Aldosterone:Renin Ratio

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Category:

Turnaround Time: 2-5 days
CPT Code:

82088, 84244

Test Type: 1 mL serum (refrigerated) and 1 mL plasma (frozen)
Reference Range:

0−30 ng/dL per ng/mL/hour

Overview:

Screening test for primary aldosteronism in higher risk groups of hypertensive patients.

A number of factors can affect the aldosterone:renin ratio and thus lead to false-positive or false-negative results.1 These include:

Factors producing falsely increased ARR (false negative)

• Potassium-wasting diuretics

• Potassium-sparing diuretics

• Angiotensin-converting enzyme (ACE) inhibitors

• Angiotensin II type 1 receptor blockers (ARBs)

• Calcium blockers, dihydropyridines (DHPs)

• Hypokalemia

• Sodium restricted

• Pregnancy

• Renovascular hypertension

• Malignant hypertension

Factors producing falsely increased ARR (false positive)

• β-adrenergic blockers

• Central α2-agonists (eg, clonidine, α-methyldopa)

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Renin inhibitors

• Potassium loading

• Sodium loaded

• Advancing age

• Renal impairment

• Pseudohypoaldosteronism type 2

The ARR should be regarded as a detection test only, and should be repeated if the initial results are inconclusive or difficult to interpret because of suboptimal sampling conditions (eg, maintenance of some medications listed above). The consensus guideline recommended that patients with a positive ARR should proceed to confirmatory testing by any of four confirmatory tests.1

The Clinical Guidelines Subcommittee of the Endocrine Society has produced a practice guideline for the detection, diagnosis, and treatment of patients with primary aldosteronism (PA).1 Primary aldosteronism (PA) is defined as a group of disorders in which aldosterone production is inappropriately high, relatively autonomous, and nonsuppressible by sodium loading.1 This inappropriate production of aldosterone can result in cardiovascular damage, suppression of plasma renin, hypertension, sodium retention, and potassium excretion that can lead to hypokalemia. PA is commonly caused by an adrenal adenoma, by unilateral or bilateral adrenal hyperplasia, or, in rare cases, by the inherited condition of glucocorticoid-remediable aldosteronism (GRA).

In the past, clinical guidelines indicated that hypokalemia was required for the diagnosis of PA. As a result, PA was considered to be a relatively uncommon cause of hypertension, accounting for <1% of cases;2,3 however, more recent studies have challenged these assumptions. Cross-sectional and prospective studies report PA in >10% of hypertensive patients, both in general and in specialty settings.4-12 Only a small subset of these patients with PA (9% to 37%) had hypokalemia.13 These studies indicate that normokalemic hypertension constitutes the most common presentation of the disease, with hypokalemia probably present in only the more severe cases. In fact, the presence of hypokalemia has low sensitivity and specificity, and a low positive predictive value for the diagnosis of PA.1

The new consensus guideline1 recommends that case detection of primary aldosteronism (PA) should be undertaken in patient groups with relatively high prevalence of PA. These include patients with:

• Joint National Commission (JNC) stage 2 (>160−179/100−109 mmHg), or stage 3 (>180/110 mmHg) hypertension

• Drug-resistant hypertension

• Hypertension and spontaneous or diuretic-induced hypokalemia

• Hypertension with adrenal incidentaloma

• Hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years).

The new consensus guideline1 also recommends case detection for all hypertensive first-degree relatives of patients with PA. The consensus group went on to recommend the use of the plasma aldosterone:renin ratio (ARR) to detect cases of PA in these patient groups.14-20 The ARR is calculated as the ratio of the serum aldosterone (in ng/dL) divided by serum plasma renin activity (in ng/mL/hour). The guideline indicates that the diagnosis of PA provides the opportunity for health benefits provided by curative approaches including surgery or improved control of hypertension through specific medical treatment.

The consensus guideline recommended that patients with a positive ARR should proceed to confirmatory testing by any of four confirmatory tests described within the document and listed below to definitively confirm or exclude the diagnosis.1

1. Oral sodium loading

2. Saline infusion

3. Fludrocortisone suppression

4. Captopril challenge

Refer to the consensus document for a more detailed description of the confirmatory test.1

1. Hurwitz S, Cohen RJ, Williams GH. Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after bed rest. J Appl Physiol (1985). 2004 Apr;96(4):1406-1414. PubMed 14660513
2. Stowasser M, Ahmed AH, Pimenta E, et al. Factors affecting the aldosterone/renin ratio. Horm Metab Res. 2012 Mar;44(3):170-176. PubMed 22147655
3. Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 May;101(5):1889-1916. PubMed 26934393
4. Laragh JH, Sealey JE. The plasma renin test reveals the contribution of body sodium-volume content (V) and renin-angiotensin (R) vasoconstriction to long-term blood pressure. Am J Hypertens. 2011 Nov;24(11):1164-1180. PubMed 21938070
5. Galati SJ. Primary aldosteronism: Challenges in diagnosis and management. Endocrinol Metab Clin North Am. 2015 Jun;44(2):355-369. PubMed 26038205
6. Galati SJ, Hopkins SM, Cheesman KC, Zhuk RA, Levine AC. Primary aldosteronism: emerging trends. Trends Endocrinol Metab. 2013 Sep;24(9):421-430. PubMed 23796656
7. Weiner ID. Endocrine and hypertensive disorders of potassium regulation: Primary aldosteronism. Semin Nephrol. 2013 May;33(3):265-276. PubMed 23953804
8. Cicala MV, Mantero F. Primary aldosteronism: What consensus for the diagnosis. Best Pract Res Clin Endocrinol Metab. 2010 Dec;24(6):915-921. PubMed 21115160
9. Van Der Gugten JG, Holmes DT. Quantitation of Plasma Renin Activity in Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Methods Mol Biol. 2016;1378:243-253. PubMed 26602136
10. Warnock DG. Liddle syndrome: Genetics and mechanisms of Na+ channel defects. Am J Med Sci. 2001 Dec; 322(6):302-307. PubMed 11780687
11. Stewart PM. 11 beta-Hydroxysteroid dehydrogenase: Implications for clinical medicine. Clin Endocrinol (Oxf). 1996 May;44(5):493-499. PubMed 8762725
12. Geller DS, Farhi A, Pinkerton N, et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 2000 Jul 7; 289(5476):119-123. PubMed 10884226
13. Simpoulos AP, Marshall JR, Delea CS, Bartter FC. Studies on the deficiency of 21-hydroxylation in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1971 Mar; 32(3):438-443. PubMed 4322392
14. Shizuta Y, Kawamoto T, Mitsuuchi Y, et al. Inborn errors of aldosterone biosynthesis in humans. Steroids. 1995 Jan;60(1):15-21. PubMed 7792802
15. Wong L, Hsu TH, Perlroth MG, Hofmann LV, Haynes CM, Katznelson L. Reninoma: Case Report and literature review. J Hypertens. 2008

Collection Details:

Patient Preparation:

Patients should be instructed to maintain an unrestricted dietary salt intake prior to testing. Washout of all interfering antihypertensive medications may be considered in patients with mild hypertension, but is potentially problematic in others and perhaps unnecessary in that medications with minimal effect on the ARR can be used in their place. The patient should not take drugs that markedly affect the ARR for at least four weeks prior to blood collection. These drugs include:

• Spironolactone, eplerenone, amiloride, and triamterene

• Potassium-wasting diuretics

• Products derived from liquorice root (eg, confectionary licorice, chewing tobacco)

More details can be found in the Endocrine Society clinical practice guideline.1

Collection Instructions:

Red-top tube or gel-barrier tube and lavender-top (EDTA) tube.

Collect blood mid morning, after the patient has been up (sitting, standing, or walking) for at least two hours and seated for 5 to 15 minutes. After collection, immediately centrifuge the lavender-top tube at room temperature, transfer plasma to a transport tube, and freeze. Label this tube "Frozen Plasma−Renin." If a red-top tube is used, transfer separated serum to a plastic transport tube. Label the serum tube "Serum−Aldosterone." To avoid delays in turnaround time when requesting multiple tests on frozen samples, please submit separate frozen specimens for each test requested.