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00019616-200409000-00007ReviewThe EndocrinologistThe Endocrinologist© 2004 Lippincott Williams & Wilkins, Inc.14September 2004 p 267-276The Aldosterone–Renin Ratio in Screening for Primary AldosteronismCME Review Article #26Stowasser, Michael FRACP, PhD*†; Gordon, Richard D. FRACP, PhD, MD†*Director and Associate Professor, Hypertension Unit, University of Queensland Department of Medicine, Princess Alexandra Hospital; and *Director, †Former Director and Professor of Medicine, Hypertension Unit, Greenslopes Private Hospital, Brisbane, Australia.The authors have disclosed that they have no significant relationships with or financial interests in any commercial company that pertains to this educational activity.Reprints: Michael Stowasser, FRACP, PhD, Hypertension Unit, University of Queensland Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane 4102, Australia. E-mail: [email protected] and [email protected] Editor’s Note:This article is the 26th of 36 that will be published in 2004 for which a total of up to 36 Category 1 CME credits can be earned. Instructions for how credits can be earned precede the CME Examination at the back of this issue.AbstractRecognition that primary aldosteronism (PAL) is a common specifically treatable form of hypertension and that most patients are normokalemic has led to a marked increase in demand for aldosterone/renin ratio (ARR) testing as a means of screening for this disorder. The value of this screening test depends on an appreciation of many factors (such as diet, posture, time of day, presence of hypokalemia, medications, age, and renal function), which can affect the results, on the care with which these factors are either controlled or their effects taken into account, and on access to reliable and reproducible assays for renin and aldosterone. Even then, physiological day-to-day variability reduces the value of a single estimation, and repeated testing is necessary before a decision that PAL is highly likely (warranting further testing) or highly unlikely can be made. Provided that testing of aldosterone suppressibility is always carried out to confirm or exclude the diagnosis, and the subtype is determined by hybrid gene testing and adrenal venous sampling, wide application of the ARR can have a major beneficial clinical impact with improved therapeutic outcomes, including possible cure in those with unilateral disease.Learning ObjectivesOutline the reasons why it is important to screen for primary aldosteronism (PAL) and why the aldosterone/renin ratio (ARR) is preferable to other screening measures.Give examples of the wide range of factors, including medications, that may alter the reliability of the ARR when screening for PAL.Summarize the best ways of using the ARR to identify PAL and the limitations of this test.In recent years, 2 major developments led to a renewed interest in primary aldosteronism (PAL) as a clinical entity. The first of these was the demonstration that PAL is a much more common cause of hypertension than was previously thought, accounting for as many as 5% to 15% of hypertensives in some series, with most patients lacking hypokalemia as a clue to the presence of this condition, and therefore masquerading as “essential hypertension.”1–7 The second major development has been the accumulation of experimental and clinical evidence suggesting that aldosterone excess may have deleterious effects on the cardiovascular system that are at least partly independent of blood pressure elevation.8–11Although Conn predicted 40 years ago that normokalemic PAL would prove to be common,12 it was not until the early 1980s that use of the aldosterone/renin ratio as a screening test by Hiramatsu revealed a prevalence of aldosterone-producing adenoma (APA) of 2.6% in 348 hypertensives and 6 of the 9 with APA were normokalemic.13 In the 1990s we,1–4 and subsequently others,5–7 began to apply the ratio to all referred hypertensives, and Conn’s hypothesis proved correct. These developments led several investigators to propose that screening for PAL be undertaken much more widely among the hypertensive population and not restricted to those with hypokalemia or resistant hypertension. In response, the demand for aldosterone/renin ratio testing by physicians who treat hypertensives has grown rapidly, making it essential that reliable assays for renin and aldosterone are widely available; and factors affecting the ratio and limitations to its reliability are defined, understood, and taken into account when ordering the test and interpreting the results. Optimal detection and management of patients with PAL is critically dependent on an awareness of these factors, and of the approaches that can be implemented to control them and render test results meaningful.WHY SHOULD WE LOOK FOR PRIMARY ALDOSTERONISM?For hypertensive patients who are found to have PAL, the rewards are potentially great, especially if they are shown to have a surgically correctable form. Patients who undergo unilateral adrenalectomy (now usually performed laparoscopically and therefore associated with more rapid recovery) for unilateral forms of PAL (most commonly APA) are either cured of hypertension (50–60%) or show significant improvement,14–17 and the majority report greatly enhanced quality of life compared with preoperatively. For patients with bilateral PAL (bilateral adrenal hyperplasia [BAH]), and for those with unilateral forms who decide not to undergo surgery or in whom surgery would be inappropriate, specific medical treatment with aldosterone antagonist medications can be offered with availability of a new, more specific aldosterone receptor blocker removing some previous impediments to satisfactory treatment.18 Most patients with PAL begun on an aldosterone antagonist will achieve hypertension control even where resistant hypertension existed before, many showing dramatic responses.17,18 Relatively small doses (for example, 12.5–25 mg of spironolactone or 5–10 mg of amiloride daily) are usually sufficient, provided that enough time (measured in weeks to months) is allowed for each dose to achieve its maximal effect while continuing nonspecific medications. The very high doses of spironolactone (100–400 mg daily) used in the 1960s and 1970s19,20 are unnecessary, associated with unacceptable gynecomastia in males and can cause hyperkalemia and azotemia in those with impaired renal function. The discovery and availability of a more specific aldosterone receptor blocker that does not block the androgen receptor21 has overcome the nuisance side effects, but the potential for renal side effects remains. The longer the duration of hypertension before PAL is eventually detected and treated, the more severe and difficult to control the hypertension will become, and the less likely that irreversible target organ damage will be prevented.22–24 Because of this, early diagnosis provides the best chance for optimal treatment and for achieving a cure.If normal blood pressure can be achieved using nonspecific antihypertensive medications, does it really matter if we miss patients with normokalemic PAL, especially if they have a bilateral form for which long-term medical treatment (with aldosterone antagonists) will be required anyway? In other words, is it enough just to normalize blood pressure in PAL? This is an important area of ongoing debate which centers around findings from both animal and human studies suggesting that aldosterone excess can induce harmful effects (vasculitis, fibrosis, and remodeling) on the cardiovascular system, which are independent of its effects on blood pressure.8–11 If correct, then specific surgical or medical treatment of PAL, as well as being more effective in controlling hypertension, would also be expected to bring about better long-term outcomes than nonspecific treatment by combating these adverse effects independent of hypertension. Studies are currently underway to further address this issue.SUPERIORITY OF THE ALDOSTERONE/RENIN RATIO OVER OTHER SCREENING TESTSMeasurement of Plasma PotassiumIt has now been well established that presence of hypokalemia lacks sensitivity for the detection of PAL.1–7 Among the 814 patients diagnosed by the Greenslopes Hospital Hypertension Unit (GHHU) with PAL after 1991, when it became policy to screen all hypertensives for PAL (and not just those with hypokalemia), only 21% were known to be hypokalemic up until the time of presentation. Only 48% of the 168 who went on to have an APA removed were hypokalemic. Within the Princess Alexandra Hospital Hypertension Unit (PAHHU) since its establishment in January 2000, similar proportions have been observed among the 122 patients (18% hypokalemic) diagnosed with PAL and the 23 patients (48% hypokalemic) undergoing removal of an APA.17 In these 936 patients, precautions were taken to avoid false elevations of plasma potassium levels25 leading to masking of hypokalemia by 1) using fist clenching only to achieve venipuncture, 2) releasing the tourniquet after venipuncture has been achieved, 3) waiting for at least 10 seconds before gently withdrawing any blood, 4) using a syringe and needle rather than a Vacutainer, so that blood can be withdrawn in a slow and careful manner, and then gently discharged down the side of the opened sample tube, and 5) separating the plasma from the cells within 30 minutes of collection. In the PAHHU series, not only was the presence or absence of hypokalemia unreliable in the detection or exclusion of PAL, or in separating APA from BAH, but it was also unhelpful in predicting whether unilateral adrenalectomy for APA would result in a cure of hypertension or biochemical cure of PAL (as judged by postoperative fludrocortisone suppression testing [FST]).17Measurement of Plasma AldosteroneDemonstration of frankly elevated plasma aldosterone levels also lacks sensitivity for PAL, because many patients (even those with APA who subsequently experience cure of hypertension after unilateral adrenalectomy) exhibit levels that lie within the wide normal range.16,17 Such “normal” levels could be viewed as “inappropriately normal” in the face of suppression of the renin–angiotensin system which, in individuals without PAL, should result in suppression of plasma aldosterone to very low values. Of 555 patients diagnosed with PAL at GHHU between 1993 and 1999, 414 (75%) had upright plasma aldosterone levels <30 ng/100 mL and 143 (26%) had levels <15 ng/100 mL. Of 136 patients who demonstrated lateralization of aldosterone production to 1 adrenal on adrenal venous sampling (AVS), consistent with APA, 78 (57%) had aldosterone levels <30 ng/100 mL and 16 (12%) had levels <15 ng/100 mL. Among a series of 68 patients who underwent unilateral adrenalectomy for APA and had repeat FST at 3 months to 10 years postoperatively as an indication of cure of autonomous aldosterone overproduction, no difference in mean preoperative upright plasma aldosterone levels was found between patients who were biochemically cured of PAL (n = 42) and those improved (n = 26).16Measurement of ReninProvided that patients are not habitually ingesting a low-sodium diet or receiving medications that can bring about increased renin production (see subsequently and Table 1) and do not have “accelerated” or malignant hypertension,26–28 renin levels are consistently suppressed in PAL. Concomitant renovascular hypertension29 also can prevent renin suppression. However, although highly sensitive for PAL, suppressed renin levels lack specificity. Treatment with beta-blocking agents, clonidine, or alpha-methyldopa (which reduce beta-sympathetic stimulation of renin release)30–32 or nonsteroidal antiinflammatory agents (which promote salt retention and also inhibit renal prostaglandin production),33 consumption of a high-salt diet,34,35 advancing age (during which renin levels gradually fall as renal function declines),36 chronic renal impairment (in which renal renin-producing capacity is reduced and salt retention contributes to renin suppression),37 and a growing list of other salt-dependent, low renin forms of hypertension may all be associated with renin suppression.38–47 The latter group includes 1) Liddle’s syndrome, in which genetic mutations of the β and γ subunits of the epithelial sodium channel (ENaC) lead to constitutive channel activation (causing salt retention, hypertension, and potassium loss) by preventing binding of these subunits to a regulatory protein (Nedd4), which normally brings about channel degradation38; 2) congenital or acquired (for example, through carbenoxolone administration or ingestion of licorice) deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), an enzyme that normally functions to prevent cortisol from gaining access to and causing excessive stimulation of the mineralocorticoid receptor, converting it to cortisone (which has no affinity for the receptor)39; 3) hypertensive forms of congenital adrenal hyperplasia caused by mutations in either the 11β-hydroxylase or 17α-hydroxylase genes, which bring about reductions in cortisol production, leading to feedback stimulation of ACTH, which in turn causes increased production of the mineralocorticoid deoxycorticosterone (DOC)40,41; 4) primary glucocorticoid resistance, which is again associated with ACTH simulation and excessive DOC production42; 5) ectopic ACTH syndrome, in which mineralocorticoid hypertension is thought to result from a combination of DOC excess and “overload” of the 11βHSD2 enzyme by very high levels of cortisol43; 6) DOC-secreting tumors44; 7) mutations of the mineralocorticoid receptor gene, which cause a modest constitutive activation of the receptor, and also permit progesterone and spironolactone to act as agonists rather than antagonists, so that hypertension may be exacerbated during pregnancy and in response to spironolactone treatment45; and (8) the syndrome of hypertension and hyperkalemia with normal glomerular filtration rate (pseudohypoaldosteronism type 2 [PHA-2]),46 recently found to be associated with defects in genes encoding serine-threonine kinases (with no lysine in the catalytic domain, WNK) expressed in the distal nephron.47 Unlike PAL, aldosterone levels are chronically suppressed (as a result of chronic suppression of renin/angiotensin II) in all of these salt-dependent, low-renin forms of hypertension with the exception of PHA-2, in which chronically elevated plasma potassium levels prevent suppression of aldosterone.JOURNAL/endst/04.03/00019616-200409000-00007/table1-7/v/2021-02-17T201744Z/r/image-tiff Factors Affecting the Aldosterone/Renin Ratio and Leading to False-Positive and False-Negative ResultsThe aldosterone/renin ratio addresses some of the limitations described here in being much more sensitive for detection of PAL than plasma potassium or aldosterone measured in isolation, and more specific that isolated renin measurements, in that if renin is suppressed and aldosterone is also suppressed, the ratio will not be elevated. However, many factors are capable of affecting the ratio, and it is not without false-positives and -negatives34,35,48,49 (Table 1). It is for this reason that the ratio should be regarded as a screening test only, and should be measured more than once (serially if conditions of sampling, including medications, are being altered) before deciding whether or go on to a suppression test to definitively confirm or exclude the diagnosis of PAL.FACTORS AFFECTING RELIABILITY OF THE ALDOSTERONE/RENIN RATIO IN SCREENING FOR PRIMARY ALDOSTERONISMIf renin was the sole (and not just the main) regulator of aldosterone production and plasma levels, the aldosterone/renin ratio would be much more robust as a screening test, and diagnosing PAL would be much easier. The fact that other important regulators (such as potassium, ACTH) and changes in hepatic blood flow will also influence levels explains why renin and aldosterone do not always move strictly in parallel in response to physiological maneuvers and certain medications. Thus, false-positive and false-negative ratios threaten the use of the ratio and need to be avoided, as discussed subsequently.PostureAfter assumption of upright posture, the translocation of blood into the lower limbs is associated with a rise in plasma aldosterone.50 This results partly from an increase in renin, released from juxtaglomerular (JG) cells in response to a fall in renal perfusion pressure and an increase in sympathetic output and beta adrenergic receptor stimulation.34 In addition, reduced metabolic clearance of aldosterone occurs as a result of reduced hepatic blood flow. Because the effect of reduced hepatic clearance is more rapid than that brought about by an increase in renin, the rise in aldosterone levels measured in samples collected before and shortly (for example, less than 1 hour) after assuming upright posture may not demonstrate a close correlation with the rise in renin. This may help to explain why Montori and coworkers,51 who sampled patients after only 30 minutes of ambulation, reported that only 6% of interindividual variation in plasma aldosterone was attributable to variation in plasma renin activity (PRA). Better correlation between changes in aldosterone and renin levels would be expected to occur in studies that used a longer period (at least 2 hours) of ambulation.In patients with angiotensin II-responsive (AII-R) forms of PAL, which includes all with AII-R APA (histologically not predominantly zona fasciculata-like52) and most with BAH, aldosterone demonstrates normal responsiveness to upright posture.53 Patients with angiotensin II-unresponsive (AII-U) forms, including those with AII-U APA (histologically predominantly zona fasciculata-like52) or with glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type I [FH-I]), demonstrate a lack of responsiveness or even a fall in plasma aldosterone, because ACTH (which falls during the early morning hours when these posture studies are carried out) assumes the dominant role over angiotensin II in regulating aldosterone in those subtypes of PAL.53 It could be predicted that samples collected for aldosterone/renin ratio measurement during upright posture may be more sensitive for detecting the AII-R forms, whereas samples collected during recumbency might be more sensitive for detecting the AII-U forms. In practice, most centers use a midmorning upright sample, usually while seated for 5 to 15 minutes. This is obviously more convenient than having to provide recumbent conditions for a period such as 1 hour. It is also less likely to miss patients with PAL, because the majority (approximately 70% of patients diagnosed by the GHHU or PAHHU) are AII-R. Although aldosterone levels in the AII-U forms fail to rise in response to upright posture, upright levels are similar to those of patients with AII-R forms (whose recumbent levels are usually much lower), and upright aldosterone/renin ratios appear to be sufficiently sensitive.Time of DayIn continuously recumbent patients, renin levels peak between approximately 4:00 am and demonstrate a nadir at approximately 4:00 pm.54 Because the stimulatory effect of upright posture on renin and aldosterone levels is greater in the early morning than in the afternoon,54 levels obtained midmorning from seated patients will tend to be higher, on average, than those measured from the same patients during an afternoon clinic.49 In patients with PAL, whose PRA levels are chronically suppressed, plasma aldosterone levels are strongly influenced by ACTH levels, which follow a striking circadian pattern with highest levels approximately 8:00 am and falling rapidly thereafter.55 The aldosterone/renin ratio is therefore more likely to be elevated in blood collected from patients with PAL during the morning rather than in the afternoon.49Dietary Sodium IntakeThe stimulatory effect of habitual dietary salt restriction on renin production may lead to a lowering of the aldosterone/renin ratio.34,35,48 Sensitivity of the ratio is therefore improved if patients maintain a liberal dietary salt intake before testing. Occasional false-positives can arise, on the other hand, in patients who consume very large amounts of salt34,35,48; this is presumably because the profound suppression of renin that occurs in these individuals may not be accompanied by an equally profound suppression of aldosterone, because stimulation by other positive regulators such as potassium and ACTH maintain production of aldosterone by the adrenal cortex.Plasma Potassium LevelBecause potassium is a powerful chronic regulator of aldosterone secretion, hypokalemia may be associated with false-negative ratios in patients with PAL.34,35,48 This can be avoided by correcting hypokalemia with supplemental slow-release potassium chloride tablets before ratio measurement. The presence of hypokalemia can be obscured, however, if care is not taken during sample collection to avoid false elevations of potassium levels.25,56–58 For example, 1) fist clenching to fill the veins drives potassium out of the muscles and into the blood, 2) failure to release the tourniquet while blood is being collected, 3) the use of Vacutainers (which can cause hemolysis) rather than syringes, 4) “difficult” sampling is often associated with obvious hemolysis and always with some hemolysis, 5) failure to separate the plasma from the cells within 30 minutes of blood collection allows potassium to leave the red cells as their metabolism slows down, 6) measurement of potassium in serum rather than plasma results in higher levels as a result of release of potassium from the cells during clotting, and 7) recumbent levels are slightly lower than upright levels.56Medications Causing False-Positive RatiosTreatment with beta-adrenergic-blocking medications is by far the most common cause of a false-positive aldosterone/renin ratio.30,31,35,48,59 Blockade of beta-adrenoceptor-mediated stimulation of renin production by JG cells brings about a profound suppression of renin levels.30,31 Aldosterone levels also fall, but not to as great a degree, possibly because of the continuing stimulatory action of potassium and ACTH, and the ratio therefore usually rises above the arbitrary cutoff point for PAL. Methyldopa32 and clonidine60 can have a similar effect by reducing central sympathetic outflow. Nonsteroidal antiinflammatory agents also suppress renin levels by inducing renal sodium and water retention and by suppressing renal prostaglandins, which normally stimulate renin release. At the same time, they promote retention of potassium leading to stimulation of aldosterone production and further elevation of the aldosterone/renin ratio.33Oral contraceptive agents and other estrogen-containing preparations have generally been thought to have little effect on the ratio when renin has been measured as PRA,61,62 which incorporates assessment of renin substrate (angiotensinogen). However, patients receiving these agents may demonstrate falsely elevated ratios when direct, immunometric measurements of active renin concentration (irR) are used rather than PRA. Increased hepatic production of angiotensinogen, induced by estrogen, would result in higher angiotensin levels if renin remained constant, but leads to increased negative feedback by angiotensin-suppressing active renin production.61–63 This usually prevents PRA from rising significantly in individuals taking these medications but will lead to suppressed renin concentration and an increased aldosterone/renin ratio.Medications Causing False-Negative RatiosFalse-negatives may be encountered in patients taking medications that stimulate renin production. These include all diuretics,34,35,64 including potassium-sparing diuretics such as spironolactone, amiloride, and triamterene. These all induce volume contraction and sympathetic nervous system stimulation. Dihydropyridine calcium channel antagonists59,65 briskly stimulate renin, probably through reflex sympathetic stimulation as blood pressure falls, natriuretic effects, and direct stimulation of calcium-dependent renin regulatory pathways. Angiotensin converting enzyme (ACE) inhibitors59 and angiotensin II receptor blockers (ARBs)59 interfere with negative feedback of angiotensin II on renin production. Nonpotassium-sparing diuretics such as thiazides have the added effect of increasing renal potassium losses and lowering plasma potassium levels, leading to reduced aldosterone secretion. Dihydropyridine calcium antagonists can reduce aldosterone production by interfering with intracellular, calcium-dependent steps in biosynthesis.66 ACE inhibitors and ARBs would also be expected to inhibit aldosterone production in patients with AII-R forms of PAL.67Presence of Renal DysfunctionFalse-positive ratios may occur in patients with renal impairment,37 in which renin levels tend to fall as a result of reduced renin secretory mass and also salt and water retention, whereas any associated hyperkalemia tends to elevate aldosterone.AgeFalse-positive ratios are also frequently encountered in the elderly as a result of falling renin levels accompanying gradually reducing renal function,36 whereas the fall in aldosterone levels is less marked.Effects of Coexisting ConditionsConditions in which previously suppressed renin is released from suppression such as pregnancy,68 renal artery stenosis,29 and malignant hypertension26–28 may render ratios falsely negative in patients with PAL. False-positive ratios occur in the syndrome of hypertension and hyperkalemia with normal glomerular filtration rate (PHA-2), in which a primary defect in renal tubular function results not only in excessive resorption of sodium (leading to hypertension and renin suppression), but also potassium (causing chronic hyperkalemia, which prevents suppression of aldosterone).46 This contrasts with Liddle’s syndrome38 in which both renin and aldosterone are suppressed.THE PROBLEM OF ASSAY RELIABILITYHighly reproducible assays are essential for the diagnosis and management of PAL. Perhaps because renin levels tend to move physiologically on a logarithmic scale, the ARR appears to be more dependent on renin than aldosterone.51 This is especially true when renin levels are low (like in patients with PAL), in which case small absolute changes can result in large changes in the ARR. It could be argued, therefore, that for the purpose of ARR measurement in screening for PAL, it is more important to measure renin accurately than aldosterone. However, false-positive and -negative ARR values may also result from inaccurate aldosterone measurement, and reliable quantification is critical during subsequent suppression testing (in which the definitive confirmation or exclusion of PAL is dependent on the aldosterone level) and adrenal venous sampling (the results of which largely determine whether a patient is a candidate for unilateral adrenalectomy or, alternatively, treatment with aldosterone antagonist medication).34,35,48As a result of the wide availability of commercial “kits” and the increasing demand associated with more widely based screening for PAL by internists and family physicians, the measurement of aldosterone and renin has moved increasingly from the basic research or specialized unit laboratory, with meticulous quality control, clinical feedback, and long experience, to the busy shrinking budget-driven general hospital laboratory or the profit-driven private laboratory.49 Limited allocations for such specific purposes make it difficult for the all-purpose publicly funded hospital or private enterprise general pathology laboratories to adopt the time-consuming and therefore expensive quality control practices followed by specialized unit laboratories, which go far above and beyond those recommended in the commercial kit product insert. For example, they may be disinclined to adopt the well-substantiated advice by Sealey and Laragh69 for PRA assays to routinely extend the incubation time from 90 minutes (the time period recommended by the manufacturer) to 3 hours, and to 18 hours for samples with levels less than 1 ng/mL/hr, to permit enough generation of angiotensin I to ensure assay reproducibility at the lower end of the scale. For both renin and aldosterone assays, general purpose laboratories may also be reluctant to use aliquots from human plasma pools, carefully selected to cover the critical range of measurements, rather than the lyophilized controls provided by the manufacturer to monitor intra- and interassay reproducibility. Although perhaps less vulnerable than PRA assays, radioimmunoassays of plasma aldosterone using commercial kits are not free from problems, for example, if the long-used antibody component is exhausted and replaced by another by the manufacturer without adequate examination of the effects of this on the assay. It should not be forgotten that the concentration of aldosterone in plasma is only approximately one thousandth that of cortisol.Faster, more convenient methods of directly measuring active renin49,70 and, more recently, aldosterone using immunometric techniques and automated machinery (Nichols Institute Diagnostics) are rapidly being adopted in large, busy laboratories. Considerable work is required to validate and improve these methods, involving cooperation between the manufacturers and the experts within the field, before they can be accepted as sufficiently accurate to provide cutoff points for decisions on further workup of patients possibly with PAL.Because of the critical role of validated assay techniques and the innate variability of both aldosterone and renin, it is essential that management decisions not be based on a single ratio. Before deciding that PAL is highly likely or highly unlikely, the ratio should be repeated until one is confident that it is raised, meanwhile adjusting medications and conditions of collection if indicated. The next step, a definitive test involving salt loading, is not entirely risk-free in patients with severe hypertension or compromised cardiac or renal function. For example, delivery of 2 L of normal saline intravenously over 4 hours is also a test of cardiorenal function.71 A single measurement of ARR should never be relied on.49MEASUREMENT OF THE ALDOSTERONE/RENIN RATIO—A SUGGESTED APPROACHGiven the complex array of factors and conditions that affect aldosterone and renin levels, it is perhaps not surprising that approaches used to control for such factors have varied considerably from 1 center to the next, and this represents a major area of difficulty in comparing or pooling laboratory or clinical results.49Table 2 summarizes the approach used by the GHHU34,35,48,49 and subsequently adopted by the PAHHU,17 which has resulted in large numbers of patients with PAL detected, including those with surgically correctable forms (which make up approximately one third of patients in our experience) who have been either cured or had hypertension markedly improved after laparoscopic adrenalectomy.16,17 Bilateral forms have responded well to medical treatment with aldosterone antagonists.17JOURNAL/endst/04.03/00019616-200409000-00007/table2-7/v/2021-02-17T201744Z/r/image-tiff Measurement of the Aldosterone/Renin Ratio—Approach Used by the Greenslopes and Princess Alexandra Hospital Hypertension UnitsIt is important to emphasize the potential danger in ceasing medications in nonhospitalized patients to achieve washout. Although this can be achieved safely in mildly hypertensive patients who are seen frequently, it is more often necessary to begin a relatively renin-neutral drug such as verapamil slow-release, hydralazine, prazosin, or doxazosin, alone or in combination.34,35,48,49 In cases in which a potentially interfering medication cannot be withdrawn, useful information can still be obtained by taking into account its known effects when interpreting the ARR result. For example, a raised ratio in patients receiving a diuretic, angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, or dihydropyridine calcium blocker would make PAL very likely, whereas a normal ARR in the presence of beta-blocker treatment would make the diagnosis very unlikely.WHAT SHOULD BE THE CUTOFF POINT FOR THE RATIO?Now that it has become widely recognized that PAL is common and specifically treatable enough to warrant active attempts at detection among the general hypertensive population, the question as to the precise cutoff point for ARR has grown to be one of great clinical importance. Lack of uniformity in diagnostic protocols and assay methods used for measurement of the ARR, however, has been associated with a substantial variability in cutoff values used by different groups ranging from 20 (when plasma aldosterone is expressed as ng/dL and PRA as ng/mL/hr) to 100.4–7,72 Within the GHHU and PAHHU, and using the protocol described in Table 2, we currently consider ratios of 30 or more to be suggestive of PAL, and accept that a “gray zone” exists between 20 and 35.34,35,48Differences between laboratories in the units used for reporting aldosterone and renin levels has added to the complexity faced by the practicing physician. It is likely, however, that this problem will diminish with time as more laboratories adopt the Systeme Internationale (SI) method of reporting aldosterone levels (in which 1 ng/dL, the “traditional” unit, converts to 27.7 pmol/L) and change over from a PRA assay to an immunometric method of directly measuring active renin concentration (in which a PRA level of 1 ng/mL/hr converts to a “direct renin” level of 8.4 mU/L).A limitation of the ARR is that, in the presence of extremely low renin levels (for example, at PRA values of 0.1 ng/mL/hr or less), the ARR may be elevated and thereby raise the possibility of PAL even when plasma aldosterone is also very low (for example, 4 ng/dL) and clearly not consistent with PAL. To avoid this problem, some investigators have suggested the inclusion of a minimum plasma aldosterone concentration within the screening criteria. For example, William Young, Jr., with extensive experience, has proposed a ratio of >20 in combination with a plasma aldosterone concentration of >15 ng/dL as a positive screen for PAL.5 As discussed here, however, this approach would have led many of our patients with PAL (including some with APA) to have been missed because their plasma aldosterone levels fell below this cutoff level. Within the GHHU and PAHHU, we continue to follow (repeating the aldosterone/renin ratio and considering, from time to time, further diagnostic workup) all patients with elevated ARR other than those whose plasma aldosterone concentration is below the level used to define normal suppression during FST (that is, 6 ng/dL).COMPLETING THE DIAGNOSTIC WORKUPResponses to specific medical treatment of PAL are usually excellent and probably provide better protection from morbidity than nonspecific treatment (see previously), justifying the effort to detect patients with this disorder. Responses to unilateral adrenalectomy in patients with unilateral forms are generally much more impressive than medications in terms of hypertension control and improved quality of life. Accurate identification of patients with surgically correctable forms of PAL, however, requires a careful, methodical diagnostic approach (Fig. 1). Reliance only on an elevated ARR and a computed tomography (CT) scan will lead to many patients with APA being missed, because CT lacks sensitivity for detection of small APAs,17,34,35,48 and on the other hand could lead to inappropriate operations because CT cannot distinguish unilateral APA from nonfunctioning nodules or bilateral adrenal hyperplasia.34,35,48JOURNAL/endst/04.03/00019616-200409000-00007/figure1-7/v/2021-02-17T201744Z/r/image-tiff Algorithm describing the diagnosis and treatment of primary aldosteronism as performed in the Greenslopes and Princess Alexandra Hospital Hypertension Units. CT, computed tomography; FH-I, familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism).Although a detailed description of methods used for confirmatory testing and subtype differentiation is beyond the scope of this review (see references 27, 28, and 41 for further information), it should be emphasized here that 1) the ARR is a screening test only, and careful further testing involving salt loading to assess suppressibility of aldosterone is required to definitively confirm or exclude PAL in patients found to have a repeatedly elevated ratio; and 2) adrenal venous sampling is the only reliable means of distinguishing surgically correctable, unilateral forms of PAL from bilateral forms. In a recently reported study describing increased rates of diagnosis of PAL associated with wide application of the ARR in 5 centers, APAs constituted a much higher proportion (28–50%) of newly diagnosed patients with PAL in the 4 centers that used adrenal venous sampling during diagnostic workup than in the center that did not (9%).73RECENT CRITICISMS OF THE ALDOSTERONE/RENIN RATIO IN DIAGNOSIS OF PRIMARY ALDOSTERONISMThere are at least 2 reasons why the usefulness of the ARR has been recently questioned. First, confusion has risen that the ARR can be used as a definitive test for PAL, sometimes based on only 1 observation. Second, the CT scan has sometimes been used as a definitive criterion for the diagnosis of PAL as a result of APA, so that an elevated ARR in the absence of an adrenal mass on CT has been interpreted as a false-positive test. As discussed fully here, this is incorrect.Those studies aimed at determining the prevalence of PAL in either referred or, less frequently, “unselected” hypertensives have, with few exceptions,6 used ARR as a definitive test without testing for lack of suppressibility of aldosterone, replacing it in some circumstances with a CT scan.Definitive study of the ARR as a screening test for PAL will require repeated testing under carefully controlled conditions, performance of a reliable aldosterone suppression test, and adrenal venous sampling in all patients whose aldosterone does not suppress, followed by removal of an adrenal in lateralizing patients, followed by a postoperative test for suppressibility of aldosterone. The comparison of pre- and postoperative aldosterone suppression tests is the only means of determining whether autonomous aldosterone production has been totally or partially corrected. Such a study has not, to our knowledge, been performed, although we have gone at least part way to achieving that goal.4,16,17With respect to bilateral overproduction of aldosterone, possibly two thirds of the population with PAL, unless agreement can be reached on diagnostic criteria (hampered by differing methodologies in between units), the true value of the ARR in diagnosing this variety of PAL simply cannot be tested.CONCLUSIONSCarefully performed ARR represents a convenient and reliable means of screening for PAL. Its wide application among hypertensives has greatly increased detection of this disorder. The value of the test and its ability to identify patients with PAL (including surgically correctable forms), however, depends on 1) the care with which confounding variables (such as medications) are controlled or their effects taken into account, 2) the reliability of assays used to measure aldosterone and renin, 3) the recognition that repeated measurements of the ARR are more informative than a single estimation, and 4) the care with which further testing is carried out to establish a definitive diagnosis and determine the PAL subtype. 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