A case of primary aldosteronism with chronic renal failure undergoing hemodialysis treatment.

The diagnosis of aldosterone-producing adenoma (APA) is challenging for endocrinologists, as APA does not always present with the typical constellation of clinical and laboratory features, such as hypertension, hypokalemia, suppressed plasma renin activity (PRA), and high plasma aldosterone concentration (PAC). Very recently, several studies have indicated that APA can be discovered even in normokalemic subjects with normal PRA more frequently than previously considered. Here we report a case of APA associated with chronic renal failure, which showed normokalemia and normal PRA. The patient was referred to our clinic for evaluation of an incidentally discovered adrenal mass with abnormally high PAC. After 6 yr, it was found that the right adrenal tumor showed a marked increase in size. Endocrinological examinations indicated normal PRA and markedly high PAC. Aldosterone showed a better response to the upright posture test than that to ACTH stimulation test. The diagnosis of APA was made based on the markedly high PAC to PRA ratio and the adrenocortical scintigraphy, which showed unequivocal uptake into the tumor. Right laparoscopic adrenalectomy was performed, revealing a right adrenocortical adenoma with massive hemorrhage. Histopathological examinations revealed the presence of two independent adrenocortical adenomas, one APA with predominant clear tumor cells and few c17 (17alpha-hydroxylase) immunoreactivity and the other, cortisol producing adenoma with compact cytoplasm and abundant C17 immunoreactivity. This case indicates a difficulty of diagnosis of "normoreninemic APA" with renal failure. This case is in line with the recent concept that APA is a continuous condition in which only a minority of patients have the classical clinical picture of primary aldosteronism such as hypokalemia. It is possible that normokalemic APA constitutes the most common presentation of the disease.

Hypertension Editors' Picks: Hyperaldosteronism.

Caution About the Overdiagnosis of Primary Aldosteronism

Caution About the Overdiagnosis of Primary Aldosteronism

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

The classic role of aldosterone is to regulate water and electrolyte balance and, therefore, blood pressure homeostasis.1 Apart from that, experimental studies have demonstrated that aldosterone induces structural and functional alterations in the heart, kidneys, and vessels with effects such as myocardial fibrosis, nephrosclerosis, vascular inflammation and remodeling, and disturbed fibrinolysis.2,3 This damage seems to be aldosterone mediated, and aldosterone blockade with mineralocorticoid receptor (MR) antagonists, such as spironolactone, may prevent the onset of these effects.4,5 On the other hand, it cannot completely be ruled out that potassium and high blood pressure also play additional key roles in this damage.6,7 This evidence has impressively been supported by clinical studies, such as the Randomized Aldactone Evaluation Study and the Eplerenone Post-Acute Myocardial Infarction Survival and Efficacy Study.8,9 For example, increased mortality in patients with chronic heart failure has been associated with elevated aldosterone plasma levels,10 and high circulating plasma aldosterone levels predict the clinical outcome in patients after myocardial infarction.11 Furthermore, primary aldosteronism (PA) has been demonstrated to enhance the risk of cardiovascular events12 and kidney disease.13 In summary, aldosterone is considered a cardiovascular risk factor, promoting disease processes such as cardiac fibrosis, nephrosclerosis, and arteriosclerosis,2,3,14 all of which are increased in patients with obesity and the metabolic syndrome.15,16 The term “metabolic syndrome” (MSyn) has evolved various definitions in recent times; most of the studies introduced here use slight modifications. Nevertheless, all of the definitions used have a common denominator, which is reflected in a definition by the American Heart Association/National Heart, Lung, and Blood Institute.17 According to this definition, the MSyn is considered as a constellation of interrelated risk factors of metabolic origin, including arterial hypertension, dyslipidemias, alterations in glucose homeostasis with type 2 diabetes mellitus, and abdominal …

Disclosure: S. Rolak: None. N. Venkatesan: None. R. Gregg Garcia: None. W.F. Young: None. I. Bancos: None. Background: Bilateral primary hyperaldosteronism (PA) is treated with mineralocorticoid receptor antagonist (MRA) therapy. However, the best way to monitor the success of MRA therapy is unclear. Aims: To compare the impact of curative adrenalectomy versus MRA therapy in patients with PA on plasma renin activity (PRA), renal function, and hypertension control. Methods: Single center retrospective study of patients with unilateral PA treated with adrenalectomy or bilateral PA treated with MRAs, 2017-2021. Patients underwent adrenal vein sampling to confirm laterality. Hypertension control was defined based on blood pressure measurements and the standardized hypertension daily dose (HDD). Minimum follow-up was defined as first nonsuppressed PRA or >1 month from therapy. Results: Of 73 patients, 53 underwent unilateral adrenalectomy for unilateral PA (median age 57, range 25-71 years, 36% women) and 20 had bilateral PA treated with MRA (median age 49, range 30-70 years, 70% women). At baseline, when compared to the bilateral PA, patients with unilateral PA had higher plasma aldosterone concentrations (median 31 ng/dL vs 19 ng/dL, P= 0.001), similarly suppressed PRA, and similar estimated glomerular filtration rate (eGFR). Uncontrolled hypertension (>130/90 mmHg) was seen in 40 (75%) of patients with unilateral PA and 14 (70%) patients with bilateral PA, despite a more intensive antihypertensive regimen in unilateral PA (median HDD 5, range 1-18 vs median HDD 3.5 in bilateral PA, range 0.5-9; P=0.016). Hypokalemia was present in 50 (94%) patients with unilateral PA and 15 (75%) in bilateral PA, P = 0.02.Following treatment, hyperkalemia developed in 10 (19%) patients post-adrenalectomy and in 2 (10%) patients treated with MRAs, P = 0.36. At a median follow up of 108 days, 24 (45%) patients treated with adrenalectomy and 16 (80%) patients treated with MRAs demonstrated PRA >1.5 ng/mL/hr, P = 0.008. eGFR decreased by at least 10 points in 15 (30%) patients treated with adrenalectomy vs in 11 (59%) patients treated with MRAs (P=0.033). Post-adrenalectomy, antihypertensive management lessened by a median of 2.5 HDD, while HDD increased in patients treated with MRAs by a median of 1.25, P<0.0001. Hypertension control improved, with a mean decrease in systolic blood pressure of -11 mmHg (95%CI -16.5-(-5.5)) without between group differences. Diastolic blood pressure decreased by a mean of -4.7 mmHg (95%CI -8.7-(-0.7)) in the adrenalectomy group but did not change in those treated with MRAs. Conclusions: Following curative adrenalectomy in unilateral PA, more than half of patients continue to have suppressed PRA. Despite less severe PA at baseline, patients treated with MRAs, as compared to those treated with adrenalectomy, demonstrate a higher prevalence of non-suppressed PRA, lower eGFR, similar hypertension control, and a more intense antihypertensive regimen during follow up. Presentation: Thursday, June 15, 2023

Despite a high prevalence of hypertension in diabetes and close relationship between primary aldosteronism (PA) and glucose metabolism, few study concerns the prevalence of PA in diabetes with hypertension. This study aimed to detect the prevalence of PA in patients with new-onset type 2 diabetes (T2D) and hypertension and to explore the association between PA and diabetes. A total of 256 outpatients with new-onset T2D and hypertension were screened for PA. Plasma aldosterone concentration (PAC), plasma renin activity (PRA) were measured. Patients with an aldosterone renin activity ratio (ARR) ≥ 30 ng/dL/ng/mL/h and PAC ≥ 15 ng/dL underwent confirmatory captopril challenge test (CCT) for PA. The diagnostic criteria for PA were, after CCT, (1) PAC decreased < 30%, (2) ARR maintained ≥ 30 ng/dL/ng/mL/h, and (3) PAC was ≥ 11 ng/dL. Of 256 consecutive patients, 99 (39%) were positive for the screening test, and 49 (19%) were diagnosed with PA. Compared with those in groups A (screening test -) and B (screening test +, CCT -), patients in group C (diagnosed with PA) had a higher percentage of systolic blood pressure of ≥ 160 mmHg, less family history of hypertension, and lower serum potassium. Patients in group B and C had higher PAC and ARR levels, but lower PRA than those in group A. Homeostatic model assessment for insulin resistance (HOMA-IR) was positively associated with PAC level among the diabetic patients. The prevalence of PA in new-onset T2D patients with hypertension is at least 19%. Higher aldosterone may be related with insulin resistance in patients with diabetes.

The majority of cases of primary aldosteronism (PA) occur sporadically. Familial forms of PA are rare with four subtypes defined. We reported a case of familial cluster of primary aldosteronism in two members, daughter and her mother. Case presentation Case 1: Daughter A 20-year-old woman with a history of hypertension and proteinuria for three years without treatment, was admitted for the treatment of accelerated hypertension of 182/121 mmHg and end stage kidney disease. Blood examination revealed low plasma renin activity (PRA) of 0.7 ng/ml/h, and high plasma aldosterone concentration (PAC) of 349 pg/mL, high aldosterone/renin ratio (ARR) of 498.6, and serum potassium (sK) of 4.9 mEq/L. (Plasma ACTH 12.9 pg /mL, plasma cortisol 7.4 mcg/dL) These findings suggested PA. Abdominal CT scan showed no adrenal mass. After control of accelerated hypertension with nifedipine GITS and alpha adrenoceptor blocker, confirmatory tests for PA, saline infusion test (SIT) were carried out and was positive test (PAC 240 min after infusion 264pg/mL). Adrenal venous sampling revealed bilateral hyper-aldosterone secretion. She was given diagnosis of bilateral adrenal hyperaldosteronism. Her blood pressure was decreased to 118/77 along with administration of spironolactone 25 mg/day. Her parents have hypertension. We investigate the cause of hypertension in her parents. Blood test of her father revealed PRA 3.4 ng/m/h, PAC 18.3 pg/ml, and sK 4.7 mEq/L. Case 2: Mother A 45-year-old women with hypertension treated with amlodipine 5 mg was referred to our hospital to examine the renal function after renal donation to her daughter. Blood test revealed mild renal dysfunction (eGFR 72,2), normal sK(4.0 mEq/L), low PRA (0.9 ng/ml/h), high PAC (118 pg/mL) for high salt intake (11.6 g/day as high as salt loading test). Abdominal CT scan showed no adrenal mass. SIT was positive (PAC 240 min after infusion 60.0 pg/mL). She was given diagnosis of PA. Discussion: Potential factors leading to BHA include rare disease-predisposing germline variants, circulating angiotensin II type 1 receptor autoantibodies, and paracrine activation of aldosterone production by adrenal mast cells have been reported. Primary hyperaldosteronism in 2 family members, a mother and daughter, suggests familial hyperaldosteronism which caused by germline mutation. We now investigate germline variants for BHA.

Objective: Although adrenal vein sampling (AVS) is the gold standard for diagnosing subtypes of primary aldosteronism (PA), it is sometimes difficult to make correct diagnosis by conventional AVS in which only adrenal central veins are selected. We recently employed a new approach, super-selective AVS (SS-AVS). We hereby present a case of aldosterone-producing adenoma (APA) diagnosed by SS-AVS and discuss the characteristics of difficult cases. Design and method: Case report: The 36-year-old patient with hypertension was treated with oral medication for five years, but the blood pressure control was poor. Endocrinological examinations were performed and it revealed low plasma renin activity (PRA 0.1 ng/ml/h) and high plasma aldosterone concentration (PAC 190 pg/ml). Imaging examinations showed a 13 mm-sized left adrenal mass. PA was suspected and AVS was performed subsequently to confirmation tests. However, aldosterone/cortisol ratios of both left and right adrenal central veins were lower than that of the inferior vena cava, and he failed to be diagnosed as APA. As we have employed SS-AVS since two years, we performed SS-AVS for the reevaluation for this case, and reviewed such undiagnosable cases. Results: A microcatheter was inserted to the tributaries of the left adrenal vein. Lateralized ratio (LR) using the aldosterone value in the tributary near the mass was 25.8 and contralateral ratio (CR) was 0.50. He was diagnosed as left APA and the surgery was performed. We diagnosed 30 APAs in total, but 8 cases failed to be diagnosed by conventional AVS. Among them, 7 cases were in the left side, and none of them were with tumor size larger than 15 mm. Conclusions: SS-AVS is useful for cases undiagnosable by conventinal AVS because a high plasma aldosterone level can be detected when a microcatheter is inserted closely to APA. It appears that such cases have much in common: a small mass in the left adrenal gland.

Objective: To compare the incidence of metabolic disorders and uric acid (UA) levels between patients with primary aldosteronism (PA) and essential hypertension (EH), and to explore factors associated with UA levels in these patients. Methods: A total of 117 PA and 117 EH patients individually matched by sex, age, blood pressure and duration of hypertension were recruited from in-hospital patients who were hospitalized in our department because of suspicion of secondary hypertension from January 2008 to December 2014. Clinical data including metabolic disorders and UA levels were analyzed. Results: (1) Body mass index (BMI), waist circumference, plasma triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), free fatty acid (FFA) were significantly higher in EH than in PA group (all P<0.05). Prevalence of diabetes mellitus or impaired glucose tolerance (DM+ IGT) was significantly higher in EH than in PA group (41.9% (49/117) vs. 17.1% (20/117), P<0.01). The prevalence of metabolic syndrome (MS) was also significantly higher in EH than in PA group (51.3% (60/117) vs. 24.8% (29/117), P<0.01). (2) EH patients had higher homeostasis model assessment for insulin resistance (HOMA-IR) and lower insulin sensitivity index composite (ISI comp) than PA patients, but basic insulin secretion index (HOMA-β) and modified β cell function index (MBCI) were significantly lower in PA than in EH group (P<0.05). (3) With regard to target organs damages, PA patients revealed higher 24-hour urinary protein, urinary albumin excretion rate (UAER), urinary IgG, urinary α-1 microglobulin, left ventricular mass index and lower urine specific gravity than EH patients (all P<0.05). There was no significant difference in estimated glomerular filtration rate (eGFR) between two groups (P=0.103). (4) UA level was significantly lower in PA group than in EH group ((314.00±89.52) μmol/L vs. (379.16±101.25) μmol/L, P<0.01). Higher plasma aldosterone concentration and lower plasma renin activity were associated with lower UA level in PA group. Conclusions: Compared with sex, age and hypertension duration matched EH patients, PA patients revealed lower UA level and less severe abnormalities of glucose and lipid metabolism, but are associated with severer renal and cardiac damages. The reduced UA level in PA patients is possibly due to the high plasma aldosterone concentration and low plasma renin activity.

SummaryA 31-year-old man with Williams syndrome (WS) was referred to our hospital because of a 9-year history of hypertension, hypokalemia, and high plasma aldosterone concentration to renin activity ratio. A diagnosis of primary aldosteronism (PA) was clinically confirmed but an abdominal CT scan showed no abnormal findings in his adrenal glands. However, a 13-mm hypervascular tumor in the posterosuperior segment of the right hepatic lobe was detected. Adrenal venous sampling (AVS) subsequently revealed the presence of an extended tributary of the right adrenal vein to the liver surrounding the tumor. Segmental AVS further demonstrated a high plasma aldosterone concentration (PAC) in the right superior tributary vein draining the tumor. Laparoscopic partial hepatectomy was performed. The resected tumor histologically separated from the liver was composed of clear cells, immunohistochemically positive for aldesterone synthase (CYP11B2), and subsequently diagnosed as aldosterone-producing adrenal adenoma. After surgery, his blood pressure, serum potassium level, plasma renin activity and PAC were normalized. To the best of our knowledge, this is the first report of WS associated with PA. WS harbors a high prevalence of hypertension and therefore PA should be considered when managing the patients with WS and hypertension. In this case, the CT findings alone could not differentiate the adrenal rest tumor. Our case, therefore, highlights the usefulness of segmental AVS to distinguish adrenal tumors from hepatic adrenal rest tumors.Learning points:Williams syndrome (WS) is a rare genetic disorder, characterized by a constellation of medical and cognitive findings, with a hallmark feature of generalized arteriopathy presenting as stenoses of elastic arteries and hypertension.WS is a disease with a high frequency of hypertension but the renin-aldosterone system in WS cases has not been studied at all.If a patient with WS had hypertension and severe hypokalemia, low PRA and high ARR, the coexistence of primary aldosteronism (PA) should be considered.Adrenal rest tumors are thought to arise from aberrant adrenal tissues and are a rare cause of PA.Hepatic adrenal rest tumor (HART) should be considered in the differential diagnosis when detecting a mass in the right hepatic lobe.Segmental adrenal venous sampling could contribute to distinguish adrenal tumors from HART.

Primary aldosteronism usually shows mild hypertension and is characterized by suppression of plasma renin activity (PRA) and elevation of plasma aldosterone concentration (PAC). Almost all previously reported cases of malignant hypertension associated with primary aldosteronism showed low PRA.3)-6) However, only I case which showed high PRA was reported by Baglin et al in 1973.2) The patient reported below is the second case of primary aldosteronism with high PRA.A 34-year-old man was admitted to our clinic because of severe hypertension, renal insufficiency, and papilledema. Both PRA and PAC were abnormally high, 4.6ng/ml/hr and 23.0ng/100ml, respectively. Serum cortisol levels and urinary catecholamine excretion were within normal ranges. Serum K was normal ranging from 3.6 to 4.9mEq/L. In spite of strong anti-hypertensive drugs, peritoneal, and hemodialysis, the patient died of pulmonaly infection about 3 months later.Postmortem examination revealed a right adrenocortical tumor of 8mm in diameter. Histologically, the tumor consisted of large clear cells; that was adenomatous hyperplasia characteristic in primary aldosteronism. Neither juxtaglomerular tumor nor renal artery stenosis was found.We thought that PRA in primary aldosteronism could rise with progress of renal involvement as secondary changes due to long-standing and untreated hypertension. Normal serum K could be explained by the fact that retention of potassium due to severely disturbed renal function exceeded its loss through aldosterone action. It must be kept in mind that normokalemia and elevated PRA can be encountered under these circumstances.

This presentation is a summary of our recent clinical studies on the therapeutic use of a new potassium-sparing diuretic, amiloride, and a converting enzyme inhibitor, MK-421, in preventing hypokalemia associated with primary and secondary hyperaldosteronism. These drugs are quite different in their physiologic action but they both may be effective in preventing the potassium depletion associated with increased aldosterone production. Amiloride, which blocks the sodium channels in distal renal tubular cells, was administered to 10 patients with primary hyperaldosteronism and five patients with Bartter's syndrome (secondary hyperaldosteronism). Amiloride, at doses of 10-40 mg/day, increased mean plasma potassium levels in both primary hyperaldosteronism (3.2-4.5 mEq/L) and, to a lesser extent, in Bartter's syndrome (2.5-3.6 mEq/L). The blood pressure fell slightly but significantly in primary hyperaldosteronism (171/112 vs 150/97 mm Hg) and remained unchanged in Bartter's syndrome (116/80 vs 117/71 mm Hg). The plasma renin activity and plasma aldosterone rose in primary aldosteronism (PRA 0.39-2.21 ng A1/m1/h and PA 28.4-54.3 ng/d1); but in Bartter's syndrome, the PRA declined (25.3-11.9 ng A1/m1/h) and the PA rose (19.5-38.0 ng/d1). The discrepancy in the PRA between primary aldosteronism and Bartter's syndrome may be due to the effects of potassium repletion on suppressing renin and stimulating aldosterone; while in primary aldosteronism, a mild diuretic effect could explain the rise in PRA. In both of these disorders, despite the rise in plasma potassium levels, amiloride produced a counter-therapeutic rise in PA which could potentiate further potassium losses. Therefore, we undertook a study to evaluate the prevention of diuretic-induced hypokalemia and secondary hyperaldosteronism using a new converting enzyme inhibitor, MK-421. Eighteen normal subjects were randomized into three groups receiving either (1) hydrochlorothiazide alone (50 mg/day), (2) MK-421 alone (10 mg/day), or (3) hydrochlorothiazide (50 mg/day) plus MK-421 (10 mg/day). Although MK-421 did not prevent diuretic-induced hypokalemia or hyperaldosteronism in the first week, after that time hypokalemia was reversed and ASR returned to normal. In these studies, it therefore appears that while potassium-sparing diuretics may remain the medical mainstay in treating primary aldosteronism, new converting enzyme inhibitors such as MK-421 may be more effective in treating secondary hyperaldosteronism, since potassium levels can be normalized without increasing aldosterone secretion.

Previous studies showed higher risk of cardiovascular and cerebrovascular (CCV) events in primary aldosteronism compared with essential hypertension, but the patients of these studies were limited to primary aldosteronism patients with high plasma aldosterone concentration (PAC). The introduction of the aldosterone-renin ratio as the screening test for primary aldosteronism led to the recognition of primary aldosteronism patients with normal PAC (nPA). However, there is no information on the risk of primary aldosteronism including nPA. In this retrospectively and cross-sectional study, the clinical features and CCV event risk of primary aldosteronism at diagnosis including nPA were investigated and compared with essential hypertension. The study included 292 consecutive primary aldosteronism patients and 498 essential hypertension outpatients. All primary aldosteronism patients were diagnosed by autonomous aldosterone secretion using confirmatory tests, and then divided into nPA (n = 130) and primary aldosteronism patients with high PAC (hPA: n = 162) using a PAC cutoff level of less than 443 pmol/l (16 ng/dl), representing the normal upper limit of PAC. nPA patients were significantly older at diagnosis of primary aldosteronism and at onset of hypertension compared with hPA patients. They had milder hypokalemia and easier-to-control blood pressure. The results suggested that nPA could be considered a mild type of primary aldosteronism but not an early-stage hPA. Moreover, the risk of all CCV events in nPA was significantly lower than that in hPA (odds ratio 0.42, 95% confidence interval 0.18-0.90, P < 0.05) and not significantly higher than that in essential hypertension (odds ratio 0.95, 95% confidence interval 0.43-1.94, P = 0.899). This study suggests that aggressive diagnostic workout for nPA is less effective to prevent CCV events.