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JAMA Diagnostic Test Interpretation |

Aldosterone-Renin Ratio in the Assessment of Primary Aldosteronism FREE QUIZ

Bharat Kumar, MD1; Melissa Swee, MD2
[+] Author Affiliations
1Department of Internal Medicine, University of Kentucky, Lexington
2Department of Internal Medicine, University of Nebraska, Omaha
JAMA. 2014;312(2):184-185. doi:10.1001/jama.2014.64.
Text Size: A A A
Published online

A middle-aged patient with diabetes and hypertension presented to his primary care physician for regular health assessment. His blood pressure was 183/116 mm Hg despite taking lisinopril (40 mg/d) and verapamil (180 mg/d). He had previously taken hydrochlorothiazide, which was discontinued due to hypokalemia approximately 1 month ago, as well as atenolol, which was stopped 2 months earlier. As part of the workup for secondary hypertension, plasma aldosterone concentration and plasma renin activity were measured (Table 1).

Table Graphic Jump LocationTable 1.  Initial Laboratory Evaluation

Box Section Ref ID

How do you interpret these test results?
  • Primary aldosteronism is confirmed.

  • Primary aldosteronism is suggested; imaging is required for confirmation.

  • Primary aldosteronism is suggested; confirmation requires an aldosterone suppression test.

  • The results are unreliable; ARR should be measured 1 month after discontinuing lisinopril.

ANSWER

C. Primary aldosteronism is suggested; confirmation requires an aldosterone suppression test.

TEST CHARACTERISTICS

Primary aldosteronism is characterized by the excess production of aldosterone and may be found in 5% to 13% of all hypertensive patients. 1 The recommended screening test is measurement of the plasma aldosterone concentration (PAC) and plasma renin activity (PRA) to derive the aldosterone-renin ratio (ARR, or PAC/PRA ratio). Although there is no established threshold for an abnormal result, an ARR greater than 30 when PAC exceeds 15 ng/dL is most commonly used.1

These values are based on a retrospective study in 1993 demonstrating 90% sensitivity and 91% specificity for detecting the presence of adrenal adenoma in patients with hypertension.2 However, because PAC and ARR depend on a number of factors, including medications, sex, phase of the menstrual cycle, body position, time of day, diet, and presence of kidney disease, the Endocrine Society’s guidelines recommend that physicians examine data in the patient’s clinical context and recognize that low renin levels increase the likelihood of a falsely positive elevated ARR (Table 2).3

Table Graphic Jump LocationTable 2.  Conditions That May Affect the Aldosterone-Renin Ratio (ARR)a

The Endocrine Society’s guidelines also stress the need for a standardized technique as follows. Potassium should be supplemented if needed and, based on consensus expert opinion, medications that interfere with the renin-angiotensin-aldosterone system must be withheld for at least 2 weeks (Box).3 Patients should also liberalize sodium intake and abstain from products derived from licorice root, including chewing tobacco licorice. Additionally, blood samples for testing renin and aldosterone levels should be obtained during mid-morning after the patient has been awake for more than 2 hours and sitting for at least 15 minutes.3

Box Section Ref ID

Box.
Effect of Common Medications on the Aldosterone-Renin Ratio (ARR)a
Medications That Elevate the ARRb

β-Blockers, central α2 agonists, direct renin inhibitors, nonsteroidal anti-inflammatory drugs

Medications That Lower the ARR

Potassium-sparing diuretics,c spironolactone,c eplerenone,c potassium-wasting diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, dihydropyridine calcium channel blockers

Antihypertensive Medications With Minimal Effect on the ARR

Verapamil, hydralazine, prazosin, doxazosin, terazosin

a

Source: Endocrine Society guideline.3

b

Medications that affect the ARR should be withheld for at least 2 weeks. Practitioners should consider substitution with a medication that has minimal effects on the ARR.

c

Withhold for at least 4 weeks.

According to the Medicare fee schedule, costs are $56.02 for PAC and $30.24 for PRA.4

APPLICATION OF TEST RESULT TO THIS PATIENT

The elevated ARR and PAC values suggest primary aldosteronism , but the diagnosis still needs to be confirmed (choice A). The next step is to test for suppression of aldosterone (choice C). A high-sodium load, either by infusion of 500 mL/h of normal saline over 4 hours or by administration of two 1-g tablets of sodium chloride 3 times daily for 3 days, should suppress urine aldosterone to below 10 μg/24 h or PAC to below 5 ng/dL. Urine aldosterone levels higher than 12 μg/24 h after sodium loading is consistent with primary aldosteronism. Alternatively, fludrocortisone suppression or captopril challenge tests may be performed.3 In fludrocortisone suppression, patients receive 0.1 mg of oral fludrocortisone every 6 hours for 4 days; a plasma aldosterone level higher than 6 mg/dL when PRA is lower than 1 ng/mL·h and when plasma cortisol concentration on day 4 is less than that obtained from 7 hours constitutes a positive result. In the captopril challenge test, 25 to 50 mg of captopril is administered while PAC, PRA, and cortisol levels are measured at baseline and at hour 1 or 2. Elevation of PAC constitutes a positive result.3

Because about a third of cases are associated with unilateral adrenal adenomas and can potentially be managed surgically, patients with primary aldosteronism should undergo abdominal imaging.1 However, due to the high prevalence of adrenal incidentalomas in patients older than 40 years, biochemical confirmation takes precedence (choice B). Additionally, computed tomography alone cannot diagnose bilateral disease nor distinguish an aldosterone-producing adenoma from a nonfunctional adenoma.

Because the patient’s ARR remained elevated despite the use of medications that lower the ARR such as angiotensin-converting enzyme inhibitors, repeat testing is not needed (choice D).

WHAT ARE ALTERNATIVE DIAGNOSTIC TESTING APPROACHES?

Measurement of the ARR is the screening test of choice for primary aldosteronism. Biochemical confirmation followed by radiographic evaluation is encouraged by the Endocrine Society.2,3 If surgery is considered, adrenal venous sampling should be performed to distinguish unilateral from bilateral disease. Additionally, in patients younger than 20 years or those with a family history of primary aldosteronism or stroke at a young age (<40 years), genetic testing for glucocorticoid-remediable aldosteronism is suggested.3

PATIENT OUTCOME

In this patient, the aldosterone suppression test confirmed the diagnosis and abdominal computed tomography revealed bilateral adrenal hyperplasia. Because the patient expressed strong reservations against surgery, adrenal venous sampling was not performed and the patient was treated medically with spironolactone. Three months after starting spironolactone, his blood pressure decreased to 137/88 mm Hg, allowing for the discontinuation of verapamil and lowering of atenolol to 20 mg/d.

Box Section Ref ID

Clinical Bottom Line: Aldosterone-Renin Ratio
  • Primary aldosteronism should be considered in hypertensive patients with blood pressure >160/100 mm Hg or with resistant hypertension despite treatment with ≥3 antihypertensive medications, regardless of potassium levels.3

  • Although a threshold ARR >30 when PAC exceeds 15 ng/dL is commonly used, there is no definitive diagnostic cutoff. Individual factors, including medication use, age, sex, and presence of kidney disease, should be taken into account.1,5

  • If PAC and ARR are abnormal, the diagnosis should be confirmed by aldosterone suppression testing.3

ARTICLE INFORMATION

Corresponding Author: Bharat Kumar, MD, University of Kentucky Department of Internal Medicine, Charles T. Wethington Bldg, Room 306, 900 S Limestone St, Lexington, KY 40536-0200 (bharat.kumar@uky.edu).

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Section Editor: Mary McGrae McDermott, MD, Senior Editor.

REFERENCES

Young  WF.  Primary aldosteronism. Clin Endocrinol (Oxf). 2007;66(5):607-618.
PubMed   |  Link to Article
Tomaschitz  A, Pilz  S.  Aldosterone to renin ratio: a reliable screening tool for primary aldosteronism? Horm Metab Res. 2010;42(6):382-391.
PubMed   |  Link to Article
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(9):3266-3281.
PubMed   |  Link to Article
CMS Clinical Laboratory Fee Schedule. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ClinicalLabFeeSched/index.html. Updated April 11, 2013. Accessed June 13, 2014.
Montori  VM, Young  WF  Jr.  Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. Endocrinol Metab Clin North Am. 2002;31(3):619-632.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Initial Laboratory Evaluation
Table Graphic Jump LocationTable 2.  Conditions That May Affect the Aldosterone-Renin Ratio (ARR)a

References

Young  WF.  Primary aldosteronism. Clin Endocrinol (Oxf). 2007;66(5):607-618.
PubMed   |  Link to Article
Tomaschitz  A, Pilz  S.  Aldosterone to renin ratio: a reliable screening tool for primary aldosteronism? Horm Metab Res. 2010;42(6):382-391.
PubMed   |  Link to Article
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(9):3266-3281.
PubMed   |  Link to Article
CMS Clinical Laboratory Fee Schedule. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ClinicalLabFeeSched/index.html. Updated April 11, 2013. Accessed June 13, 2014.
Montori  VM, Young  WF  Jr.  Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. Endocrinol Metab Clin North Am. 2002;31(3):619-632.
PubMed   |  Link to Article
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