**Diagnosis and Treatment of Primary Aldosteronism**

Ozlem Tiryaki\* and Celalettin Usalan *Gaziantep University School of Medicine, Department of Nephrology Turkey*

#### **1. Introduction**

124 Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease

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Malatino, L.S., 2000. Inflammation is associated with carotid atherosclerosis in dialysis patients. Creed Investigators. Cardiovascular Risk Extended Evaluation in Primary aldosteronism (PAL) is a clinical disorder characterized by excessive production and release of aldosterone from the cortical zona glomerulosa of the adrenal gland. The high level of circulating aldosterone increases sodium reabsorption with potassium loss in the distal tubule, leading to mild hypernatremia, hypertension (HTN), severe hypokalemia, and alkalosis. 1,2 Primary aldosteronism, as originally described by Conn in the 1950s.3,4 (PAL)is characterized by an increased secretion of aldosterone that seems to be autonomous of the renin–angiotensin system, as the secretion of renin is suppressed. PAL represents the most common form of secondary hypertension.5,6 In recent years, the large- scale hypertension trials, It is now widely recognized that PAL is much more common than previously thought, being present in up to 5–13% of unselected hypertensive patients7 and in resistant HTN (BP above goal with three or more antihypertensive medications) with a reported prevalence of 20% to 23% in this group of patients.5,8 As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease.5 In ALLHAT, older age, higher baseline systolic blood pressure, LVH, and obesity all predicted treatment resistance as defined by needing 2 or more antihypertensive medications. Overall, the strongest predictor of treatment resistance was having CKD as defined by a serum creatinine of ≥1.5 mg/dL. Other predictors of the need for multiple medications included having diabetes mellitus and living in the southeastern United States. African-American participants had more treatment resistance, as did women, such that black women had the lowest control rate (59%) and non-black men the highest (70%).8 Furthermore, experimental and clinical studies showed that excess aldosterone has detrimental effects on the heart, brain and kidneys that are partly hypertensionindependent.9 Patients diagnosed with PAL, compared with patients with essential hypertension seems to increase the left ventricular wall thickness.10 In addition, aldosterone excess appears to independently increase the risk of cardiac fibrosis.11 Likewise, mineralocorticoid receptor blockage has been showed to diminish the effects of aldosterone

<sup>\*</sup> Corresponding Author

Diagnosis and Treatment of Primary Aldosteronism 127

patients with: **1)** resistant hypertension; **2)** hypertension grade 2 or 3; **3)** hypertension and spontaneous or diuretic-induced hypokalaemia **4)** hypertension with adrenal incidentaloma; **5)**hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 year); **6)** all hypertensive first-degree

There is a general consensus that aldosterone:renin ratio (ARR) is the most reliable available means for PAL screening; however there is no agreement on either the ARR cut-off or whether the absolute aldosterone level should also be taken into account. Aldosterone renin ratios (ARRs) were calculated from these values using the following Formula (ARR): Plasma aldosterone (ng/dL)**/**Plasma renin (ng/mL-h) . Individuals with an ARR of ≥30 were suspected of having primary aldosteronism, while an ARR of <30 was considered normal.1 However, it is now recognized the prevalence is higher (5-13% of all patients with hypertension) when the PAC to PRA ratio (ARR) is used to screen for PAL. Measurements

Several factors affect ARR, the most important being antihypertensive therapy: mineralocorticoid receptor antagonists and diuretics lead to false-negative results and thus should always be withdrawn for at least 4–6 weeks (6– 8 for spironolactone); dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists can potentially, but infrequently, led to false-negative results25; in contrast, beta-blockers and central 2-agonists can cause false positives.26 The direct renin inhibitor aliskiren lowers PRA, resulting in false-positive ARR for renin

An increased ARR is not diagnostic by itself, and PAL must be confirmed by demonstrating over- production of aldosterone. The Endocrine Society guidelines recommend the following four confirmatory tests; an oral sodium test, saline infusion test, fludrocortisone test and captopril challenge test.1 Patients should receive 12.8 g sodium chloride for 3 days in the oral sodium loading test. The captopril challenge test shows excellent sensitivity despite relatively low specificity and due to its simplicity can be

**Oral sodium loading test:** This test is performed to evaluate the suppression of aldosterone by oral sodium loading. The oral sodium loading test is also not practical in hypertensive patients because of their high-salt intake, and the intravenous saline infusion test is not common as it is dangerous for elderly patients or those with left ventricular hypertrophy or a previous myocardial infarction, all of which are commonly complicated by PAL. The most commonly used test to verify the diagnosis oarl sodium loading test. Patients should increase their sodium intake to 200 mmol/d (6 g/d) for 3 day, verified by 24-h urine sodium content. Patients should receive adequate slow-release potassium chloride supplementation to maintain plasma potassium in the normal range. Urinary aldosterone is measured in the 24-h urine collection from the morning of d 3 to the morning of day 4. PAL is unlikely if urinary aldosterone is lower than 10 µg/24 h (27.7 nmol/ d) in the absence of renal disease where PAL may coexist with lower measured urinary aldosterone levels. Elevated urinary aldosterone excretion >12 µg/24 h (>33.3 nmol/d) at the Mayo Clinic, >14 µg/24 h (38.8 nmol/d) at the makes PAL highly likely.

of PAC and PRA are recommended for the diagnosis of PAL.

measured as PRA and false negatives for renin measured.1

performed at the outpatient clinic.

relatives of patients with PAL.

on PAI-1 levels. In recent years, clinical trials have demonstrated an additive effect of combined ACEI and aldosterone receptor antagonism on cardiovascular morbidity and mortality.12,13 The mechanism, named aldosterone escape, referring to chronic ACEI that leads aldosterone to return to baseline concentrations, might clarify the additional effects of aldosterone on PAI-1 levels.14,15 We study, administration of an ACEI (fosinopril) and an ACEI plus aldosterone antagonist (spironolactone) both caused a significant decrease in PAI-1 levels, which might be attributed to aldosterone escape.16

Several studies have shown that patients with either aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA) appear to have increased cardiovascular morbidity compared with age-, sex-, and systolic and diastolic BP-matched patients with essential hypertension.17,18 Patients with PAL, stroke, MI and significantly increased risk of atrial fibrillation.19 Optimal BP control and specific management of aldosterone excess by either adrenalectomy or medical treatment with mineralocorticoid receptor (MR) antagonists is fundamental for the prevention of cardiovascular events in patients with PA.20

The adverse effects of aldosterone excess stress the importance of establishing the diagnosis of PAL and its underlying cause. The most common subtypes of PAL are APA (35% of cases) and IHA (60% of cases).21 Many other subtypes of PAL have also been described, including primary or unilateral adrenal hyperplasia (2%), pure aldosterone-secreting adrenocortical carcinoma (<1%) and ectopic aldosterone- secreting tumours (e.g. neoplasms in the ovary or kidney) (<0.1%).22
