Download Aldosterone is produced exclusively in the zona glomerulosa of

Aldosterone, Serum
Aldosterone is the major mineralocorticoid and is produced by the adrenal cortex.
Aldosterone is produced exclusively in the zona glomerulosa of adrenal cortex under a separate control
pathway from that of cortisol. Although ACTH does play a role in regulation of zona glomerulosa
function, angiotensin II is the most important regulator of aldosterone secretion. The zona glomerulosa,
like the rest of the adrenal cortex, requires ACTH to prevent atrophy of the tissue.
The major stimulus for aldosterone synthesis is angiotensin II.
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Angiotensinogen (precursor glycoprotein for angiotensin II) is synthesized and released by the
liver. Angiotensinogen in serum is cleaved to form angiotensin I by rennin.
Renin is a very specific protease synthesized by the juxtaglomerular apparatus of the kidney.
Angiotensin I is then converted to the active angiotensin II by Angiotensin Converting Enzyme.
Cleavage by renin is the rate limiting step for the production of angiotensin II.
The rate of angiotensin II production depends on both the concentration of renin and the
concentration of angiotensinogen.
The release of angiotensinogen from the liver is constitutive, but can be stimulated by cortisol,
by estrogens, and by angiotensin II.
Renin release from the kidney is stimulated by ECF depletion, by low serum sodium
concentrations, and by decreases in blood pressure; renin release is inhibited by angiotensin II,
aldosterone, and by elevated blood pressure.
Note that angiotensin II also acts as a vasoconstrictor; thus both angiotensin II and aldosterone
are directly involved in raising blood pressure.
The zona glomerulosa responds to increases in serum potassium levels by increasing
aldosterone synthesis. While decreases in serum sodium levels also stimulate aldosterone
synthesis, the effect of sodium is almost certainly mediated by increased angiotensin II
secondary to increased renin release from the kidney. In contrast, the regulation by increased
potassium appears to be due to a direct effect of high serum potassium levels on the adrenal.
Function of aldosterone
Aldosterone stimulates sodium transport across cell membranes, particularly in the distal renal tubule
where sodium is exchanged for hydrogen and potassium. Secondarily, aldosterone is important in the
maintenance of blood pressure and blood volume.
The syndrome of primary aldosteronism consists of:
Hypertension
Hypokalemia
Suppressed plasma renin activity
Increased aldosterone excretion
Primary aldosteronism is most commonly diagnosed in middle-aged adults and is more common in
women than in men. Symptoms include tiredness, muscle weakness, thirst, polyuria and nocturia. The
coexistence of hypertension and hypokalemia predicts primary hyperaldosteronism in 50% of cases.
Some patients may have normal potassium levels; therefore, normokalemia does not exclude the
diagnosis of primary aldosteronism.
Individuals Suitable for Testing
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Individuals with drug-resistant hypertension (>140/>90 mm Hg despite treatment with 3
medications)
Individuals with moderate to severe hypertension (>160-179/100-109 mm Hg or >180/110 mm
Hg)
Individuals with hypertension and spontaneous or diuretic-induced hypokalemia
Individuals with hypertension with adrenal incidentaloma
Individuals with hypertension and a family history of hypertension or cerebrovascular accident
before age 40 years
Individuals with hypertension and a first-degree relative with PA (primary aldosteronism)
The best screening tests are the paired measurements of plasma renin activity and plasma aldosterone
concentration. The principle underlying this test is that as aldosterone secretion increases, plasma renin
activity should decrease because of sodium retention. Plasma aldosterone concentration is typically
>200 ng/L (>20 ng/dL), whereas the plasma renin activity is low.
 A plasma aldosterone (ng/dL) to plasma renin activity (ng/mL/h) ratio of 20 or more (measured
while the patient is upright) supports the diagnosis of an aldosterone-producing tumor.
 If plasma aldosterone and plasma renin activity are increased and the ratio is < /=10, the patient
should be investigated for secondary causes of hyperaldosteronism, which include renovascular
hypertension, diuretic use, renin secreting tumor, malignant phase hypertension, and
coarctation of the aorta.
 If both aldosterone and renin are depressed, other adrenal and metabolic disorders should be
considered.
The test is useful for
Investigation of primary aldosteronism (eg, adrenal adenoma/ carcinoma and adrenal cortical
hyperplasia) and secondary aldosteronism (renovascular disease, salt depletion, potassium loading,
cardiac failure with ascites, pregnancy, Bartter's syndrome)
Specimen Required See "Renin - Aldosterone Studies"(in this chapter) in Special Instructions for more
detailed instructions.
Beta blockers and calcium channel blockers may interfere with the diagnostic reliability of the
aldosterone to plasma renin ratio. They should be withheld for two weeks prior to testing.
Spironolactone and loop diuretics induce secondary hyperaldosteronism and should be withheld for 6
weeks before testing. Diltiazem does not interfere and can be used to control blood pressure during
testing.
After a positive screening test is obtained, autonomous aldosterone secretion should be confirmed with
either a saline infusion test or a 24-hour urine aldosterone excretion during oral salt loading.
The principle of these tests is that failure to suppress aldosterone excretion with intravascular volume
expansion indicates autonomous aldosterone production. The saline infusion test is performed by
administering 2 liters of isotonic saline over 4 hours and then measuring plasma aldosterone. A plasma
aldosterone level greater than 10 ng/dL (277.4 pmol/L) is diagnostic of primary hyperaldosteronism,
while a level between 5 and 10 ng/dL is considered borderline.
The oral salt loading test is performed by having the patient ingest 12 gram sodium chloride tablets for 3
days and then measuring 24-hour urinary aldosterone. A urinary aldosterone excretion value greater
than 12 ug/day (27.7 to 38.8 nmol/day) with urine sodium greater than 250 mEq/24 hours confirms the
diagnosis of primary hyperaldosteronism. A 24-hour urinary aldosterone less than 8 ug/d excludes the
diagnosis.
Reference Values
0-30 days: 17-154 ng/dL *
1-11 months: 6.5-86 ng/dL *
1-10 years: <=40 ng/dL (supine) *
<=124 ng/dL (upright) *
> or = 11 years: <=21 ng/dL (a.m. peripheral vein specimen)
Reference range based on upright a.m. collection from subjects on ad lib sodium intake.
*Loeuille GA, Racadot A, Vasseur P, Vandewalle B: Blood and urinary aldosterone levels in normal
neonates, infants and children. Pediatrie 1981;36:335-344
Aldosterone/PRA Ratio: 0.9-28.9
This reference range is consistent with the most commonly adopted cutoff value (ie, ARR of 30).
Interpretation
A high ratio of serum aldosterone (SA) in ng/dL to plasma rennin activity (PRA) in ng/mL per hour is a
positive screening test result, a finding that warrants further testing.
A SA/PRA ratio > or = 20 is only interpretable with a SA > or = 15 ng/dL and indicates probable primary
aldosteronism.
Renal disease, such as unilateral renal artery stenosis, results in elevated renin and aldosterone levels.
Renal venous catheterization may be helpful. A positive test is a renal venous renin ratio
(affected/normal) >1.5.
Cautions
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The PRA cannot be interpreted if the patient is being treated with spironolactone
(Aldactone). Spironolactone (Aldactone) should be discontinued for 4 to 6 weeks before
testing.
Late p.m. levels can be up to 30% lower than early am levels.
Supine values are on average 50% lower that upright collections.
Sodium deplete subjects have significantly elevated serum aldosterone levels potentially
exceeding the upper limit of the salt replete upright reference range several fold. To account
for these variables at least in part, it is recommended that PRA is measured concomitantly.
In situations of physiological variability PRA should be altered in the same direction as
Aldosterone. (see"Renin - Aldosterone Studies"' in Special Instructions.)
Angiotensin converting enzyme (ACE) inhibitors have the potential to “falsely elevate" PRA.
Therefore, in a patient treated with an ACE-inhibitor, the findings of a detectable PRA level
or a low SA/RA ratio do not exclude the diagnosis of primary aldosteronism. In addition, a
strong predictor for primary aldosteronism is a PRA level undetectably low in a patient
taking an ACE-inhibitor.
Table 1. Impact of Medications on the Aldosterone/Renin Ratio (ARR)
False-positive ARR
False-negative ARR
β-Adrenergic blockers
Potassium-wasting or -sparing diuretics
Central α2 agonists (eg, clonidine, α-methyldopa) ACE inhibitors
NSAIDs
Angiotensin II type 1 receptor blockers
Renin inhibitors
Calcium blockers (eg, dihydropyridine)
NSAIDs, nonsteroidal anti-inflammatory drugs; ACE, angiotensin-converting enzyme.
Renin-Aldosterone Studies
A. Renin-Angiotensin-Aldosterone System:
1. Renin is secreted by the juxtaglomerular cells of the kidneys in response to changes in plasma volume.
An increase in rennin normally produces an increase in aldosterone through angiotensin intermediates.
Renin’s physiological effects are manifested mainly through its changes on aldosterone production.
Aldosterone is produced by the adrenal glands and fluctuates normally with changes in renin levels.
With aldosterone-producing tumors, the serum aldosterone level is elevated even though renin is
suppressed. Aldosterone production results in retention of sodium and excretion of potassium.
B. Usual Laboratory Test Findings in Renin-Aldosterone Disorders:
1. Renal disease, such as unilateral renal artery stenosis, results in elevated renin and aldosterone levels.
Renal venous catheterization may be helpful. A positive test is a renal venous renin ratio
(affected/normal) >1.5.
2. Primary aldosteronism is manifested by low renin and elevated aldosterone levels. The aldosterone
level will not be suppressed by a high salt intake, whereas in normals it will. An elevated urinary
aldosterone excretion rate and increased levels of serum aldosterone associated with low plasma renin
activity is presumptive evidence for primary aldosteronism.
C. Preparation of Patient for Plasma Renin Activity Determination:
1. When screening for primary aldosteronism, no preparation is required. The plasma renin activity
cannot be interpreted if the patient is being treated with spironolactone (Aldactone®). Spironolactone
should be discontinued for 4 to 6 weeks before testing.
2. When performing renal vein renins to investigate renovascular hypertension, the angiotensin
converting enzyme (ACE) inhibition protocol may be used. It has been shown that acute administration
of drugs which block the action of ACE will enhance renin lateralization. Surprisingly, the effect is not
seen if 3 drugs are given chronically. An advantage of this protocol is that the inhibiting effects of other
drugs can be eliminated, and it is unnecessary to allow a washout period to pass. Captopril (Capoten®—
Squibb) is available as a converting enzyme inhibitor. Reports of renal toxicity by a variety of
mechanisms are known. It would appear, however, that a single dose for testing purposes is relatively
innocuous.
Administer captopril 25 mg by mouth 30 minutes prior to the procedure. Caution should be taken to
guard against orthostatic hypotension.
D. Preparation of Patient and Specimens for Primary Aldosteronism Study:
1. Screening testing—the serum aldosterone to plasma renin activity (SA/PRA) ratio
a. No salt depletion is necessary.
b. Collect a simultaneous blood specimen for plasma aldosterone and plasma renin activity before 10
a.m. No special posture instructions are needed. Blood should be drawn in the seated position. The
SA/PRA ratio may be performed while the patient is on antihypertensive medications. Spironolactone is
the only medication that will absolutely interfere with interpretation of the ratio. ACE inhibitors have
the potential to “falsely elevate” PRA. Therefore, in a patient treated with an ACE-inhibitor, the findings
of a detectable PRA level or a low SA/PRA ratio do not exclude the diagnosis of primary aldosteronism.
In addition, a strong predictor for primary aldosteronism is a PRA level undetectably low in a patient
taking an ACE-inhibitor. A high ratio of SA (in ng/dL) to PRA (in ng/mL/hour) is a positive screening test
result, a finding that warrants further testing. An SA/PRA ratio m20 and SA m15 ng/dL indicates
probable primary aldosteronism.
2. Confirmatory testing—aldosterone suppression testing
An elevated SA/PRA ratio is not diagnostic by itself, and primary aldosteronism must be confirmed by
demonstrating inappropriate aldosterone secretion. The list of drugs and hormones capable of affecting
the renin-angiotensin-aldosterone axis is extensive. Frequently, in patients with severe hypertension, a
“medication-contaminated” evaluation is unavoidable. Calcium channel blockers, α1-adrenergic
receptor blockers, and ß-adrenergic receptor blockers do not affect the diagnostic accuracy in most
cases. It is impossible to interpret data obtained from patients receiving treatment with spironolactone.
Therefore, spironolactone treatment should not be initiated until the evaluation is completed and the
final decisions about treatment are made. If primary aldosteronism is suspected in a patient receiving
treatment with spironolactone, the treatment should be discontinued for at least 6 weeks.
Aldosterone suppression testing can be performed with orally administered sodium chloride and
measurement of urinary aldosterone or with intravenous sodium chloride loading and measurement of
SA. Our practice has been oral salt loading over 3 days. After hypertension and hypokalemia are
controlled, patients should receive a high sodium diet (supplemented with sodium chloride tablets if
needed) for 3 days. The risk of increasing dietary sodium in patients with severe hypertension must be
assessed in each case. Because the high salt diet can increase kaliuresis and hypokalemia, vigorous
replacement of potassium chloride should be prescribed. On the third day of the high sodium diet, a 24hour urine specimen is collected for measurement of aldosterone, sodium, and potassium. The 24-hour
urinary sodium excretion should exceed 200 mEq to document adequate sodium repletion. Urinary
aldosterone excretion >12 mg/24 hours in this setting is consistent with hyperaldosteronism
Reference
1. Young WF Jr: Primary aldosteronism: A common and curable form of hypertension.
Cardiol Rev 1999;7:207-214
2. Michael Stowasser Update in Primary AldosteronismJCEM 2009 94: 36233630; doi:10.1210/jc.2009-1399
3. Young WF Jr: Pheochromocytoma and primary aldosteronism: diagnostic approaches.
Endocrinol Metab Clin North Am. 1997;26:801-82
4. Hurwitz S, Cohen RJ, Williams GH: Diurnal variation of aldosterone and plasma renin
activity: timing relation to melatonin and cortisol and consistency after prolonged bed
rest. J Appl Physiol 2004;96:1406-1414
5. Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of
patients with primary aldosteronism: an Endocrine Society Clinical Practice Guideline. J
Clin Endocrinol Metab. 2008;93:3266-3281.
6. Graeme Eisenhofer, David S. Goldstein, McClellan M. Walther, Peter Friberg, Jacques W.
M. Lenders, Harry R. Keiser, and Karel Pacak Biochemical Diagnosis
of Pheochromocytoma: How to Distinguish True- from False-Positive Test Results
JCEM 2003 88: 2656-2666; doi:10.1210/jc.2002-030005