STEP 1: Aldosterone Renin Ratio (ARR)
The diagnosis of primary aldosteronism starts with a blood test called aldosterone renin ratio.
The test is not standardized. In the US, the FDA does not require this type of test to be approved when used for clinical purposes. Major laboratories often develop their own tests, and as a result, they may use different methods to measure the hormones and report the results.
Even more so than for routine tests, it is thus important that patients understand how tests work and what results mean.
What is Measured
Testing laboratories measure the ratio of aldosterone to renin. The test not only shows the level of each hormone, it determines the relative amount of aldosterone to renin present in the blood. In healthy individuals, these levels rise and fall together. In those who have primary aldosteronism, aldosterone is high while renin is low — renin is said to be “suppressed.” The higher the ARR result, the more likely a person has primary aldosteronism.
What Results Mean
While measuring aldosterone is fairly straightforward, renin can be evaluated through different methods. Until recently, Plasma Renin Activity (PRA) was the most common way to measure “active renin.” It is now frequently replaced with a faster method, Direct Renin Concentration (DRC). Unfortunately, this method may not be optimal to measure low levels of renin, which is exactly what must be ascertained with primary aldosteronism.
| Conventional Units | Lower Limit | Upper Limit |
|---|---|---|
| Plasma Renin Activity (PRA) | 0.7 ng/mL/hr | 3.3 ng/mL/hr |
| Plasma Aldosterone Concentration (PAC) | 7 ng/dL | 30 ng/dL |
On average for adults, the range of the Plasma Renin Activity runs between 0.7 and 3.3 ng/mL/hr (or 0.7 and 3.3 mcg/L/hr in SI units), and the range of the Plasma Aldosterone Concentration (PAC) goes from 7 to 30 ng/dL (or 190 to 830 pmol/L in SI units).
| ARR Cutoff Values | Renin (ng/mL/h) | Renin (pmol/L/min) |
|---|---|---|
| Aldosterone (as ng/dL) | 30 | 2.5 |
| Aldosterone (as pmol/L) | 750 | 60 |
The ARR compares the amount of aldosterone to that of renin, and the resulting number – a ratio – is then compared with a “cutoff” value currently set at 30 (or 750 when measurements are expressed in SI units). Below this value, the result is considered normal. Above this value, primary aldosteronism is suspected.
How to Prepare for the Test
Aldosterone production is influenced by a lot of factors which need to be minimized before the test. When these factors cannot be optimally controlled, they have to be taken into consideration when interpreting results.
Since aldosterone is at its highest in the morning, the best time to get your blood drawn is after having been up for two hours. It is also recommended to be seated for 15 minutes before starting the test.
The hormonal levels are affected by our sodium and potassium intake. To limit the impact on test results, it is recommended to maintain potassium in the normal range, and to refrain from restricting sodium intake during the three days preceding the test.
Because aldosterone rises briskly during the luteal phase (i.e., between ovulation and menses), it is recommended that premenopausal women be tested only during the follicular phase (i.e., between menses and ovulation). During pregnancy, renin rises more than aldosterone. As a result, the ratio may be falsely low if the test is performed when you are pregnant.
NSAIDs (i.e., anti-inflammatory drugs such as Ibuprofen) and higher creatinine levels (i.e., if you have kidney disease) cause falsely elevated ARRs. Because renin tends to decrease more than aldosterone in patients aged over 65, age is another important factor to take into consideration.
If you need to be tested, you likely have hypertension, and already take medications to control it. Some antihypertensive drugs increase the hormonal levels, while others decrease them. Being on any of these medications can thus falsely elevate or lower the test results. This is particularly true if you are taking either Eplerenone or Spironolactone – the two medications available to treat primary aldosteronism. Although patients used to have to discontinue all blood pressure medications before the test, it is now acknowledged that such practices are potentially harmful. Instead, Eplerenone and Spironolactone should be discontinued during a minimum of four weeks, and all other interfering antihypertensives for two weeks preceding the test. Non-interfering medications include Doxazosin (an α-adrenergic blocker), Verapamil (a calcium channel blocker), and Hydralazine (a vasodilator).
ARR Accuracy
To be accurate, tests must be sensitive (they must detect the condition in people who have it), and specific (they must rule out the condition in people who don’t have it). Highly sensitive tests are usually less specific: they trigger “false-positives,” which means some patients are told they have the condition while they don’t. Highly specific tests tend to have lower sensitivity: they trigger “false-negatives,” which means some patients are told they do not have the condition while they do.
ARRs are considered sensitive tests, and thus lack specificity. Up to 50% of elevated ARRs may be “false-positives.” To remediate this risk, PA patients must undergo confirmatory testing to validate or rule out false positive ARR results.
Determining what is considered an abnormal result is as important as the accuracy of the test. ARR cutoff values are somewhat arbitrary, and based on current understanding of excess aldosterone. The lower the cutoff value, the more people are diagnosed, and vice versa.
In light of the findings of The Unrecognized Prevalence of Primary Aldosteronism, current ARR cutoff values may be too high. As a result, the Endocrine Society may revise its guidelines in the near future. Should there be any change, the Primary Aldosteronism Foundation will update all applicable values on its website.
| Blood Pressure Medications | Effect on Aldosterone | Effect on Renin | Effect on ARR |
|---|---|---|---|
| Beta blockers (e.g., Atenolol) | ↓ | ↓↓ | ↑ |
| Alpha-2 agonists (e.g., Clonidine) | ↓ | ↓↓ | ↑ |
| Potassium-wasting diuretics (e.g., Hydrochlorothiazide) | → to ↑ | ↑↑ | ↓ |
| Potassium-sparing diuretics (e.g., Spironolactone) | ↑ | ↑↑ | ↓ |
| ACE inhibitors (e.g., Enalapril) | ↓ | ↑↑ | ↓ |
| ARBs (e.g., Losartan) | ↓ | ↑↑ | ↓ |
| Dihydropyridine calcium channel blockers (e.g., Nifedipine) | → to ↓ | ↑ | ↓ |
| Renin inhibitors (e.g., Aliskiren) | ↑ | ↓ | ↑ |
Except for step 3 (CT scan), patients prepare for all other tests the same way they do for the ARR. To prevent the risks associated with repeatedly changing blood pressure medications, Centers of Excellence usually schedule the full diagnosis process in the shortest amount of time possible.
References
- Morera, J., & Reznik Y. (2019). Management of endocrine disease: the role of confirmatory tests in the diagnosis of primary aldosteronism. European Journal of Endocrinology, 180(2), R45-R58.
- Funder, J. W., Carey, R. M., Mantero, F., Murad, M. H., Reincke, M., Shibata, H., Stowasser, M., & Young Jr, W. F. (2016). The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 101(5), 1889-1916.
- Rehan, M., Raizman, J. E., Cavalier, E., Don-Wauchope, A. C., & Holmes, D. T. (2015). Laboratory challenges in primary aldosteronism screening and diagnosis. Clinical Biochemistry, 48(6), 377-387.
- Mulatero, P., Rabbia, F., Milan, A., Paglieri, C., Morello, F., Chiandussi, L., & Veglio, F. (2002). Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension, 40(6), 897-902.
