Updated 15 July 2010
Aldosterone is the principal mineralocorticoid in man. Its functions include regulation of extracellular volume and potassium homeostasis through its effects on the renal distal convoluted tubule. Extra-renal actions of aldosterone on cardiovascular tissues, the colon and salivary glands are also well established. Excess production of aldosterone, due to either primary or secondary disorders, is prevalent in the general population, and is an important cause of morbidity and mortality. This chapter reviews the physiology of aldosterone action, as well as the clinical features, biochemical diagnosis, and treatment of hyperaldosteronism.
Aldosterone is synthesized in the zona glomerulosa of the adrenal gland. Its production is restricted to this layer of the adrenal cortex because of zonal-specific expression of aldosterone synthase (CYP11B2). Aldosterone secretion is under the control of three primary factors: angiotensin II, potassium, and adrenocorticotropic hormone (ACTH).
The renin-angiotensin system (RAS) is a principal regulator of aldosterone secretion. Renin, an enzyme produced in the juxtaglomerular apparatus of the kidney, catalyzes the conversion of angiotensinogen (an inactive precursor peptide) to angiotensin I. Angiotensin I undergoes further enzymatic conversion by angiotensin-converting enzyme (ACE) to produce angiotensin II. Angiotensin II acts via the angiotensin receptor to stimulate the release of aldosterone by increasing the transcription of aldosterone synthase. The RAS serves to regulate two critical functions in the human body: sodium homeostasis and arterial pressure (1). Through complex negative feedback loops (Figure 1), activity of the RAS can be suppressed or enhanced by sodium balance, intravascular volume, and other factors. For example, renin (and consequently aldosterone) production is stimulated by low tubular sodium or low renal perfusion; conversely, renin is suppressed by high sodium content or high perfusion pressure. Angiotensin II and other components of the RAS are also expressed locally in the zona glomerulosa and regulate aldosterone production in a paracrine fashion.
Aldosterone secretion is also directly stimulated by potassium (Figure 1), which increases transcription of aldosterone synthase in the zona glomerulosa. ACTH is another aldosterone secretagogue, although the effect is modest and transient. Prolonged ACTH infusion over 24 hours leads to a return of aldosterone levels to baseline (2). Other factors that regulate aldosterone include dopamine, atrial natriuretic peptide (ANP) and heparin, which all inhibit its production (2).
Figure 1. Renin-angiotensin-aldosterone and potassium-aldosterone negative-feedback loops. Aldosterone production is determined by input from each loop. (Adapted and redrawn from Williams GH, Dluhy RG. Disease of the adrenal cortex. In: Fauci AD, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 15th ed. New York: McGraw-Hill, 2001)
The primary functions of aldosterone are to regulate extracellular volume and potassium balance. These effects are mediated through the effects of aldosterone on the distal nephron. Aldosterone binds to the type I mineralocorticoid receptor in the cytosol of distal cortical collecting principal cells. Translocation of the hormone-receptor complex to the nucleus leads to modification of target gene expression, and subsequently increased number of �open� sodium channels on apical cell membranes. The resulting increase in reabsorption of sodium generates a negative electrical gradient in the tubular lumen, which promotes potassium and hydrogen ion excretion to maintain electrical neutrality (2, 3).
Emerging evidence suggests that aldosterone has additional effects beyond regulation of sodium-potassium balance and arterial pressure, and that aldosterone excess leads to cardiovascular and renal toxicity and contributes to increased morbidity and mortality. Importantly, these adverse actions of aldosterone occur only in the sodium replete state when levels are inappropriately elevated, and appear to be at least in part independent of elevated blood pressure (4-7). Animals treated with excessive doses of aldosterone develop cardiovascular injury (6, 8). Patients with primary aldosteronism (PA), when compared with matched essential hypertensives, have increased left ventricular wall and carotid intima media thickness, as well as impaired diastolic and endothelial function (9-12). PA is also associated with higher incidence of myocardial infarction and stroke than essential hypertension with similar degree of blood pressure elevation (13, 14). Furthermore, small studies have shown improvement in endothelial function in hyperaldosteronism treated surgically or with mineralocorticoid receptor antagonists (11). The excess cardiovascular events associated with hyperaldosteronism also appear to be reversed after treatment (15).
Excessive aldosterone production may also result in renal injury through mechanisms independent of blood pressure. Patients with PA have higher urinary albumin excretion and decreased intrarenal vascular resistance than controls matched for blood pressure elevation; these findings were reversed by medical or surgical treatment (16). Finally, there is some evidence to support an association between aldosterone and the metabolic syndrome: primary aldosteronism has been associated with hyperglycemia and insulin resistance in some (17) but not all (18) studies.
In 1954, Conn first reported the clinical syndrome of hypertension, hypokalemia, and metabolic alkalosis resulting from autonomous production of aldosterone due to an adrenal adenoma � a syndrome that continues to bear his name. Since that time, numerous studies have investigated the prevalence of primary aldosteronism (PA) and reported rates between 0.05% and 14.4% among hypertensive individuals. Disparity in these percentages is probably due to the use of different laboratory screening techniques, study design, and varying populations (19-24). Initial studies primarily diagnosed patients with both hypertension and �spontaneous� (not diuretic-induced) hypokalemia. Recently, however, milder, normokalemic forms of hyperaldosteronism are being diagnosed with increased frequency (25).
Secondary hyperaldosteronism is increasingly diagnosed with the assistance of improved radiological and hormonal testing (26). However, it is likely that many cases of secondary hyperaldosteronism are never detected, as clinical reasons to suspect the diagnosis, such as refractory hypertension or renal failure, do not always develop (26).
50 million people in the United States are currently estimated to be hypertensive. Accumulating evidence suggests that about 10% of hypertensive individuals will have hypertension due to or associated with hyperaldosteronism (19-24, 27, 28). Awareness of this fact is crucial, as the large number of patients with these disorders is likely to effect clinical decision-making.
Mineralocorticoid excess states (Table 1) comprise a group of disorders that can be separated into those mediated by the principal mineralocorticoid, aldosterone, and those caused by non-aldosterone etiologies. This chapter focuses on the former. Non-aldosterone mediated mineralocorticoid excess states, including the syndrome of Apparent Mineralocorticoid Excess (AME) and Liddle�s Syndrome are discussed further in Chapter 26 (�Overview of Endocrine Hypertension�).
Hyperaldosteronism can result from autonomous secretion of aldosterone from one or both adrenal glands, which is referred to as primary aldosteronism (PA). In this circumstance, the plasma renin activity (PRA) will be suppressed, and the plasma aldosterone to renin ratio will be elevated. In secondary hyperaldosteronism, excessive activation the RAS is the initiating event, and this secondarily results in excess aldosterone production. The distinction between primary and secondary etiologies of hyperaldosteronism is of importance, as the manifestations, as well as the subsequent testing and treatment, differ.
Table 1: Mineralocorticoid-Excess States
Mineralocorticoid Excess with low plasma renin activity
Mineralocorticoid Excess with high plasma renin activity (Secondary Hyperaldosteronism)
*In these disorders, non-aldosterone mediated renal sodium reabsorption results in volume expansion and suppression of both plasma renin activity and plasma aldosterone.
The five subtypes of PA include: aldosterone-producing adenoma (APA), bilateral adrenal hyperplasia (BAH), unilateral adrenal hyperplasia (UAH), glucocorticoid-remediable aldosteronism (GRA), and adrenal carcinoma (Table 1). Previously it was thought that APA accounted for 65% of cases of primary aldosteronism, with BAH accounting for 30-40%, and GRA accounting for 1-3% (29). More recent studies, however, have suggested higher rates of BAH, likely due to improved detection of milder cases, a higher index of suspicion, and improved screening tests. Current estimates are that APA accounts for about 35% of cases of PA, and BAH for about 60% (4, 30, 31). Definitive diagnosis of the cause of PA can be a challenge in individual patients. Making the correct diagnosis, however, is of utmost importance, since the treatment for each underlying etiology is different.
APA are often small tumors, usually less than 2 cm in diameter, and occur more commonly in women than in men (32). Histopathology of APA reveals �hybrid� cells which have histological features of both zona glomerulosa and zona fasciculata cells. BAH probably represents a spectrum of disorders (20, 33). The extent of hyperaldosteronism is often milder in BAH compared to APA, and consequently the severity of hypertension, hypokalemia and suppression of PRA is often less (2).
Unilateral adrenal hyperplasia (UAH), sometimes referred to as primary adrenal hyperplasia, shares many biochemical features with APA. This diagnosis if often made based on evidence of unilateral production of aldosterone (primarily from adrenal vein sampling, see Diagnosis Section) in the absence of a discrete radiographic mass. Similar to APA, however, in UAH the hypertension and biochemical abnormalities may be cured or ameliorated by unilateral adrenalectomy (4, 34).
Glucocorticoid-remediable aldosteronism (also known as familial hyperaldosteronism type I) is an autosomal dominant disorder characterized by a chimeric duplication, whereby the 5�-promotor region of the 11b-hydroxylase gene (regulated by ACTH) is fused to the coding sequences of the aldosterone synthase gene. Aldosterone synthesis is therefore abnormally and solely regulated by ACTH (35, 36).
Adrenal carcinomas, an exceedingly rare cause of primary aldosteronism, are usually large (>4 cm) at the time of diagnosis. Adrenal carcinoma cannot be differentiated from adrenal adenoma on the basis of fine needle aspiration or core biopsy. Rather, the diagnosis is based upon evidence of extension of the tumor through the adrenal capsule or a high mitotic index on histological examination.
Other mineralocorticoid-excess states with low plasma renin activity include congenital adrenal hyperplasia (CAH), the syndrome of apparent mineralocorticoid excess (AME), and Liddle�s syndrome. CAH, most often diagnosed in infancy, results from inherited defects in enzymes that regulate cortisol biosynthesis. Ineffective glucocorticoid synthesis results in excess mineralocorticoids (such as 11-deoxycorticosterone) and androgens, secondary to shunting of precursors from blocked to unblocked pathways (37). Sometimes there is marked virilization of female infants in the most severe form of CAH. When adequately treated with glucocorticoids, however, abnormal mineralocorticoid production is reversed (37).
AME results from abnormal activation of the Type I mineralocorticoid receptor in the kidney by cortisol, secondary to an acquired (licorice ingestion or chewing tobacco) or congenital deficiency of the renal isoform of the enzyme 11b-OH steroid dehydrogenase (11b-HSD). The 11b-HSD2 isoenzyme normally metabolizes cortisol to the inactive compound cortisone in the renal distal convoluted tubule (37, 38). However if there is 11b-HSD deficiency, the Type I mineralocorticoid receptor is no longer �protected� from activation by cortisol. In Liddle�s syndrome, constitutive activation of the renal epithelial sodium channel (ENaC) results from activating mutations in the ENaC gene. In both AME and Liddle�s syndromes, the intrinsic renal abnormalities described lead to unregulated and excessive sodium reabsorption, and therefore a biochemical phenotype of suppressed PRA, hypokalemia, and undetectable levels of plasma aldosterone (38).
Secondary hyperaldosteronism is the result of the hypersecretion of aldosterone as a consequence of increased activation of the renin-angiotensin system (RAS). The subgroups are best understood by contrasting the etiologies that usually produce hypertension from those that do not (Table 1). The most common causes of secondary aldosteronism are medical illnesses that result from a reduction in perceived or �effective� circulating blood volume, such as congestive heart failure and nephrotic syndrome. Secondary hyperaldosteronism in these disorders is the result of renal baroreceptor activation and thus a physiologic response to the decompensated state. Importantly, treatment and correction of the underlying medical illness result in reversal of the activated RAS.
Diuretic use can also cause secondary hyperaldosteronism. The findings can mimic those seen in renovascular hypertension, especially in a hypertensive patient. With chronic diuretic use, moderate to severe extracellular and intravascular volume depletion results in renal hypoperfusion, increased release of renin, and subsequently excessive aldosterone production. In rare occasions, surreptitious use of diuretics can produce misleading biochemical findings. A high degree of suspicion should be present in the appropriate setting, such as unexplained hypokalemia in a medical or paramedical worker.
Importantly, a distinction should be made between renal vascular disease, and renal vascular hypertension. While a large proportion of the adult population may have renal vascular disease (defined as a 50% or greater decrease in renal artery luminal diameter), only a small portion of these patients experience critical renal hypoperfusion and ischemia (26). Therefore, documentation of both structural and functional abnormalities is required before therapeutic intervention in such patients.
Renovascular hypertension remains the most common cause of secondary aldosteronism associated with hypertension, and is defined as hypertension associated with either unilateral or bilateral ischemia of the renal parenchyma. There are numerous causes of this disorder. Atherosclerosis of the renal arteries is the most common, accounting for 90% of cases. Fibromuscular dysplasia accounts for less than 10% of cases (26). In these disorders, decreased renal perfusion causes tissue hypoxia and decreased perfusion pressure, thereby stimulating renin release from the juxtaglomerular cells, resulting in excessive aldosterone release. Coarctation of the aorta can produce a similar pathophysiology due to renal hypoperfusion.
Although renal vascular hypertension can affect patients of all ages, it is commonly seen in older adults (>50 years) due to the increased prevalence of atherosclerosis in this population. When found in patients less than 50 years of age, renal vascular hypertension is more common in women, usually as a result of fibromuscular dysplasia of one of both of the renal arteries (26).
In very rare cases, juxtaglomerular cell tumors of the kidney that hypersecrete renin have been described (39). Such patients often have severe hypertension, accompanied by elevated renin and aldosterone levels, hypokalemia, and a mass lesion in the kidney. Confirmation includes documentation of unilateral renin secretion in the absence of renal artery stenosis. While very rare, such cases are important to diagnose, as surgical removal of the tumor can be curative.
The clinical features of hyperaldosteronism are non-specific and variable, often resulting in or associated with hypertension (Table 2). Renal potassium wasting often results in hypokalemia. But the phenotype depends largely on the underlying cause and the degree of the aldosterone excess, as well as the presence of other comorbidities. The classic features of moderate-to-severe hypertension, hypokalemia, and metabolic alkalosis are highly suggestive of mineralocorticoid excess (usually primary aldosteronism). In the majority of cases, however, only subtle clues of hyperaldosteronism exist, such as the recent onset of refractory hypertension (defined as refractory to treatment with three classes of antihypertensives, including a diuretic) (25).
Table 2. CLINICAL MANIFESTATIONS OF PRIMARY HYPERALDOSTERONISM
Hypertension is common among patients with primary aldosteronism (PA). Hypertension results from inappropriately high aldosterone secretion because of plasma volume expansion and increased peripheral vascular resistance. Hypertension may be severe or refractory to standard antihypertensive therapies. However, some patients have minimal blood pressure elevations and, as a result, severe hypertension is not a sine qua non for this diagnosis (40). On the other hand, some subgroups of patients with secondary hyperaldosteronism are normotensive or have low blood pressure due to renal sodium wasting (see below).
Spontaneous hypokalemia in any patient with or without concurrent hypertension warrants consideration of hyperaldosteronism as the etiology. Additionally, patients that develop severe hypokalemia after institution of a potassium-wasting diuretic (such as hydrochlorothiazide or furosemide) should be investigated. However, in recent studies of patients with confirmed PA, only 9 to 37% had hypokalemia (25). Thus in the majority of cases of PA serum potassium levels are normal, probably reflecting a milder form of the diagnosis. Dietary sodium restriction, which leads to decreased sodium delivery to the distant collecting system of the kidney is also associated with less potassium wasting.
PA results in extracellular fluid volume expansion secondary to excess sodium reabsorption. However, after the retention of several liters of isotonic saline, an �escape� from the renal sodium-retaining actions of aldosterone occurs in part due to the increased secretion of atrial natriuretic peptide. Therefore, peripheral edema is rarely a feature of PA if cardiac and renal functions are normal.
Metabolic alkalosis occurs secondary to renal distal tubule urinary hydrogen ion secretion. It is usually mild, causing no significant sequelae, and may go unnoticed. Hypomagnesemia and mild hypernatremia (likely secondary to resetting of the osmostat) can also be observed.
Rarely, patients experience neuromuscular symptoms, including paresthesias or weakness, due to the electrolyte disturbances caused by the hyperaldosteronism. Nephrogenic diabetes insipidus, caused by renal tubule antidiuretic hormone resistance due to the hypokalemia, can cause nocturia and mild polyuria and polydipsia. In severe cases of hypokalemia, cardiac arrhythmias occur and can be life threatening.
Secondary causes of hyperaldosteronism have broad phenotypic variation. Renovascular etiologies, as well as coarctation of the aorta, almost always result in hypertension. In contrast, diuretic use (whether surreptitious or prescribed) causes secondary hyperaldosteronism due to sodium and volume depletion. Secondary hyperaldosteronism in renal �salt-wasting� syndromes such as Gitelman�s and Bartter�s syndromes, and pseudohypoaldosteronism Type I (due to resistance to the actions of aldosterone on the kidney) result in mild hypotension due to excess sodium loss. Similarly, illnesses such as congestive heart failure, nephrotic syndrome, and hepatic cirrhosis exhibit a reduction in the �effective� circulating blood volume and are associated with hypotension, despite avid salt retention and total body sodium overload.
Secondary causes of hypertension (including hyperaldosteronism) should be considered initially in all hypertensive individuals. A thorough medical history and physical examination can greatly assist the clinician in deciding which patients should be further evaluated and what tests should be performed. Although the sensitivity of testing for hyperaldosteronism increases when limited to patients with moderate-to-severe hypertension, many patients with hyperaldosteronism have mild to moderate hypertension. The recent onset of refractory or accelerated hypertension, especially in a patient known to be previously normotensive, can be a valuable clinical clue. Therefore, the clinician must remain vigilant to the possibility of hyperaldosteronism, especially in the appropriate clinical setting.
Who to Screen
In 2008, The Endocrine Society established a task force and published clinical practice guidelines for the diagnosis and treatment of patients with PA (28). The task force recommended screening patients with predicted high prevalence of disease, as follows. Patients with stage 2 (>160�179/100�109 mm Hg), stage 3 (>180/110 mm Hg), or drug-resistant hypertension should be screened for PA. Patients should be screened if they have hypertension associated with either spontaneous or diuretic-induced hypokalemia; hypertension and incidentally discovered adrenal adenoma; or hypertension with a family history of early-onset hypertension or cerebrovascular accident at age less than 40 years. Furthermore, screening was recommended in all hypertensive first-degree relatives of patients with PA, although there is insufficient data from prospective studies (28).
GRA should be considered in patients with early-onset hypertension (<20yr) in the setting of suppressed PRA. A family history of PA or early cerebral hemorrhage (<40yr) should also raise suspicion for GRA. Screening of GRA kindreds has revealed that most affected individuals are not hypokalemic (28, 41).
Evaluation for PA begins with hormonal screening, specifically determination of plasma aldosterone concentration (PAC) and plasma renin activity (PRA) with validated, sensitive assays, for calculation of a plasma aldosterone to renin ratio (ARR). An ARR ratio less than 20 is seen in normotensive or essential hypertensive subjects. In most studies, an ARR greater than 20:1 is considered suspicious for PA. An ARR >30, especially in the setting of a PAC > 15 ng/dl, has been shown to be 90% sensitive and 91% specific for the diagnosis of PA (28, 42). A ratio of 50 or greater is virtually diagnostic of PA (42).
To optimize the initial screening evaluation for PA, several aspects of the testing conditions must be considered. To begin with, the ARR is most sensitive when collected in the morning, after patients have been ambulatory for 2 hours, and have been seated for 5-15 minutes prior to blood drawing (28). Hypokalemia should also be corrected prior to screening as it directly inhibits aldosterone release. Furthemore, drugs that alter aldosterone or renin secretion can result in false positive or false negative results. Beta-adrenergic blockers and central alpha agonists lower PRA secretion and often produce a false positive ARR in patients with essential hypertension. Diuretics, ACE-inhibitors (ACEI) and angiotensin receptor blockers (ARB) and dihydropyridine calcium channel blockers (CCB) can increase PRA and result in false negative screening results. However, if the ARR while on ACEI, ARB, CCB, or central alpha-blocker therapy is high, with frankly elevated PAC and suppressed PRA, the likelihood of primary aldosteronism remains high. The mineralocorticoid receptor antagonists spironolactone and eplerenone, as well as renin inhibitors, can cause false negative ARR (4, 28, 42).
Understanding the impact of various medications on the ARR helps in the interpretation of results. If possible, the antihypertensive agents described above that affect the ARR should be withdrawn 2-4 weeks prior to screening for PA; spironolactone and eplerenone, because of longer effect duration, should be stopped at least 4-6 weeks prior to testing. However, withdrawal of anti-hypertensives may not be feasible in patients with moderate to severe hypertension. Medications with neutral effects on the ARR, such as non-dihydropyridine calcium channel blockers, hydralazine, or alpha-blockers, can be used instead to control arterial pressure during the screening evaluation.
Confirming the Diagnosis
In patients with a positive ARR, subsequent confirmation or exclusion of autonomous aldosterone secretion is necessary. Methods to demonstrate autonomy of aldosterone production focus on volume-expanding maneuvers. Options for volume expansion include oral sodium loading and saline infusion. Other confirmatory testing can be done by fludrocortisone suppression and capropril challenge (28).
For the oral sodium loading test to confirm PA, patients are instructed to eat a high sodium (200 mmol/day) diet for 3 days. This can best be accomplished by adding 4 boullion packets per day to a regular diet (each packet contains 1100 mg, or 48 mmol, of sodium). NaCl tablets can also be used, though in our experience these are poorly tolerated. On the third day of the high sodium diet, a 24-hour urine collection for urinary aldosterone, creatinine, and sodium is collected. Oral salt loading results in extra- and intra-vascular volume expansion and RAS suppression in normal individuals. Aldosterone excretion greater than 12 to 14 ug/d in the presence of a urinary sodium excretion greater than 200 mmol/24 hours makes PA highly likely. The advantage of oral sodium loading is that it is easier for both the patient and clinician, as it can be performed on an outpatient basis. However, this should not be performed on patients with severe uncontrolled blood pressure or hypokalemia; blood pressure and potassium levels should be monitored during the testing, as hypertension and hypokalemia can be precipitated or exacerbated (28, 43).
For the saline suppression test, 2-3 liters of isotonic saline are infused (500cc/h) over 4 hours. This test should not be performed in patients with compromised cardiac function due to the risk of pulmonary edema. Acute intravascular volume expansion should suppress the RAS. In normal subjects, PAC decreases below 5 ng/dl at the end of the saline infusion; levels greater than 10 ng/dl are considered diagnostic of autonomous aldosterone production. Values between 6 and 10 ng/dl are considered indeterminate (43, 44).
Once the biochemical diagnosis of primary hyperaldosteronism has been confirmed, further testing is required to determine the etiology of this disorder. Distinguishing between APA, BAH, and less common forms of PA, such as GRA, is important. Unilateral adrenalectomy cures hypertension in 30-69% of patients with APA or UAH, and invariably reverses hypokalemia (34, 45). In contrast, bilateral adrenalectomy in BAH cures hypertension in only 19% of patients (34, 46). Hence, the treatment of choice is surgical in APA or UAH, and medical in BAH and GRA.
Biochemical characteristics can assist with diagnosis of the various causes of PA. Young age (<50 years old), severe hypokalemia (<3.0 mmol/L), high plasma aldosterone concentrations (> 25 ng/dl), and high urinary aldosterone excretion (>30 ug/24hr) favor the diagnosis of APA versus BAH. However, while sensitive, these findings lack specificity, and therefore cannot be relied on as a means to determine the underlying etiology in individual patients (4, 28, 42).
Patients with PA should undergo radiographic evaluation of the adrenal glands. Computed tomography (CT) scanning with thin-slice (3mm) spiral technique is the best radiographic procedure to visualize the adrenal glands, and serves primarily to exclude large masses that may represent adrenocortical carcinoma, which are usually more than 4 cm in size. Observation of a solitary hypodense adrenal nodule, usually < 2 cm in size, supports the diagnosis of APA. However, even when biochemical features suggestive of APA are present, only one-third to one-half of patients have positive CT findings for a solitary adenoma (47, 48). It is also not uncommon for both adrenal glands to be anatomically abnormal in patients with primary aldosteronism. Furthermore, it is emphasized that a radiographic abnormality does not correlate with a functional equivalent. Non-functioning adrenal �incidentalomas� are not rare, especially in patients above the age of 40; these are radiographically indistinguishable from APA, and can co-exist with an APA in the ipsilateral or contralateral adrenal gland. Therefore, data suggest that adrenal anatomy determined by CT scanning may wrongly predict etiology as well as lateralization of hyperaldosteronism in a significant proportion of patients (48, 49).
Adrenal vein sampling (AVS) is considered the �gold standard� to diagnose lateralization of aldosterone secretion, and distinguish unilateral versus bilateral disease in PA (28, 48, 49). AVS involves sampling from the right and left adrenal veins, as well as from the inferior vena cava (IVC) for measurement of aldosterone and cortisol concentrations. Some favor performing AVS with adrenocorticotropin (ACTH) stimulation, which can be administered continuously or as a bolus, and may minimize stress-induced fluctuations in aldosterone secretion during the procedure as well as maximize aldosterone secretion from an APA (16, 25, 28). However, others suggest that ACTH does not improve the diagnostic accuracy of the procedure, in part because it may increase secretion from the contralateral side more than from the APA and therefore blunt lateralization (50).
Multiple variables derived from AVS can be used to determine lateralization of aldosterone hypersecretion. Cortisol-corrected aldosterone ratios are determined by dividing the aldosterone concentrations from the right and left adrenal veins by the cortisol concentrations, which corrects for dilutional effects. The cortisol-corrected aldosterone ratios can be compared between sides to assess lateralization (dominance) of aldosterone production. In addition, the cortisol-corrected aldosterone ratio in the non-dominant adrenal compared to that of the IVC can be used to assess where there is aldosterone suppression in the non-dominant side.
The criteria used to determine lateralization of aldosterone hypersecretion depend on whether the AVS protocol involves ACTH stimulation. When the cortisol-corrected aldosterone ratios are compared between sides, if continuous ACTH is administered a ratio of more than 4:1 strongly favors unilateral excess, while a ratio of less than 3:1 suggests BAH (28, 48, 49). Using this criteria, AVS has a sensitivity of 95% and a specificity of 100% to detect unilateral disease (49). If ACTH is not used during AVS, a side-to-side ratio of more than 2:1 is considered consistent with unilateral disease (51). In addition, suppression of the contralateral adrenal, as reflected by a ratio of less than 1 when cortisol-corrected aldosterone ratios in the non-dominant side are compared to the IVC, also has high specificity and sensitivity for the diagnosis of unilateral disease (49, 52).
Adrenal vein sampling may not be necessary in patients with a high probability of APA by biochemical criteria, and a >1cm unilateral adrenal nodule with an anatomically normal contralateral gland if they are less than 40 years old (28, 49). In all cases, if adrenal vein sampling is performed, it should be done by an experienced angiographer to increase the likelihood of a successful procedure (49).
When GRA is suspected, direct screening by either Southern blot or long polymerase chain reaction can be performed to detect the gene duplication (28).
When there is clinical suspicion for renovascular hypertension, and initial screening has revealed a normal or elevated PRA, further testing for renovascular hypertension should be considered. Clinical features that should raise suspicion for renovascular hypertension include abrupt-onset hypertension, unexplained acute or progressive renal dysfunction, renal dysfunction induced by ACE inhibitors, asymmetric renal dimensions, or suspicion of fibromuscular disease in a young patient. Importantly screening is only recommended if intervention will be pursued if a significant lesion is detected (53, 54).
The diagnosis of renovascular hypertension requires two criteria: 1) the identification of a significant arterial obstruction (structural abnormality), and 2) evidence of excess renin secretion by the affected kidney (functional abnormality) (55). Structural abnormalities can be detected by a variety of imaging techniques. The gold standard is renal arteriography, but computed tomography (CT) scanning, duplex Doppler ultrasonography, and magnetic resonance angiography are reasonable noninvasive alternatives (53, 56). Despite the multiple screening options, there is currently no single test that if negative completely excludes a stenotic lesion in the real arteries. Choosing among the various options is largely dependent on degree of clinical suspicion, availability of the technology, cost of the examination, physician experience in performing and interpreting the results, and. The presence of renal insufficiency is an important consideration in determining the most appropriate diagnostic approach (53, 54, 56).
Evaluating the functional significance of a stenotic lesion in the renal arteries can be accomplished by captopril renography. For this procedure, 25-50 mg of captopril is administered one hour before a radioisotope is injected. Under normal conditions, administration of an ACE inhibitor reduces angiotensin II-mediated vasoconstriction and leads to relaxation of the efferent arteriole and an increase in glomerular filtration rate (GFR). This response is attenuated if the afferent blood flow is fixed by the presence of a stenotic lesion, and thus the difference between radioisotope excretion between the two kidneys is enhanced. Delayed excretion on the affected relative to the unaffected side provides functional evidence of renal artery narrowing (57). Although the captopril renogram is not recommended as a screening test for renal artery stenosis because of variable sensitivity and specificity depending on the populations studied (53), it is a tool for assessing the clinical significance of a stenotic lesion, and has high positive and negative predictive values for beneficial revascularization results (57).
Treatment for PA is dependent on the underlying etiology. Surgery is most often the treatment of choice for APA, and is often performed with laporoscopic techniques, which reduce patient recovery time and hospital cost. Resection of APA may cure or ameliorate hypertension, and invariably reverses hypokalemia. Unilateral adrenalectomy cures hypertension in 30-69% of patients with APA or UAH (34, 46). Data suggests that resolution of hypertension after adrenalectomy for PA is less likely if there is family history of hypertension and use of two or more antihypertensive agents pre-operatvely (34, 45, 58). Caution should be exercised in the perioperative (59) and postoperative management of APA patients. Pre-operatively, hypertension and hypokalemia should be well controlled, which may require the addition of a mineralocorticoid receptor antagonist (28). Post-operatively, suppression of aldosterone secretion in the contralateral adrenal gland is expected, and may result in a transient hyporeninemic hypoaldosterone state. As a result, some patients exhibit post-operative salt wasting, mild hyperkalemia, and are at increased risk of dehydration if sodium restricted. Potassium and mineralocorticoid receptor antagonists should be withdrawn after surgery. PAC and PRA should be measured post-operatively as an indication of surgical response. Blood pressure tends to show maximal improvement 1-6 months post-operatively. For patients who are not operative candidates, or choose not to undergo surgery, medical management of hyperaldosteronism should be pursued (28), as described below for BAH.
BAH is best treated medically with the use of a mineralocorticoid receptor (MR) antagonist; the available options are eplerenone or spironolactone (4, 60). Spironolactone doses required are usually between 50 mg and 400 mg per day, usually administered twice daily. Studies have reported reductions in mean systolic and diastolic blood pressure of 25% and 22%, respectively (61, 62). However, while it is effective for controlling blood pressure and hypokalemia, the use of spironolactone is limited by side effects. Gynecomastia and erectile dysfunction often occur during long-term treatment in males due to the anti-androgenic actions of spironolactone. The incidence of gynecomastia in males after 6 months of use at a dose of > 150 mg/d was as high as 52% (63). In women, spironolactone may lead to menstrual dysfunction, primarily intermenstrual bleeding. Fatigue and gastrointestinal intolerance are other common side effects. Epleronone, which has similar antagonistic actions at the type I renal MR, has no anti-androgen activity since it does not bind to androgen or progesterone receptors, and therefore has fewer side effects. It is felt to have 60% of the MR antagonist potency of spironolactone (28). However, compared to prior spironolactone usage, with eplerenone there is increased uncertainty in dosing, lack of clinical trial evidence for use in this indication, and markedly increased cost.
When blood pressure is not controlled with spironolactone/eplerenone, or side-effects limit tolerability, the addition of other antihypertensive therapies may be required. Potassium-sparing diuretics, such as triamterene or amiloride, have been used, although they are usually are not as effective as spironolactone (64). The dihydropyridine calcium channel antagonists have also been shown to effectively reduce blood pressure. Dietary sodium restriction (< 100 mmol/day), regular aerobic exercise, and maintenance of ideal body weight contribute to the success of pharmacologic treatment for hypertension in BAH.
Glucocorticoid-remediable aldosteronism (GRA) can be successfully treated with low doses of glucocorticoids such as dexamethasone (41). By inhibiting ACTH release, the abnormal production of aldosterone can be suppressed. The lowest dose of glucocorticoid that can normalize blood pressure and potassium levels should used to minimize side effects. PRA and PAC can be measured to assess treatment effectiveness and prevent overtreatment. The MR antagonists eplerenone and spironolactone are alternative treatments of hypertension in GRA (65).
Renal artery stenosis is managed through medical therapy alone or combined with revascularization. The goal of treatment is blood pressure control, as well as prevention of decline in renal function and secondary cardiovascular disease (53, 56). For renal artery fibromuscular dysplasia, primary angioplasty is the recommended endovascular procedure. In the case of atherosclerotic renovascular disease, angioplasty with stent placement is preferred over angioplasty alone, because data suggest improved outcomes in ostial renovascular stenosis. However, it must be noted that there is a paucity of level 1 data from randomized control trials demonstrating that revascularization has survival advantage in atherosclerotic renovascular disease (66). In all cases, an experienced interventional angiographer should perform angioplasty. Surgery for repair of renal vascular hypertension is reserved for patients with prior unsuccessful angioplasties.
Aggressive medical therapy should also be instituted, and may be sufficient in many patients with atherosclerotic renovascular hypertension. Given the central role of the RAS in the pathophysiology of the disease, ACE inhibitors and ARB are the agents of choice for medical management, and have anti-hypertensive as well as renoprotective effects. Caution must be taken, however, as initiation of either agent can rarely be associated with precipitation of acute renal failure, particularly in patients who have critical, bilateral renal artery stenosis. As a corollary, acute deterioration of renal function after initiation of these medications in patients with hypertension should prompt clinicians to consider the diagnosis of bilateral renal artery stenosis (26, 53).