findings for the subtype diagnosis of primary aldosteronism (PA). The contribution of adrenal volumetric assessment to PA subtyping was also investigated. Thirty-five patients with adequate cannulation in adrenal venous sampling (AVS) were included. Laboratory data, the saline infusion test (SIT), and the AVS results of patients with PA were retrospectively evaluated. Volumetric assessment was performed using magnetic resonance imaging (MRI) and the ratio of adrenal volumes was calculated after adjusting for gender- and side-specific mean reference values of both adrenal glands. The AVS was consistent with unilateral PA in 49% and bilateral in 51% of the patients. Hypertension as a reason for work-up, the highest aldosterone/lowest potassium value higher than 12, the percentage of plasma aldosterone concentration (PAC) reduction after SIT by equal or less than 43.5%, the use of oral potassium replacement, unilateral disease at pre-AVS imaging, and a ratio of adjusted adrenal volumes equal to or below 1.7 were indicative of unilateral disease in univariate logistic regression analysis concerning the distinction of PA subtyping (p < 0.05). Multivariate logistic regression analysis also revealed that adrenal volumetric assessment has an impact on PA subtyping (p < 0.05). In the prediction model, when each of the six parameters that were significant in the univariate logistic regression analysis was assigned one point, < 4 predicted bilateral PA, whereas ≥ 4 predicted unilateral PA (AUC:0.92, p < 0.001). This prediction model before AVS may serve as a convenient and practical approach, while an adjusted adrenal volumetric assessment can make a positive contribution to PA subtyping.

Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling for the subtyping of primary aldosteronism: a prospective study.

Adrenal venous sampling (AVS) is key for primary aldosteronism subtype identification. However, the value of adrenocorticotropic hormone (ACTH) stimulation in AVS is still controversial. In this prospective study, we investigated the role of continuous ACTH infusion on the performance and interpretation of bilateral simultaneous AVS using a standard protocol in 59 primary aldosteronism patients. We analyzed the selectivity index and lateralization index in AVS pre and post-ACTH and estimated the prognosis of patients who underwent adrenalectomy with different cutoff points of lateralization index post-ACTH. The confirmed success rate of bilateral adrenal vein catheterization increased from 84% pre-ACTH to 95% post-ACTH. Fifty percent of the patients had a decline in lateralization index post-ACTH, 30% of patients showed unilateral primary aldosteronism pre-ACTH but bilateral primary aldosteronism post-ACTH according to lateralization index at least 2 pre-ACTH and lateralization index at least 4 post-ACTH. The outcomes of the patients with primary aldosteronism after adrenalectomy indicated that all patients achieved clinical and biochemical success regardless of lateralization index at least 4 or less than 4 post-ACTH. Receiver operating characteristic curves showed that lateralization index cutoff 2.58 post-ACTH stimulation yielded the best threshold in lateralization with a sensitivity of 73.1% and a specificity of 92.9%. ACTH stimulation increased the AVS success rates in patients with primary aldosteronism, reduced lateralization index in some cases and decreased the proportion of identified unilateral primary aldosteronism, resulting in some patients losing the opportunity for disease cure. Compared with lateralization index at least 4, a lower cutoff point of lateralization index at least 2.58 after ACTH stimulation has better accuracy of lateralization diagnosis.

What We Know about and What Is New in Primary Aldosteronism.

Primary aldosteronism (PA), a significant and curable cause of secondary hypertension, is seen in 5-10% of hypertensive patients, with its prevalence contingent upon the severity of the hypertension. The principal aetiologies of PA include bilateral idiopathic hypertrophy (BIH) and aldosterone-producing adenomas (APAs), while the less frequent causes include unilateral hyperplasia, familial hyperaldosteronism (FH) types I-IV, aldosterone-producing carcinoma, and ectopic aldosterone synthesis. This condition, characterised by excessive aldosterone secretion, leads to augmented sodium and water reabsorption alongside potassium loss, culminating in distinct clinical hallmarks: elevated aldosterone levels, suppressed renin levels, and hypertension. Notably, hypokalaemia is present in only 28% of patients with PA and is not a primary indicator. The association of PA with an escalated cardiovascular risk profile, independent of blood pressure levels, is notable. Patients with PA exhibit a heightened incidence of cardiovascular events compared to counterparts with essential hypertension, matched for age, sex, and blood pressure levels. Despite its prevalence, PA remains frequently undiagnosed, underscoring the imperative for enhanced screening protocols. The diagnostic process for PA entails a tripartite assessment: the aldosterone/renin ratio (ARR) as the initial screening tool, followed by confirmatory and subtyping tests. A positive ARR necessitates confirmatory testing to rule out false positives. Subtyping, achieved through computed tomography and adrenal vein sampling, aims to distinguish between unilateral and bilateral PA forms, guiding targeted therapeutic strategies. New radionuclide imaging may facilitate and accelerate such subtyping and localisation. For unilateral adrenal adenoma or hyperplasia, surgical intervention is optimal, whereas bilateral idiopathic hyperplasia warrants treatment with mineralocorticoid antagonists (MRAs). This review amalgamates established and emerging insights into the management of primary aldosteronism.

Multifocal, Asymmetric Bilateral Primary Aldosteronism Cannot be Excluded by Strong Adrenal Vein Sampling Lateralization: An International Retrospective Cohort Study.

Primary aldosteronism (PA) has been broadly dichotomized into unilateral and bilateral forms. Adrenal vein sampling (AVS) lateralization indices (LI) ≥2 to 4 are the standard-of-care to recommend unilateral adrenalectomy for presumed unilateral PA. We aimed to assess the rates and characteristics of residual PA after AVS-guided adrenalectomy. We conducted an international, retrospective, cohort study of patients with PA from 7 referral centers who underwent unilateral adrenalectomy based on LI≥4 on baseline and/or cosyntropin-stimulated AVS. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue. The cohort included 283 patients who underwent AVS-guided adrenalectomy, followed for a median of 326 days postoperatively. Lack of PA cure was observed in 16% of consecutive patients, and in 22 patients with lateralized PA on both baseline and cosyntropin-stimulated AVS. Among patients with residual PA postoperatively, 73% had multiple CYP11B2 positive areas within the resected adrenal tissue (versus 23% in those cured), wherein CACNA1D mutations were most prevalent (63% versus 33% in those cured). In adjusted regression models, independent predictors of postoperative residual PA included Black versus White race (odds ratio, 5.10 [95% CI, 1.45-17.86]), AVS lateralization only at baseline (odds ratio, 8.93 [95% CI 3.00-26.32] versus both at baseline and after cosyntropin stimulation), and CT-AVS disagreement (odds ratio, 2.75 [95% CI, 1.20-6.31]). Multifocal, asymmetrical bilateral PA is relatively common, and it cannot be excluded by robust AVS lateralization. Long-term postoperative monitoring should be routinely pursued, to identify residual PA and afford timely initiation of targeted medical therapy.

Urine steroid metabolomics as a diagnostic tool in primary aldosteronism

Primary aldosteronism (PA) causes 5–10% of hypertension cases, but only a minority of patients are currently diagnosed and treated because of a complex, stepwise, and partly invasive workup. We tested the performance of urine steroid metabolomics, the computational analysis of 24-hour urine steroid metabolome data by machine learning, for the identification and subtyping of PA. Mass spectrometry-based multi-steroid profiling was used to quantify the excretion of 34 steroid metabolites in 24-hour urine samples from 158 adults with PA (88 with unilateral PA [UPA] due to aldosterone-producing adenomas [APAs]; 70 with bilateral PA [BPA]) and 65 sex- and age-matched healthy controls. All APAs were resected and underwent targeted gene sequencing to detect somatic mutations associated with UPA. Patients with PA had increased urinary metabolite excretion of mineralocorticoids, glucocorticoids, and glucocorticoid precursors. Urine steroid metabolomics identified patients with PA with high accuracy, both when applied to all 34 or only the three most discriminative steroid metabolites (average areas under the receiver-operating characteristics curve [AUCs-ROC] 0.95–0.97). Whilst machine learning was suboptimal in differentiating UPA from BPA (average AUCs-ROC 0.65–0.73), it readily identified APA cases harbouring somatic KCNJ5 mutations (average AUCs-ROC 0.79–85). These patients showed a distinctly increased urine excretion of the hybrid steroid 18-hydroxycortisol and its metabolite 18-oxo-tetrahydrocortisol, the latter identified by machine learning as by far the most discriminative steroid. In conclusion, urine steroid metabolomics is a non-invasive candidate test for the accurate identification of PA cases and KCNJ5-mutated APAs.

Sex modifies the predictive value of computed tomography combined with serum potassium for primary aldosteronism subtype diagnosis.

We aimed to investigate the predictive value of the CT findings combined with serum potassium levels for primary aldosteronism (PA) subtype diagnosis, with a particular interest in sex differences. In this retrospective study, we eventually included 482 PA patients who underwent successful adrenal venous sampling (AVS) and had available data. We diagnosed the subjects as having either unilateral (n = 289) or bilateral PA (n = 193) based on AVS. We analyzed the concordance rate between AVS and adrenal CT combined with serum potassium and performed a logistic regression analysis to assess the prevalence of unilateral PA on AVS. The total diagnostic concordance rate between CT findings and AVS was 51.5% (248/482). The prevalence of hypokalemia in men and women was 47.96% (129/269) and 40.85% (87/213), respectively. The occurrence of unilateral lesions on CT and hypokalemia was significantly associated with an increased prevalence of unilateral PA [odds ratio (OR) 1.537; 95% confidence interval (CI) 1.364-1.731; p < 0.001]. In male participants, G2 (bilateral lesion on CT and normokalemia), G3 (unilateral lesion on CT and normokalemia), G4 (bilateral normal on CT and hypokalemia), G5 (bilateral lesion on CT and hypokalemia), and G6 (unilateral lesion on CT and hypokalemia) were significantly increased for the prevalence of unilateral PA on AVS (G2: OR 4.620, 95% CI 1.408-15.153; G3: OR 6.275, 95% CI 2.490-15.814; G4: OR 3.793, 95% CI 1.191-12.082; G5: OR 16.476, 95% CI 4.531-59.905; G6: OR 20.101, 95% CI 7.481-54.009; all p < 0.05), compared with G1 (patients with bilateral normal on CT and normokalemia). However, among female participants, we found an increased likelihood for unilateral PA in patients with unilateral lesions on CT and hypokalemia alone (OR 10.266, 95% CI 3.602-29.259, p < 0.001), while no associations were found in other groups (all p > 0.05). Sex had a significant effect on modifying the relationship between unilateral PA and the combination of CT findings and serum potassium (p for interaction <0.001). In conclusion, our results indicated that CT findings combined with serum potassium levels have a great value for predicting the subtype of PA and are stronger in men.

Unilateral adrenalectomy for a drug-resistant bilateral primary aldosteronism with heart failure: pathophysiology and surgical indication

BackgroundPatients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy.Case presentationA 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration (PAC; 1,410 pg/mL). Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient’s heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient’s heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment.ConclusionsUnilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA.

Epidemiology and diagnosis of primary aldosteronism. What have we learned from the SPAIN-ALDO registry?

To summarize the available data on the prevalence, clinical repercussion, and diagnosis of primary aldosteronism (PA) and to discuss the SPAIN-ALDO registry's findings, which is the largest PA patient registry in Spain. A comprehensive review of the literature focused on the prevalence, clinical presentation and diagnosis of PA was performed. PA is the most common cause of secondary arterial hypertension. In addition, PA patients have a higher cardio-metabolic risk than patients with essential arterial hypertension matched by age, sex, and blood pressure levels. However, despite its high prevalence and associated metabolic and cardiovascular complications, PA remains largely under-recognized, with less than 2% of people in at-risk populations ever tested. The diagnostic investigation is a multistep process, including screening, confirmatory testing, and subtype differentiation of unilateral from bilateral PA forms. Data from the SPAIN-ALDO registry have shed light on the cardiometabolic impact of PA and about the limitations in the PA diagnosis of these patients in Spain. The most common cause of secondary hypertension is PA. One of the most challenging aspects of the diagnosis is the differentiation between unilateral and bilateral PA because adrenal venous sampling is a difficult procedure that should be performed in experienced centers. Data from the SPAIN-ALDO registry have provided important information on the nationwide management of this pathology.

Corticotropin Stimulation in Adrenal Venous Sampling for Patients With Primary Aldosteronism

Adrenal venous sampling (AVS) is usually recommended to distinguish between unilateral and bilateral primary aldosteronism (PA) before definitive surgical or medical treatment is offered. Whether a treatment decision based on AVS with or without corticotropin (ACTH) stimulation leads to different biochemical and clinical remission rates in patients with PA remains unclear. To evaluate whether treatment decisions based on AVS with or without ACTH stimulation lead to different biochemical and clinical remission rates in patients with PA. This randomized clinical trial (RCT) was conducted at a tertiary hospital in China from July 8, 2020, to February 20, 2023, among patients with PA aged 18 to 70 years. Patients were followed up for 12 months after the initiation of treatment. An intention-to-diagnose analysis was conducted. Patients were randomly assigned to undergo either ACTH-stimulated or non-ACTH-stimulated AVS. The primary end point was the proportion of patients with complete biochemical remission after 12 months of follow-up. Secondary outcomes included the proportion of patients who achieved complete clinical remission after 12 months of follow-up, dosages of antihypertensive agents, rate of successful bilateral AVS, and adverse events. Of 228 patients with PA, 115 were randomized to the non-ACTH-stimulated group (median age, 50.0 years [IQR, 41.0-57.0 years]; 70 males [60.9%]) and 113 to the ACTH-stimulated group (median age, 50.0 years [IQR, 43.5-56.5 years]; 63 males [55.8%]). A total of 68 patients (59.1%) underwent adrenalectomy in the non-ACTH group and 65 (57.5%) in the ACTH group. There was no significant difference in the proportion of patients with complete biochemical remission who were managed on the basis of AVS with vs without ACTH stimulation (with: 56 of 113 [49.6%]; without: 59 of 115 [51.3%]; P = .79). There also was no significant difference in the proportion of patients who achieved complete clinical remission between the non-ACTH and ACTH groups (26 of 115 [22.6%] and 31 of 113 [27.4%], respectively; P = .40). The intensity of therapy with antihypertensives, successful catheterization of bilateral adrenal veins, and incidence of adverse events did not significantly differ between the non-ACTH and ACTH groups. In this RCT, treatment of PA on the basis of non-ACTH-stimulated or ACTH-stimulated AVS did not lead to significant differences in clinical outcomes for the patients. These results suggest that ACTH stimulation during AVS may not have clinical benefit, at least in the Chinese population. ClinicalTrials.gov Identifier: NCT04461535.

Characteristics of cardiac arrhythmia and heart rate variability in Chinese patients with primary aldosteronism.

We applied 24-h Holter monitoring to analyze the characteristics of arrhythmias and heart rate variability in Chinese patients with primary aldosteronism (PA) and compared them with age-, sex-, and blood pressure-matched primary hypertension (PH) patients. A total of 216 PA patients and 261 PH patients were enrolled. The nonstudy data were balanced using propensity score matching (PSM), and the risk variables for developing arrhythmias were then analyzed using logistic regression analysis. Before PSM, the proportion of PA patients with combined atrial premature beats and prolonged QT interval was higher than the corresponding proportion in the PH group. After PSM, the PA group had a larger percentage of transient atrial tachycardia and frequent atrial premature beats, and it had higher heart rate variability metrics. The proportion of unilateral PA combined with multiple ventricular premature beats was higher than that of bilateral PA. Older age, grade 3 hypertension, and hypokalemia were independent risk factors for the emergence of arrhythmias in PA patients. PA patients suffer from a greater prevalence of arrhythmias than well-matched PH patients.

OR02-04 Peripheral Blood Steroid Profiling Discriminates Aldosterone-producing Adenoma Genotypes From Bilateral Primary Aldosteronism

Abstract Disclosure: A.F. Turcu: None. C. Lee: None. Z. Salman: None. H. Liu: None. A. Rabbah: None. S.M. Konzen: None. W.E. Rainey: None. T.J. Giordano: None. L. Zhao: None. A. Udager: None. Background: Primary aldosteronism (PA) is dichotomized into 2 major subtypes: unilaterally dominant PA, often caused by aldosterone-producing adenomas (APAs), and bilateral PA (BPA). Adrenal vein sampling (AVS)-guided unilateral adrenalectomy is often curative in patients with APA and offers marked cardiovascular and renal benefits. The diagnosis and subtyping of PA is a complex, multistep process, hindered by expertise and resource limitations. Objective: To develop steroid fingerprints that can distinguish genotype specific APAs from BPA in peripheral blood. Design And Methods: We enrolled 120 patients with PA who underwent AVS in a single tertiary referral center. Liquid-chromatography tandem mass spectrometry was used to simultaneously quantify 17 steroids in adrenal veins (AV) and periphery, both at baseline, and 10-20 min after cosyntropin stimulation. Aldosterone synthase (CYP11B2) immunohistochemistry-guided next generation sequencing was employed to identify aldosterone-driver mutations. Kruskal-Wallis tests were performed for comparison of continuous variables across multiple groups. Receiver operating characteristic (ROC) curves were plotted to discriminate APAs from BPA. Results: The 120 study participants included 75 patients with APA who underwent unilateral adrenalectomy and had documented aldosterone-driver mutations, and 45 patients with BPA. Of patients with APAs, 36 carried somatic mutations in CACNA1D, 24 in ATPase, and 15 in KCNJ5 genes, respectively. Patients with KCNJ5 mutations were younger and most were women. In the dominant AVs, the KCNJ5 group had marked elevations of 18-hydroxycortisol, 18-oxocortisol, aldosterone, and 11-deoxycorticosterone (DOC); conversely, the BB group had the lowest concentrations of mineralocorticoid and androgen precursors, despite comparable cortisol levels across all groups. Similar patterns were observed in peripheral blood. Linear discriminant analysis incorporating all steroids measured in baseline peripheral serum showed areas under the curve (AUC) of 0.98, 0.97, and 0.92 for distinguishing APAs with KCNJ5, ATPase, or CACNA1D mutations, respectively, from BPA. Conclusions: Single-assay steroid profiles measured in peripheral serum can distinguish genotype-specific APAs from BPA. Once validated, such tests might circumvent the need for AVS in large subset of PA patients. Presentation: Thursday, June 15, 2023

FRI130 Usefulness Of The Upright Posture Test In The Diagnosis Of Primary Aldosteronism

Abstract Disclosure: N. Younes: None. M. St-Jean: None. M. Desrochers: None. I. Bourdeau: None. A. Lacroix: None. Objectives: Renin-independent aldosterone excess characterizes primary aldosteronism (PA). We have previously shown that PA is frequently regulated by aberrant stimuli, including the upright posture stimulation test (UPT), in which plasma aldosterone concentrations (PAC) increase in a renin-independent manner. In this study, we further examined the usefulness of UPT in diagnosing PA. Methods: We conducted a retrospective analysis of the medical records of 187 adult patients who underwent an UPT as part of their evaluation for possible PA and 25 control subjects, in 2 referral university centers between January 2011 and December 2021. UPT was conducted in an ambulatory setting, mostly in patients with potential false negative or borderline results of oral/IV saline confirmation tests. UPT was performed in a fasting state, early morning, 72 hours off beta-blockers, ACE, or ARBS. Patients were in a supine posture for 1 hour, followed by ambulation for 2 hours. Blood samples were collected for PAC, renin, and cortisol, at baseline and at 30 minutes intervals during ambulation. An abnormal response was defined as a ≥50% rise in PAC with a suppressed renin (≤10.1 ng/L or ≤1 ng/mL/h) and a cortisol increase ≤50%. Results: Median age of patients was 55.0 [IQR (46.0; 63.0)], 52.4% were female. 93.6% were taking at least one antihypertensive medication and 32% had hypokalemia. 43.5% did not have adrenal nodules at imaging. 76.5% (n=143) were diagnosed with PA, based on either IV/oral sodium load or UPT. When compared to controls, PA patients had higher basal PAC and lower basal renin levels (p&amp;lt;.0001) and achieved a higher maximal PAC and lower maximal renin (renin max) in response to posture [median PAC (IQR): 802.0 pmol/L (569.0, 1244.0) in PA v/s 624.0 pmol/L (500.0, 736.0) in controls, p=0.0081 and median renin 5.0 ng/L [IQR (3.0, 8.0)] in PA v/s 27.5 ng/L in controls (19.0, 46.0); p&amp;lt;.0001]. Renin max ≤10.1 had the best sensitivity and specificity for predicting PA (90% and 92%, respectively). 95.3% of PA patients increased PAC by at least 50% on UPT (median increase 363%), while renin remained suppressed. All 42 PA patients with a false negative (PAC ≤162 pmol/L) on IV saline test had a renin max ≤10.1 during UPT and 97.6% increased aldosterone by at least 50%. 84% of PA patients with a borderline response (162-240 pmol/L) on IV saline test, had a renin max ≤10.1 and all patients increased aldosterone by at least 50%. 42 patients underwent adrenal vein sampling: 50% had lateralized PA (potassium was lower than in bilateral PA, p=0.003). However, the aldosterone and renin response to UPT did not significantly differ between the two subtypes of PA. Conclusion: A renin-independent aldosterone increase during UPT can be used to confirm PA diagnosis, which was particularly useful in patients with false negative saline loading tests. Renin-independent PAC response to UPT occurred equally in lateralized and bilateral PA. Presentation: Friday, June 16, 2023

OR02-03 Twenty-four-hour Tissue Microdialysis Of Aldosterone And Metabolites In Primary Aldosteronism

Abstract Disclosure: M.A. Grytaas: None. P. Methlie: None. I. Marinelli: None. E. Zavala: None. M. Øksnes: None. T. Upton: None. K. Simunkova: None. D.A. Vassiliadi: None. K. Løvås: None. S. Bensing: None. I. Botusan: None. K. Berinder: None. G.M. Russell: None. G. Ueland: None. O. Kampe: None. S. Tsagarakis: None. S.L. Lightman: None. E.S. Husebye: None. Background: Primary aldosteronism (PA) is the most common cause of secondary hypertension but is grossly underdiagnosed. Early detection, accurate discrimination between unilateral and bilateral PA and appropriate treatment are vital to prevent cardiovascular and renal complications. The current workup however is a cumbersome, multistep process that may not detect dynamic aldosterone variability or nocturnal hypersecretion. Furthermore, subtype determination with adrenal venous sampling is invasive and technically challenging. Novel dynamic 24-hour steroid profiling may represent a major step forward in the diagnostics and subtyping of PA. Aim: To assess 24-hour rhythmicity of aldosterone and metabolites in PA, and to develop a novel dynamic diagnostic tool to discriminate PA from healthy subjects (HS), using tissue microdialysis. Material and methods: Twenty-minute frequency microdialysis fractions were collected over 24 hours from 64 ambulatory patients with PA (26 bilateral, 24 unilateral, 14 with undetermined subtype) using the U-Rhythm sampler followed by multiplex hormone assay liquid chromatography tandem mass spectrometry (LC-MS/MS). Sixteen patients subsequently treated with adrenalectomy for unilateral PA had additional postoperative samplings. Microdialysis samplings from 214 HS were used as controls. We calculated statistical distributions of dynamic biomarkers of abnormality, and developed a machine learning classifier that discriminates PA from HS. Results: Although there were large interindividual variations, PA patients did show a disturbed circadian rhythmicity of aldosterone compared with HS, including some with multiple very high ultradian spikes. Unilateral PA had higher aldosterone spikes and more disturbed rhythmicity compared with bilateral PA. A profound reduction of aldosterone levels and normalisation of rhythmicity was seen post adrenalectomy. Applying a Random Forest classifier in a subgroup of 20 PA patients, 82% specificity and 85% sensibility were achieved to discriminate PA from HS. Our analysis also suggests 18-hydroxycortisol as the most discriminative dynamic biomarker. Conclusions: We demonstrate for the first time circadian and ultradian rhythms of aldosterone in a large cohort of PA compared with HS. Based on our preliminary results, dynamic 24-hour samplings may provide a novel method for diagnosing and subtyping PA, and assess biochemical cure after adrenalectomy. Presentation: Thursday, June 15, 2023

FRI125 Recurrence Of Primary Aldosteronism Long-Term After Adrenalectomy For Aldosterone-Producing Adenoma With KCNJ5 Gene Mutation: A Two-Cases Report

Abstract Disclosure: K. Aiga: None. M. Kometani: None. D. Aono: None. S. Karashima: None. T. Yoneda: None. Primary aldosteronism (PA) is a major cause of secondary hypertension. PA is known to have higher prevalence of cerebral or cardiovascular complications, indicating the importance of early detection and treatment for PA. PA is caused by autonomous secretion of aldosterone in the adrenal glands. PA is characterized by high plasma aldosterone concentration, low plasma renin activity and hypokalemia. PA is classified into unilateral PA (aldosterone-producing adenoma [APA] or unilateral hyperplasia) and bilateral PA (bilateral adrenal hyperplasia). PA with aldosterone excess in bilateral adrenal glands is defined as bilateral PA. On the other hand, PA with aldosterone excess in unilateral adrenal gland is defined as unilateral PA. Strategies for PA treatment depends on the subtype of PA. Medication by mineralocorticoid receptor antagonists is a common treatment for bilateral PA. Adrenalectomy is the most efficient treatment for unilateral PA. In general, patients tend to maintain normal serum potassium level and blood pressure after adrenalectomy, and recurrence of PA is extremely rare. Recently, mutation in the gene named KCNJ5 was found to derive APA. Herein, we report two cases of PA recurrence more than 10 years after surgical treatment for APA. Somatic mutation in KCNJ5 was detected in the first occurrence of PA in both cases. First case, a 52-year-old woman was examined for hypertension 22 years after total adrenalectomy of the right adrenal gland. Recurrent PA was diagnosed based on high aldosterone-renin-ratio (ARR), identification of left adrenal gland tumor by computed tomography (CT), and a confirmatory test. Second case, a 65-year-old man was examined for hypertension 17 years after total adrenalectomy of the left adrenal gland. He had maintained his blood pressure using medication since the onset of hypertension 4 years after the surgery. A year later, a high ARR was observed. PA recurrence was determined by a right adrenal gland tumor noted on CT and a confirmatory test. Tissues of the adrenal gland were obtained from adrenalectomy in both cases. Histopathological analysis revealed presence of one adenoma in the first case, while two adenomas were confirmed in the second case. Somatic mutation in KCNJ5 gene was detected in both cases. To date, there are no specific guidelines established for the management of recurrent PA. Early detection is crucial for the prevention of severe cardiovascular diseases. Long-term follow-up is recommended after the treatment of PA. Presentation: Friday, June 16, 2023

FRI145 Prevalence Of Type 2 Diabetes Mellitus And Risk Factors For Its Development In Patients With Primary Aldosteronism

Abstract Disclosure: M. Araujo-Castro: None. M. Paja Fano: None. M. González Boillos: None. B. Pla Peris: None. E. Pascual-Corrales: None. A. García Cano: None. P. Parra: None. P. Martín Rojas-Marcos: None. J. Ruiz-Sanchez: None. A. Vicente Delgado: None. E. Gómez Hoyos: None. R. Ferreira: None. I. García Sanz: None. M. Recasens Sala: None. R. Barahona San Millan: None. M. Picón César: None. P. Díaz Guardiola: None. J. García González: None. C.M. Perdomo: None. L. Manjón Miguélez: None. R. García Centeno: None. Á. Rebollo Román: None. P. Gracia Gimeno: None. C. Robles Lázaro: None. M. Morales-Ruiz: None. M. Calatayud Gutiérrez: None. S. Simone Andree Furio Collao: None. D. Meneses: None. M. Sampedro Nuñez: None. V. Escudero Quesada: None. E. Mena Ribas: None. A. Sanmartin Sánchez: None. C. Gonzalvo Diaz: None. C. Lamas: None. F. Hanzu: None. Purpose: To evaluate the prevalence of type 2 diabetes mellitus (T2DM) in patients with primary aldosteronism (PA) and the risk factors for its development. Methods: A retrospective multicenter study of PA patients in follow-up in 27 Spanish tertiary hospitals (SPAIN-ALDO Register). Adrenal venous sampling (AVS) was informative of laterality in 128 out of 226 patients and adrenalectomy was performed in 201 patients. Unilateral PA was defined as biochemical cure after adrenalectomy or as a lateralization index in AVS &amp;gt; 2 with ACTH or &amp;gt;3 without ACTH stimulation. Results: Overall, 649 patients with PA were included. Median age was 55.5 (range 27.3-81.6) years, 59.1% were female and 58.5% had hypokalemia at diagnosis. A total of 224 patients were classified as unilateral PA (142 based on biochemical cure after adrenalectomy and 82 based also on AVS results) and 49 as bilateral PA. At diagnosis, 21.2% (n=137) had T2DM and 25 of them had microvascular complications, being diabetic kidney disease the most common (n=19). We identified as risk factors of type 2 diabetes: male sex (OR 2.80 [1.81-4.34], P&amp;lt;0.001), older age (OR 1.05 [1.03-1.07], P&amp;lt;0.001), familiar history of T2DM (OR 4.64 [2.39-8.99]), P&amp;lt;0.001), dyslipidemia (OR 4.05 [2.67-6.14], P&amp;lt;0.001), cardiovascular (OR 1.30 [1.14-1.48], P&amp;lt;0.001) and cerebrovascular disease (OR 1.59 [0.92-2.74], P=0.003), sleep apnea syndrome (SAS) (OR 2.21 [1.34-3.63], P=0.003), higher BMI (OR 1.06 per unit [1.03-1.10], &amp;lt;0.001), hypertension duration (OR 1.04 per year [1.02-1.06], P&amp;lt;0.001) and the number of antihypertensive drugs (OR 1.50 [1.29-1.74], P&amp;lt;0.0001). In the multivariant analysis, all these variables were independent risk factors for T2DM except for SAS, hypertension duration, sex, and BMI. No association was observed with plasma aldosterone concentration, potassium levels, unilaterality of PA or other parameters. No significant differences in the evolution of the glycemic control (fasting plasma glucose and HBA1c) were observed between T2DM who underwent surgery and those medically treated (P&amp;gt;0.05). Conclusion: Type 2 diabetes affects about one quarter of patients with PA and risk factors for its development are common than to the general population. Medical and surgical treatment provide a similar benefit in terms of glucose control in patients with PA and T2DM. Presentation: Friday, June 16, 2023

FRI140 Impact Of Circadian Rhythm Of Aldosterone And Cortisol Levels Upon Adrenal Vein Sampling In Primary Aldosteronism

Abstract Disclosure: M. Kometani: None. M. Yoneda: None. K. Aiga: None. D. Aono: None. S. Karashima: None. Y. Takeda: None. T. Yoneda: None. Purpose: Adrenal venous sampling (AVS) is the gold standard technique for subtype differentiation of primary aldosteronism (PA). AVS is an invasive and challenging test; however, because of the high frequency of PA, it is currently performed at many institutions in Japan. Considering the effects of diurnal variations in the levels of aldosterone and cortisol, the guidelines recommends that AVS without ACTH loading should be performed in the morning. However, owing to staffing issues and general limitations, AVS is performed in the afternoon in many facilities. In this study, we examined the effects of AVS timing (AM/PM) on AVS results. Methods: This multicenter, retrospective, observational study included a total of 753 patients diagnosed with PA at four specialized institutions. The patients were divided into two groups according to the timing of the AVS procedure. The group classification of patients according to the time of the day when AVS was performed was not prospectively designed but rather determined based on feasible conditions at each facility. Among them, 504 and 249 patients underwent AVS in the morning (AM-AVS) and in the afternoon (PM-AVS), respectively. Results: The success rate of basal AVS in the AM-AVS group was 81% and that of ACTH-stimulated AVS was 92%. The success rate of basal AVS in the PM-AVS group was 74% and that of ACTH-stimulated AVS was 88%. There was no significant difference in the AVS success rate between the AM-AVS and PM-AVS groups. There was no significant difference between the AM-AVS and PM-AVS groups concerning the rate of unilateral diagnosis by AVS before ACTH stimulation, the rate of unilateral PA diagnosis by AVS after ACTH stimulation, and the percentage of cases with discrepancies between the two AVSs. Regarding patients with unilateral PA, aldosterone concentrations in adrenal venous blood did not differ between the two groups on the dominant or non-dominant side. Conversely, regarding patients with bilateral PA, aldosterone concentrations in adrenal venous blood were significantly higher in the AM-AVS than in the PM-AVS group. Conclusions: This study evaluated the effect of AVS timing. Although this was a multicenter study, there were no differences in the success rate of AVS, diagnostic rate of subtype, or frequency of deviation in the subtypes between the AM-AVS and PM-AVS groups. These results are relevant for facilities that can perform AVS only in the afternoon. Concerning aldosterone levels, no differences were observed between patients with unilateral lesions in the AM-AVS and PM-AVS groups, whereas its levels were different between patients with bilateral lesions in the AM-AVS and PM-AVS groups, suggesting the involvement of different mechanisms that regulate aldosterone secretion according to the circadian rhythm in patients with unilateral or bilateral lesions. Presentation: Friday, June 16, 2023

FRI134 Transcriptomic Profiling Of Monocytes To Seek A Potential Biomarker For Primary Aldosteronism

Abstract Disclosure: R. Libianto: None. N. Karthigan: None. J. Morgan: None. D. Powell: None. P.J. Fuller: None. M.J. Young: None. J. Yang: None. Primary aldosteronism (PA), the most common endocrine cause of hypertension, is associated with increased cardiovascular risk compared with essential hypertension. The diagnosis of PA currently relies on measurements of plasma aldosterone and renin levels which can be compromised by patient- or assay-related issues and relies on arbitrary thresholds. A cellular marker that reflects excess endogenous aldosterone activity could enhance the diagnostic process. Mineralocorticoid receptor (MR) activation in macrophages has previously been shown to play a key role in mediating cardiovascular injury. Macrophage precursors, the monocytes, also express MR and can be easily isolated from circulation. We therefore sought to identify unique transcriptomic markers of aldosterone excess in peripheral blood monocytes. Monocytes were isolated from nine male patients with unilateral PA before and 3 months after curative adrenalectomy. Each patient’s post-adrenalectomy samples served as the control for comparison with the pre-adrenalectomy samples. RNA sequencing (RNA-seq) was performed on monocyte RNA samples to identify differentially expressed genes (DEGs), followed by evaluation using a second method by real-time quantitative PCR (RT-qPCR). Distinct clustering of gene expression was observed between the “before” and “after-surgery” samples with 1679 significantly differentially expressed (false discovery rate &amp;lt;0.05). The top 26 DEGs were selected for evaluation by RT-qPCR. Differences were observed in the relative expression of phosphoglycerate mutase 1 (PGAM1), ferrochelatase (FECH), and nuclear enriched abundant transcript 1 (NEAT1) genes pre- and post-surgery. The ratios of the relative expression of these genes accentuated the difference between the before- and after-surgery samples. In conclusion, differential gene expression was found between monocytes of patients with unilateral PA before and after adrenalectomy. Further validation studies are needed in female patients and those with bilateral PA and essential hypertension. These transcriptomic markers or their ratios have the potential to serve as novel biomarkers of aldosterone excess. Presentation: Friday, June 16, 2023

Diagnostic performance of the adrenal vein to inferior vena cava aldosterone ratio in classifying the subtype of primary aldosteronism.

Adrenal vein sampling (AVS) is the standard procedure for distinguishing unilateral primary aldosteronism (PA) from bilateral PA. In cases where only one adrenal vein is successfully cannulated, it has been suggested that subtype classification can be determined based on the ratio of the concentration of aldosterone between the adrenal vein and the inferior vena cava (AV/IVC index). However, diagnostic performance of the ipsilateral versus contralateral AV/IVC index in predicting lateralization has not been directly compared. In a retrospective cohort of 133 patients with confirmed PA who underwent successful AVS, the performance of the AV/IVC index to predict laterality was evaluated and the area under the receiver operating characteristic (AUROC) curves was calculated. In detecting left unilateral PA (n = 47), the AUROC of the right AV/IVC index (RAV/IVC) was significantly higher than the AUROC of the left AV/IVC (LAV/IVC) index (0.967 vs. 0.871, p = 0.008). In detecting right unilateral PA (n = 30), the AUROC of the LAV/IVC index tended to be higher than that of the RAV/IVC index, but the difference did not reach statistical significance (0.966 vs. 0.906, p = 0.08). In detecting left unilateral PA, the sensitivities of the RAV/IVC and LAV/IVC indices were 83% and 46%, respectively, while the specificities of both were above 90%. In detecting right unilateral PA, the sensitivities of the LAV/IVC and RAV/IVC indices were 80% and 43%, respectively, while the specificities of both were above 90%. The AV/IVC index has superior diagnostic performance in detecting contralateral unilateral PA compared to ipsilateral unilateral PA.