Gene mutations that promote adrenal aldosterone production, sodium retention, and hypertension

Figures & data

Table 1 The influence of medications and factors on PAC, PRA, and ARR

Drugs and factors that lower PRA and PAC, and have a variable effect on ARR

• β-adrenergic blockers

• Central α2 adrenergic agonists

• Nonsteroidal anti-inflammatory agents

• Direct renin inhibitors (can raise renin in direct renin assays)

• High-sodium diet

• Advanced age

• Renal impairment

Drugs and factors that raise PRA and PAC, and have a variable effect on ARR

• Thiazide and loop diuretics

• Dihydropyridine calcium channel blockers

• Other potent vasodilators

• Low sodium diet

• Renovascular hypertension

• Malignant hypertension

Drugs and factors that raise PRA and/or lower PAC, and can falsely lower ARR

• Converting enzyme inhibitors

• Angiotensin 2 receptor blockers

• Hypokalemia

Abbreviations: PAC, plasma aldosterone concentration; PRA, plasma renin activity; ARR, aldosterone-to-renin ratio.

Table 2 The four commonly used confirmatory tests for diagnosing PA

Confirmatory test	Procedure	Interpretation	Concerns
Oral salt loading test	Patients should increase their sodium intake to >200 mmol (∼6 g) per day for 3 days, verified by 24-hour 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-hour urine collection from the morning of day 3 to the morning of day 4.	PA is unlikely if urinary aldosterone is lower than 10 mcg/24 hours (27.7 nmol/day) in the absence of renal disease where PA may coexist with lower measured urinary aldosterone levels. Elevated urinary aldosterone excretion (>12 mcg/24 hours [>33.3 nmol/day] Mayo Clinic data; >14 mcg/24 hours [38.8 nmol/day] Cleveland Clinic data) makes PA highly likely.	This test should not be performed in patients with severe uncontrolled hypertension, renal insufficiency, cardiac insufficiency, cardiac arrhythmia, or severe hypokalemia. Twenty-four-hour urine collection may be inconvenient. Laboratory-specific poor performance of the radio-immunoassay for urinary aldosterone may blunt diagnostic accuracy – obviated by mass spectrometry methodology. Aldosterone glucuronide is a renal metabolite, and its excretion may not rise in patients with renal disease.
Normal saline suppression test	Patients stay in the recumbent position for at least 1 hour before and during the infusion of 2 L of 0.9% saline IV over 4 hours, starting at 8–9.30 am. Blood samples for renin, aldosterone and plasma potassium are drawn at time zero and after 4 hours, with blood pressure and heart rate monitored throughout the test.	Postinfusion plasma aldosterone levels <5 ng/dL make the diagnosis of PA unlikely, and levels >10 ng/dL confirms PA. Values between 5 ng/dL and 10 ng/dL are indeterminate.	This test should not be performed in patients with severe uncontrolled hypertension, renal insufficiency, cardiac insufficiency, cardiac arrhythmia, or severe hypokalemia.
Fludrocortisone suppression test	Patients receive 0.1 mg of oral fludrocortisone 6 hours for 4 days, together with slow-release KCI supplements every 6 hours at doses sufficient to keep plasma K^+ near 4.0 mmol/L; slow-release NaCl supplements (30 mmol three times daily with meals); and sufficient dietary salt to maintain a urinary sodium excretion rate of at least 3 mmol/kg body weight. On day 4, plasma aldosterone and PRA are measured at 10 am with the patient in a seated posture, and plasma cortisol is measured at 7 am and 10 am.	Upright plasma aldosterone >6 ng/dL on day 4 at 10 am confirms PA, provided PRA is <1 ng/mL/hour and the plasma cortisol concentration is lower than the value obtained at 7 am (to exclude a confounding ACTH effect).	While some centers conduct this test in the outpatient setting (provided that patients are able to attend frequently to monitor their potassium), in other centers, several days of hospitalization are customary. Most of the data available come from the Brisbane group, which has established, on the basis of a very large series of patients, a cut-off plasma aldosterone concentration of 6 ng/dL at 10 am in an ambulatory patient on day 4.
Captopril challenge test	Patients receive 25–50 mg of captopril orally after sitting or standing for at least 1 hour. Blood samples are drawn for the measurement of PRA, plasma aldosterone, and cortisol at time zero and at 1 hour or 2 hours after the challenge, with the patient remaining seated during this period.	Plasma aldosterone is normally suppressed by captopril (>30%). In patients with PA, it remains elevated, and PRA remains suppressed. Differences may be seen between patients with APA and those with IHA, in that some decrease in aldosterone levels is occasionally seen in IHA.	There are reports of a substantial number of false negative or equivocal results.

Abbreviations: PA, primary aldosteronism; HPLC, high-performance liquid chromatography; IV, intravenous; PRA, plasma renin activity; ACTH, adrenocorticotropic hormone; IHA, idiopathic hyperaldosteronism.

Table 3 Example of AVS data and A:C ratios

Location	Aldosterone (ng/dL)	Cortisol (μg/dL)	Selectivity index	A:C ratio
Right adrenal	200	800	800/20=40	200/800=0.25
Left adrenal	6,000	600	600/20=30	6,000/600=10
IVC	22	20	–	22/20=1.1

Abbreviations: AVS, adrenal venous sampling; IVC, inferior vena cava.

Figure 1 A normal adrenal zona glomerulosa cell and a cell with a KCNJ5 mutation.

Notes: (A) A normal adrenal zona glomerulosa cell. Upon stimulation by Ang2 binding to its type 1 receptor, inhibition of potassium channels on the cell surface depolarizes the cell. The rise in potential activates voltage-gated calcium channels, and the increased intracellular calcium activates a cascade leading to increased transcription of CYP11B2 and increased aldosterone production. (B) A cell with a KCNJ5 mutation. This channel is unselective, which depolarizes the cell and drives aldosterone production in the absence of Ang2.
Abbreviations: Ang2, angiotensin 2; AT2R, angiotensin-2 receptor.

Figure 2 Ion fluxes in zona glomerulosa cells controlling aldosterone production and points where intracellular calcium might be regulated.

Notes: In addition to KCNJ5, this diagram also shows ATP1A1, which maintains resting membrane potential and high intracellular potassium. Both L- and T-type calcium channels and STOC on the cell surface bring calcium into the cell, while ATP2B3 pumps calcium out, and NCX bring calcium into the endoplasmic reticulum. Intracellular calcium activates calmodulin and its kinase (Cam/CamK), which drives CYP11B2 expression and aldosterone production, in conjunction with transcription factors Nurr1 and CREB/ATF.
Abbreviations: Ang2, angiotensin 2; ATR1, angiotensin 2 receptor type 1; ATP, adenosine triphosphate; STOC, store-operated calcium channels; NCX, sodium–calcium exchangers.