Introduction
In 2008 the WHO reported a 40% global prevalence for hypertension in adults (≥25 of
age). Hypertensive individuals, whose condition is caused by PA (or hyperaldosteronism),
can be treated efficiently once a correct diagnosis has been reached. For a long time,
hypokalemia was considered a key symptom of PA and the diagnosis was rarely taken
into consideration in hypertensive patients when serum potassium was normal. However,
more recent data confirm that a large proportion of patients affected from PA are
normokalemic [1]. This group of patients remained un(der)diagnosed in the past. Consequently, extending
search for PA to normokalemic patients had significant impact on prevalence of the
disease: While prevalence of PA was believed to be less than 1% 20 years ago, currently
it is estimated that approximately 10% of all cases of hypertension are caused by
PA [2]. It is very important to identify patients with PA at an early stage since 1) their
condition is, in many cases, more severe compared to patients suffering from essential
hypertension, due to adverse effects caused by the high aldosterone concentrations
in addition to the hypertension itself and 2) their treatment differs from other types
of hypertension [3]
[4]
[5]
[6]
[7]. When the disease is caused by a unilateral aldosterone-producing adenoma (APA)
or unilateral adrenal hyperplasia, adrenalectomy can potentially cure hypertension.
In case of bilateral adrenal hyperplasia, management of hypertension is usually achieved
by mineralocorticoid receptor antagonist treatment [2]
[8].
PA is not only characterized by an increased aldosterone production but also decreased
renin secretion. Already in 1981, determination of the ARR was suggested as a screening
tool to identify PA patients among hypertensive individuals [9]. In the late 90s, a more widespread use of ARR as a screening tool to detect PA
began and, in the following years, the number of cases diagnosed in several centers
worldwide increased significantly [10]. Today, ARR is routinely used to screen hypertensive patients who could potentially
have PA. The aim of this review is to discuss the “dos and don’ts” of ARR screening
and to highlight potential pitfalls related to the use of various laboratory methods.
Physiology behind the ARR
The renin-angiotensin-aldosterone system (RAAS) is stimulated by hypotension and normalizes
blood pressure by vasoconstriction as well as water and salt retention. Excessive
activity of the system leads to hypertension. Renin is an enzyme that is secreted
from the juxtaglomerular cells of the kidney in response to low blood pressure. Renin
cleaves angiotensinogen into angiotensin I and thereby launches the RAAS. Angiotensin
converting enzyme (ACE) leads to the production of Angiotensin II, which in turn stimulates
production of aldosterone, a steroid hormone that increases blood pressure by renal
sodium- and water retention and potassium excretion. Furthermore, it has a direct
vasoconstrictive effect and stimulates the secretion of arginine-vasopressin, which
also acts as a vasopressor agent [11]. In contrast to the physiological situation, where stimuli cause an increase in
aldosterone secretion via high renin concentrations, the high aldosterone concentrations
seen in PA patients in almost all cases are caused by excessive, autonomous production
of aldosterone in the adrenal gland. The two main causes of the disease are unilateral
aldosterone producing adenomas and bilateral hyperplasia (sporadic and familial cases).
Furthermore, there are less common forms of hyperaldosteronism such as unilateral
adrenal hyperplasia, aldosterone-producing adrenocortical carcinomas and ectopic aldosterone-secreting
tumors [12]
[13]
[14]. In PA, the high aldosterone concentrations are accompanied by inadequately low
renin, because renin secretion is suppressed as a consequence of the negative feedback
loop. During the development of PA, there is a continuum ranging from normal renin
and aldosterone values in healthy individuals to clearly increased aldosterone with
completely suppressed renin in overt PA. Between these extremes, the aldosterone to
renin ratio continuously increases. At a time when total aldosterone is not yet considerably
elevated, an elevated ARR already can indicate that - in relation to renin concentrations
– aldosterone concentrations are inadequately high. This explains why the ARR is a
more sensitive screening parameter than aldosterone alone, and why significantly more
cases of PA are being detected since introduction of ARR screening [10].
Who should be screened?
As for all screening tests, pretest probability of the presence of a disease strongly
determines negative and positive predicted values and thus efficacy of the ARR as
a screening tool. Current guidelines limit the recommendation for screening to patients
with an increased risk for PA. However, since PA is believed to be the most frequent
cause of secondary hypertension, most recommendations place a high value on avoiding
missing a PA diagnosis, while accepting the risk associated with additional diagnosis
for false positive cases. The Endocrine Society recommends screening for PA in the
following cases: Blood pressure of >150/100 mmHg taken on three different days, drug
resistant hypertension (with at least three conventional antihypertensive drugs),
controlled hypertension with ≥ four antihypertensive drugs, hypertension with spontaneous
or diuretic-induced hypokalemia, hypertension with adrenal incidentaloma, hypertension
with a family history of hypertension or cerebrovascular events at a young age (<40
years), people with both, hypertension and sleep apnea and all first-degree relatives
of patients with PA [2]. Germline mutations that cause familial hyperaldosteronism account for 1–10% of
all PA cases and new mutations continue to be discovered [15]. As atrial fibrillation (AF) seems to be overrepresented in PA it might be diagnostically
important to screen patients with both, AF and hypertension [3]
[16].
Biological variation in aldosterone and renin
Multiple biological factors affect circulating aldosterone and renin and need to be
taken into account when 1) collecting samples for ARR screening and 2) interpreting
results (for overview see [Table 1]).
Table 1 Influence of different biological factors on the ARR.
Factor
|
Influence on ARR
|
Management
|
Age >50 years
|
↑
|
Under debate: adjustment of cut-off values?
|
Females
|
↑
|
Under debate: adjustment of cut-off values?
|
Increased salt intake
|
↔↓
|
No particular recommendation concerning salt intake because of the relatively small
effect on ARR.
|
Restricted salt intake
|
↑
|
Potassium should lie within normal ranges and should be corrected before measurement.
No particular recommendation concerning potassium intake.
|
Hypokalemia
|
↓
|
Increased potassium intake
|
↑
|
Blood sampling in the morning after patient has been up for at least 2 h. Prior to
the collection the patient should be seated for 5 – 15 min.
|
Standing position
|
↑
|
Recumbency
|
↑
|
No specific recommendations.
|
Renal impairment
|
↓
|
Stress
|
↑
|
Prior to blood sampling the patient should rest (in a seated position) for 5–15 min
and additional stress should be avoided.
|
↑ increased (false positive ARR). ↓ decreased (false negative ARR). ↔ No or minor/negligible
impact on ARR.
Age and sex
Plasma renin activity (PRA) and plasma renin concentration (PRC) as well as aldosterone
concentrations decline with age, but, since renin might decrease more strongly, falsely
elevated ARR sometimes is observed in elderly patients[2]
[17]
[18]. A population based study in 1347 healthy subjects suggested age-adjusted reference
intervals for aldosterone, PRC and the ARR with the upper limit of normal for the
ARR being approximately 10 points higher in older (55–74 years) as compared to the
younger (25–54 years) subjects [19]. They further reported sex related differences in both age groups with higher upper
ARR limits in females. This confirms earlier and recent observations in healthy and
hypertensive subjects, where females had higher ARR than males [20]
[21]. Several studies suggest that this is due to regulatory effects of estrogen, progesterone
and testosterone on the RAAS [22]
[23]. In healthy women, both PRA and aldosterone concentrations have also been shown
to be influenced by the menstrual cycle [24]. However, as both parameters increase from the follicular to the luteal phase, the
ARR remains unchanged. The same observation has been made in female patients with
low-renin hypertension: Although the ARR tended to be higher in the second part of
the menstrual cycle, these changes did not reach significance [25]. Nonetheless, there may be individual cases in which significant changes of the
ARR occur throughout the menstrual cycle: In a study with healthy women, 2 out of
19 had an increased ARR in the luteal phase if PRC was used to calculate the ARR [26]. In the same subjects no significant changes of the ARR could be detected using
PRA.
Until today, no study formally investigated the impact of age- and sex-adjusted reference
intervals on sensitivity and specificity of ARR screening for PA. Considering the
evidence for an impact of age and sex on ARR this might, however, be of clinical importance
and further studies are desirable.
Circadian variation
Both, renin and aldosterone, show circadian variation with peaks in the morning and
declining values in the afternoon and the ARR has also been shown to vary with the
time of day in hypertensive patients [27]
[28]. The latter study used PRA to calculate ARR. However, a more recent study – using
PRC - did not confirm this finding in healthy subjects [19]. Generally, the potential effect of sampling time alone on the ARR seems to be small
compared to the much stronger effects of posture, stress, drugs and potassium. Nevertheless,
as most of the studies investigate the diagnostic cut-off for the ARR, for reasons
of consistency blood sampling should preferably be done in the morning. In this context
it is important to note that current guidelines recommend that samples should be taken
at least 2 h after getting up [2].
Salt intake
Restricting dietary salt leads to an increase in aldosterone and renin whereas a salt
load results in their suppression. Literature does not agree whether or how this affects
the ARR. The Endocrine Society guideline warns that high dietary salt intake may lead
to false positive ARR values [2]. In contrast, two studies found increased sodium intake to negatively correlate
with ARR: In normotensive individuals, before and after a 3-day salt load (9 g NaCl/day
in addition to normal diet) the ARR was found to be unchanged when using PRA but decreased
using PRC [29]. In hypertensive patients a negative correlation between ARR and natriuresis, an
indicator of salt consumption, has been shown, suggesting that higher salt intake
could lead to a decreased ARR [30]. However, the overall effect seems to be small, and recent recommendations suggest
liberalizing rather than restricting sodium intake [2].
Plasma potassium
It is important to know the patient’s potassium status when determining ARR. Hypokalemia
is associated with decreased aldosterone concentrations, possibly combined with increased
renin. Therefore, hypokalemia could lead to false negative ARRs in individuals with
PA [31]. Accordingly, guidelines recommend correction of hypokalemia with oral potassium
supplementation before a blood sample is taken to determine the ARR. However, particularly
in patients with PA, correction of hypokalemia can be challenging. Analysis in our
own cohort revealed that 52% (13 out of 25) of the PA patients received potassium
substitution (105.4+/-91.1 mval per day) during the diagnostic procedure, but 69.2%
of these patients remained hypokalemic despite substitution (serum K 2.82+/-0.21 mmol/l)
[32].
Posture
The Endocrine Society guideline recommends that an ARR sample is collected after the
patient has been out of bed for a minimum of 2 h and seated for 5–15 min right before
drawing blood [2]. Several studies have investigated the impact of posture on aldosterone and renin
and their consequences for ARR. In one study with patients with borderline essential
hypertension, the first sample was collected after 30 min in supine position followed
by the second one after 30 min in standing position. During standing, aldosterone
increased more substantially than PRA, leading to an elevated ARR. This has also been
shown in other studies [33]
[34]. After four hours of ambulation ARR was decreased compared to overnight recumbency,
both, in patients with PA and essential hypertension [27]. Change of position, from sitting to lying (for one hour) resulted in a decreased
ARR in PA as well as in essential hypertension, although the difference reached significance
only in the latter group [35]. A recent study showed that ARR in seating position is fairly correlated to ARR
in supine and upright position in hypertensive patients . Due to the discrepant findings
from the published studies it is difficult to predict how exactly posture will affect
ARR determinations. Therefore, we suggest compliance with recommendations from the
Endocrine Society guidelines in order to get comparable data.
Renal impairment
In PA and other forms of hypertension renal damage is caused by the elevated blood
pressure but also by high concentrations of angiotensin II and aldosterone, both of
them promoting vascular fibrosis [7]
[36]
[37]
[38]
[39]. Nevertheless, in most patients with PA, creatinine clearance is significantly increased
compared to patients with essential hypertension as well as in healthy controls [40]. This might be due to relative renal hyperfiltration caused by increased glomerular
hydrostatic pressure and reduced afferent resistance [41]. These pathophysiological processes contribute to decreased renin secretion from
the juxtaglomerular apparatus. Interestingly, in patients with PA, higher PRC may
indicate a more severe renal damage [40]. This renin escape (from aldosterone suppression) is most likely induced by progressive
glomerular hypoperfusion due to persisting vascular changes. In terms of diagnosing
PA by use of ARR the impact of renal damage on renin concentrations can cause problems:
Increased PRC or PRA, respectively, can lead to falsely low ARR values, thus masking
PA [42].
Stress
It has been shown that stress might lead to an ACTH-induced aldosterone hypersecretion
and thus an elevated ARR: Following the application of an ultralow-dose of ACTH (0.03 µg),
30 hypertensive patients (27%) had a significant increase in aldosterone without increase
of cortisol. [43]. The authors speculate that an increased responsiveness of the zona glomerulosa
is the underlying mechanism. Since stress increases aldosterone but not renin, falsely
elevated ARRs can be observed [44]
[45]
[46]. In consequence, samples must be taken under resting conditions, and care must be
taken to avoid stress during sampling.
Interference by drugs
Use of several drugs is known to alter aldosterone and renin, and possibly lead to
a false positive or negative ARR. Most - although not all - of these interfering drugs
are antihypertensive agents. Of course it is recommended to withdraw - whenever clinically
possible - the drugs with the greatest influence on the ARR to obtain unbiased results
for aldosterone and renin and, in consequence, the calculation of the ARR. When interfering
drugs are stopped, most of the patients will need alternative therapy to control blood
pressure. Recommended alternative preparations with no or negligible impact on ARR
are non-dihydropyridines (i. e. verapamil), α-1 blockers (i. e. doxazosin, urapidil,
prazosin) or the direct smooth muscle relaxant hydralazine [2]. Moxonidine has also been shown not to significantly influence the ARR [47]. However, interrupting an established antihypertensive medication for ARR screening
potentially has severe side effects and may often not be feasible at all. In such
cases, correct interpretation of ARR can be difficult or even impossible, but knowing
how the different types of drugs can affect the ARR certainly helps to avoid misinterpretation.
For example, if the ARR is below the cut-off even when the concomitant medication
is known to significantly lower renin and thus elevate the ARR (e. g. in a patient
taking a beta blocker), the diagnosis of PA is unlikely. In contrary, if a patient
is on diuretics or ACE inhibitors - drugs known to eventually decrease ARR – an increased
ARR makes the diagnosis of PA even more likely. In the following we will discuss in
detail the impact of the various types of medications on the ARR; a summary of the
findings is also provided in [Table 2].
Table 2 Influence of drugs on the ARR.
Drug
|
Influence on ARR
|
Management
|
Major influence on the ARR
|
Aldosterone antagonists
|
↓
|
Stop taking medication for 4 weeks.
|
Potassium sparing diuretics
|
↓
|
Stop taking medication for 4 weeks.
|
Potassium wasting diuretics
|
↓
|
Stop taking medication for 4 weeks.
|
Antidepressant agents (see text)
|
↓
|
Stop taking medication for 4 weeks.
|
Drospirenone-containing oral contraceptives
|
↑
|
Stop taking medication for 4 weeks.
|
ß-Blocker
|
↑
|
Stop taking medication for 2 weeks.
|
Central alpha 2 agonists
|
↑
|
Stop taking medication for 2 weeks.
|
liquorice
|
↑↓
|
Stop consuming for 4 weeks.
|
Minor influence on the ARR
|
ACE-inhibitor
|
↓
|
Stop taking medication for 2 weeks.
|
Angiotensin II receptor antagonists
|
↓
|
Stop taking medication for 2 weeks.
|
Calcium channel blockers (dihydropyridines)
|
↓ (↔)
|
Stop taking medication for 2 weeks.
|
Thiazide diuretics
|
↓
|
Stop taking medication for 2 weeks.
|
Renin inhibitors
|
↑↓ (dependent on method)
|
Stop taking medication for 2 weeks.
|
Very low influence on the ARR
|
oral contraceptives
|
↑
|
Stop taking medication for 1 week (only if alternative effective contraception is
available)
|
ASS
|
↑
|
Stop taking medication for 2 weeks.
|
Verapamil
|
↔
|
Medication can be continued or used as alternative drug if other antihypertensive
drugs have to be discontinued for ARR measurement.
|
Hydralazine
|
↔
|
|
Prazosin
|
↔
|
|
Doxazosin
|
↔
|
|
Moxonidine
|
↔
|
|
↑ increased (false positive ARR). ↓ decreased (false negative ARR). ↔ No or minor/negligible
impact on ARR.
Interference by antihypertensive drugs
Among the antihypertensive drugs aldosterone antagonists (spironolactone, eplerenone)
and potassium-sparing diuretics (triamterene, amiloride) have the strongest lowering
impact on the ARR and therefore should be withdrawn at least 4 weeks before measurement
[2]
[48]. Loop diuretics (i. e. furosemide and torsemide), thiazide diuretics/thiazide-like
diuretics (i. e. hydrochlorothiazide, chlorothiazide, chlorthalidone and indapamide)
and dihydropyridines (calcium channel blockers such as amlodipine, nifedipine and
lercanidipine) should not be taken at least 2 week prior to measurement as they have
been shown to increase PRC and PRA and thus decrease the ARR [2]
[48]
[49]. In case of dihydropyridines some studies did not show an increase in PRA with unaltered
ARR, however, withdrawing the medication may improve the diagnostic value of the ARR
[50]. A less pronounced decrease of the ARR can be observed with angiotensin converting
enzyme (ACE) inhibitors (i. e. ramipril, captopril) and angiotensin II receptor agonists
(i. e. candesartan, valsartan) [48]
[49]
[51]. Both classes of drugs lead to a decrease of aldosterone leading to loss of sodium
and water and a subsequent increase of PRC and PRA. Medication intake should be stopped
at least 2 week before measurement [2]. This also applies to β-blockers (i. e. bisoprolol, metoprolol, atenolol) and central
α-2 agonists (i. e. α-methyldopa, clonidine), which lead to a false positive ARR due
to a marked decrease of PRC and PRA and a slight decrease of aldosterone [48]
[49]
[52]
[53]. In case of renin inhibitors (aliskiren), which also has to be paused for at least
1 week, the influence on the ARR depends on the procedure of renin-measurement: measuring
PRC will result in increased values and a false negative ARR whereas PRA is decreased
resulting in an increased ARR [54]
[55].
Other interfering drugs and substances
In addition to antihypertensive drugs, other types of medications and plant substances
have been found to alter the ARR. Nonsteroidal anti-inflammatory drugs such as aspirin
reduce PRA and lead to false positive ARR values. Even small doses of 100 mg can influence
the measurement and should not be taken 1 week prior to measurement if PRA is measured
[56]. Use of serotonin uptake inhibitors (SSRIs) has been shown to greatly increase PRA
and PRC and therefore decrease ARR [57]. Even though the study was conducted in normotensive depressed patients, the potential
for false negative ARRs in PA patients on antidepressant medication should not be
ignored. A 4-week pause would be suggested but might be difficult to realize in depressive
patients with hypertension. Ideally, measurement of aldosterone and renin is conducted
before initializing treatment with SSRIs in depressive and hypertensive patients.
In women receiving hormone replacement therapy or oral contraceptives, aldosterone
is increased and PRC (but to a lesser extent PRA) is decreased. As a consequence,
ARR can be markedly increased (up to 2-fold) [19]
[22]
[23]. In young healthy normotensive women on oral contraceptives, the influence on aldosterone
and renin is further modulated by the progestin component, renin assay method and
route of administration [26]. Since drospirenone-containing oral contraceptives have been shown to lead to false
positive screening test results, they should be paused at least 4 weeks before ARR-measurement
[58]. Recently, products containing desogestrel and gestodene have been demonstrated
to haven an even greater impact on ARR than those with drospirenon [59]. Interestingly, treatment with subdermal etonogestrel does not seem to change aldosterone
concentrations, PRC, PRA and the ARR [60]. Patients who regularly eat liquorice (glycyrrhetinic acid) can develop pseudoaldosteronsim
(apparent mineralocorticoid excess syndrome). Glycyrrhetinic acid inhibits the conversion
of cortisol to cortisone through inhibition of the 11-beta-hydroxysteroid dehydrogenase
type 2 (11-beta-HSD2). Non-converted cortisol activates the mineralocorticoid receptor
and leads to increased sodium concentrations, water retention and hypertension. Furthermore,
a decrease in PRA and in aldosterone concentrations occurs [61]. In normal subjects ARR decreased following acute liquorice ingestion [62]. However, the net effect of liquorice consumption on ARR may depend on several factors.
Generally, as both hormones tend to be very low, the calculation of ARR under chronic
liquorice ingestion may be misleading. Therefore, for diagnostic purposes patients
should be advised to stop the intake 4 weeks before aldosterone and renin measurements
[2].
Analytical Variability – The Impact of Assay Methods on ARR
There is a wide range of assay combinations being used to determine aldosterone and
renin for calculation of ARR. Unfortunately, there is considerable lack of standardization
between the different assays, leading to significant discrepancies in obtained results
[63]. Immunoassays have traditionally been used to measure concentrations of aldosterone,
and still are most frequently used. Antibody specificity, sensitivity and the use
– or the lack of – extraction steps have been shown to have considerable impact on
the measured concentrations [64]. During the last years new automated immunoassays became available, which show good
correlation to older analytical methods (i. e. radioimmunoassays)[65]
[66]. The more recently developed assays based on mass spectrometry certainly bear the
potential to solve some of the assay related problems in determination of aldosterone
[67]
[68]
[69]
[70]. The results from specialized laboratories in the field are promising. However,
if and to what extent LC/MS-MS assays can improve inter-laboratory agreement of the
measured concentrations remains to be determined and might only be known after such
methods become broadly available and more frequently used under routine conditions.
Data from recent external quality assessment schemes (e. g. Reference Institute for
Bioanalytics at https://www.rfb.bio/) illustrate that discrepancies between laboratories
can remain even when using mass spectrometry. In this context, the availability and
quality of the materials used for calibration remains an issue [71]. Another major contributor to the assay-related discrepancies in ARR values is the
parallel use of assays that measure PRA and actual renin concentration or “direct
renin” (PRC). Measurement of PRA adds another variable since it depends on patients’
angiotensinogen concentrations, but also allows a more sensitive measurement by extension
of incubation time. Measurement of PRC is technically easier, less affected by individual
laboratories expertise and thus more standardized [72]. A handful of studies have compared the different assay combinations and especially
the consequence of using PRA vs. PRC. The results are rather contradictory – while
some authors conclude that ARR is very similar whether it is based on PRA or PRC others
state that diagnosis may depend on whether PRA or PRC was used to determine the ARR
[29]
[73]
[74]
[75]
[76]. Generally, external quality assessment schemes for laboratories suggest better
laboratory agreements for laboratories using PRC as opposed to laboratories using
PRA (as an example see the quarterly results from the German external quality assessment
scheme at https://www.rfb.bio/). The smaller differences between measurements in different
laboratories using the same analytical method certainly provide a major advantage
of measurement of PRC over PRA as it might facilitate use of uniform cut-offs.
Defining the cut-off
Owing to the wide variety of aldosterone and renin assays being used to determine
the ARR, the use of both PRC and PRA and the inconsistency in units that are used
to report the ARR, there is no universal cut-off above which PA must be suspected.
The various cut-offs reported are based on different assay combinations and, to further
complicate the situation, have been validated and tested in different patient populations.
Many studies are limited to very specific patient populations, while others report
ARR values in the general population [35]
[51]
[77]. An overview illustrating the wide spectrum of cut-off values reported and used
from different studies is given in [Table 3]. The guidelines of the Endocrine Society from 2016 list a number of cut-offs being
used and showed that cut-offs between 20 and 40 (ng/dl)/(ng/ml/h) are most commonly
used in ambulatory patients [2]. However, they did not recommend one specific cut-off to be used in daily clinical
practice. Because of the lack of standardization between assay methods and the significant
differences between the results from different laboratories, each assay manufacturer
or each laboratory ideally should determine their own method specific cut-off, but
this might be difficult to achieve.
Table 3 ARR: Published cut-offs from different studies between 2000-2015.
Cut-off based on*/used in** which cohort?
|
n
|
ARR cut-off
|
Units
|
Aldosterone cut-off
|
Reference
|
Year
|
Hypertensive patients
|
160
|
3,7*
|
(ng/dL)/(µU/mL)
|
N/S
|
[35]
|
2014
|
Hypertensive patients
|
53
|
19*
|
(pg/mL)/(µUI/mL)***
|
N/S
|
[39]
|
2015
|
Hypertensive patients without interfering medication
|
152
|
1,2*
|
(ng/dL)/(mIU/mL)
|
N/S
|
[65]
|
2015
|
Hypertensive patients
|
100
|
2,7**
|
(ng/dL)/(mIU/mL)
|
N/S
|
[66]
|
2015
|
Hypertensive patients
|
160
|
5,7*
|
(ng/dL)/(ng/L)
|
N/S
|
[35]
|
2014
|
Hypertensive patients
|
350
|
20**
|
(ng/dL)/(ng/mL/h)
|
>15 ng/dl
|
[81]
|
2000
|
Hypertensive patients
|
305
|
25**
|
(ng/dL)/(ng/mL/h)
|
>16 ng/dl
|
[82]
|
2000
|
Hypertensive patients on medication
|
90
|
100**
|
(ng/dL)/(ng/mL/h)
|
N/S
|
[83]
|
2001
|
Hypertensive patients in 4 different centers
|
5727
|
20**
|
(ng/dL)/(ng/mL/h)
|
>15 ng/dl
|
[10]
|
2004
|
Hypertensive patients in 4 different centers
|
6650
|
25**
|
(ng/dL)/(ng/mL/h)
|
N/S
|
[10]
|
2004
|
Hypertensive patients in 4 different centers
|
860
|
30**
|
(ng/dL)/(ng/mL/h)
|
N/S
|
[10]
|
2004
|
Hypertensive patients in 4 different centers
|
9580
|
40**
|
(ng/dL)/(ng/mL/h)
|
>15 ng/dl
|
[10]
|
2004
|
Hypertensive patients ambulatory
|
62
|
13,1*
|
(ng/dL)/(ng/mL/h)
|
N/S
|
[27]
|
2005
|
Hypertensive patients recumbent
|
62
|
35*
|
(ng/dL)/(ng/mL/h)
|
N/S
|
[27]
|
2005
|
Hypertensive patients
|
160
|
30*
|
(ng/dL)/(ng/mL/h)
|
N/S
|
[35]
|
2014
|
Hypertensive patients
|
100
|
30**
|
(ng/dL)/(ng/mL/h)
|
N/S
|
[66]
|
2015
|
Healthy males, age 25 - 54
|
416
|
14,2*
|
(ng/L)/(ng/L)
|
N/S
|
[19]
|
2010
|
Healthy females, age 25-54
|
618
|
20,3*
|
(ng/L)/(ng/L)
|
N/S
|
[19]
|
2010
|
Healthy males, age 55 - 74
|
130
|
22,4*
|
(ng/L)/(ng/L)
|
N/S
|
[19]
|
2010
|
Healthy females, age 55-74
|
183
|
25,5*
|
(ng/L)/(ng/L)
|
N/S
|
[19]
|
2010
|
Hypertensive patients
|
465
|
750**
|
(pmol/L)/(ng/mL/h)
|
N/S
|
[84]
|
2000
|
Studies are grouped by units. Studies using the same unit are sorted according to
the year of publication. N/S not specified. *** in this study a conversion factor
of 1 µUI=1 ng was used for PRC.
It should be kept in mind that the cut-off - even when validated for the assay combination
in use so that analytical variability can be ignored – does not represent a clear-cut
distinction between patients with and without PA. It rather represents a compromise
between sensitivity and specificity of the screening test to detect PA. If it is considered
important to detect all cases of PA, the cut-off must be lower. If false positive
cases need to be avoided, it might be appropriate to increase the cut-off. Furthermore,
when comparing different studies it is important to realize that any cut-off derived
to distinguish PA patients from normotensive individuals (as an example see reference
[78]) inherently is associated with higher specificity and sensitivity than a cut-off
derived to distinguish between PA patients and patients with essential hypertension.
The latter, however, obviously is the more interesting scenario for clinical routine
[65].
As shown in [Table 3] some of the earlier studies used an aldosterone concentration exceeding 15 ng/dl
as an additional diagnostic criterion, while others demonstrated that this cut-off
might be too high and therefore patients with PA could be missed [79]. Although many clinicians might tend to look for PA mainly in cases with moderate
to high aldosterone concentrations, the use of a specific aldosterone cut-off is currently
not suggested by the Endocrine Society guideline[2]. More data from prospective studies are warranted to finally clarify the impact
of such an additional criterion on sensitivity and specificity during screening.
Based on the experience in our clinic and within the German Conn Registry we use an
ARR cut-off of 12 (pg/ml)/(mU/l) based on an aldosterone concentration above 50 pg/ml
(as measured by an automated immunoassay). Note: To convert renin from mU/L to ng/L
multiply by 1.66. To convert aldosterone from ng/dL to pmol/L, multiply by 27.7.
Future directions
Despite its challenges, determining the ARR is a valuable tool in identification of
PA patients among hypertensive individuals. PA is a common cause of secondary hypertension
and the consequences of undiagnosed or late diagnosed disease and the resulting economic
impact justify (repeated) ARR determination in the defined group of patients. Furthermore,
testing is simply done and without risk for the patient and there are different effective
treatment options for patients suffering from PA [2].
It is however important to keep in mind that ARR is a screening method and one of
the common confirmatory tests (saline infusion test, captopril test, fludrocortisone
suppression and oral sodium loading) is required for final diagnosis. In cases with
ambiguous results a second test (out of those four) will be needed to confirm the
diagnosis.
To increase the predictive significance of the ARR it is mandatory to take into account
the influencing factors (such as age, gender, concomitant medication and renal function)
in every determination of the ARR. After considering the risks and benefits for the
individual patient ARR-influencing drugs should be paused (as suggested in [Table 2]) or replaced. Ideally, testing should be performed under identical conditions: blood
sampling in the morning, after the patient has been up for 2 h and after a 10 min
rest in a seated position. Furthermore it is important to know the analytical procedure
for aldosterone, PRA and PRC, respectively, and to define a minimal aldosterone concentration.
Looking towards the future, more uniformity in assay methods and consensus on the
appropriate ARR cut-offs will hopefully further improve the clinical value of this
powerful screening tool. Considering the available data definition of age- and sex-specific
ARR cut-offs is highly desirable. As recent studies pointed out the influence of aldosterone-producing
adenomas on plasma prorenin concentrations might become a further component of the
diagnostic approach of PA [80].