This article discusses the diagnosis of aldosteronism and hypertension management
Jacopo Burrello MD
Andrea Falcetta MD
Franco Veglio MD
Paolo Mulatero MD
Department of Medical Sciences,
Division of Internal Medicine and Hypertension, University of Torino,
Torino, Italysis of primary aldosteronism and hypertension management
Hypertension is the most frequent modifiable cardiovascular risk factor and a continuous relationship between blood pressure, cardio- and cerebrovascular fatal and non-fatal events has been extensively demonstrated.1 Overall, the prevalence of hypertension ranges between 30% and 45% in the general population, but increases steeply with ageing, thereby representing one of most important contributors to mortality and morbidity in Western countries. In light of these considerations, it becomes clear that adequate control of blood pressure is an issue of enormous public health importance.
The evaluation of the activity of the renin–angiotensin–aldosterone system (RAAS) by measurement of renin and aldosterone levels is a fundamental step in the assessment of hypertensive patients. In fact, measurement of these two hormones plays a central role in the diagnosis of primary aldosteronism (PA) (which is a major cause of resistant hypertension) and in guiding clinicians in the management of essential hypertensive patients.
Aldosterone and renin measurements for diagnosis of PA
PA is the most frequent form of secondary hypertension, accounting for 4–5% of the hypertensives in the general population and for up to 10–11% in tertiary referral hypertension centres.2 PA exclusion is of fundamental importance because affected hypertensive patients develop myocardial infarction, ischaemic and haemorrhagic stroke, heart failure and arrhythmias more frequently than essential hypertensives with similar blood pressure levels and cardiovascular risk profiles.3 This excess of cardiovascular risk is determined by the detrimental effects of aldosterone on target organs, which are at least partially independent from the effects on blood pressure.4
Ideally, all hypertensive patients should be screened for PA, at least those that are newly diagnosed and of relatively young age (for example, younger than 50 years of age); however this is not always feasible. The Endocrine Society (ES) guidelines suggest to screen the categories of patients with a high prevalence of the disease,5 including hypertensive patients at stage 2 and 3, drug-resistant hypertensive patients (where PA prevalence can be as high as 20%), hypertensive patients with spontaneous or diuretic-induced hypokalaemia, hypertension with adrenal incidentaloma, or hypertensive patients with suspected familial hyperaldosteronism.5
Other groups of patients displayed an increased PA prevalence,6 but the indication for a systematic screening of these patients is still debated. This group comprises hypertensive patients with metabolic syndrome, obstructive sleep apnoea syndrome or type II diabetes associated with resistant hypertension.6 A systematic discussion of the populations that should be screened for PA is reviewed elsewhere.6
The screening test suggested by the ES guidelines is the aldosterone to renin (or plasma renin activity) ratio (ARR).5 In fact many PA patients have aldosterone levels within the normal range but associated to suppressed renin levels: these patients would be missed if the ARR is not calculated. However, it should be taken into account that a minimum aldosterone concentration (for example aldosterone >10–15ng/dl) is required together with an increased ARR, to avoid considering the ARR as positive in the presence of low aldosterone and a very suppressed renin levels as observed in some conditions (for example liquorice abuse, Liddle’s syndrome etc.).7 It should be noted that hypokalaemia is not considered anymore a prerequisite for pursuing diagnostic tests for PA, since only a minority of PA patients are hypokalaemic at diagnosis (20–40%).8
The screening test should be requested by the general practitioner and performed in sitting position in the morning as for the other blood tests (recumbent and standing measurement of aldosterone and renin is not required anymore). It is important to underline that hormone measurements should be performed without any interfering antihypertensive medication.5
Ideally, ARR should be measured after withdrawal of antihypertensive drugs; when this is not feasible, drugs that are relatively neutral on aldosterone and renin levels can be administered to the patients. In particular, α1-adrenergic receptor blockers (doxazosin, terazosin, prazosin) and non-dihydropyridine calcium channel blockers (CCB) (verapamil and diltiazem) have minimal effects on renin and aldosterone levels and can be used to control hypertension during case findings and confirmatory testing.5
However, in some patients with resistant hypertension more drugs are necessary to keep blood pressure levels reasonably under control: in these cases dihydropyridine CCBs, angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) can also be used. This point is in favour of performing the screening at diagnosis of hypertension or at least before the introduction of a diuretic. Due to the variability of aldosterone and renin assays the ES does not suggest a definite cut-off for the ARR.5 Most units use an ARR cut-off value of 2.4–3.3 (ng • dl-1/mU • L-1) if plasma renin concentration is used and 30–40 if plasma renin activity is measured (ng • dl-1/ng • ml-1 • h-1).
All patients with an increased ARR should undergo a confirmatory/exclusion test for final confirmation of the non-suppressibility of aldosterone secretion and therefore PA diagnosis.
The ES guidelines suggest four possible tests to confirm/exclude PA diagnosis in patients with an increased ARR.5 These test are the fludrocortisone suppression test, the oral or intravenous saline load test and the captopril challenge test. A systematic discussion of the characteristics and performance of the different confirmatory tests for PA is reviewed elsewhere.9 In our unit we perform the intravenous saline loading test by infusing two litres of 0.9% NaCl in four hours (500ml/h). If aldosterone levels are suppressed after the test (<5ng/dl) PA is excluded, if not (>10ng/dl) PA is confirmed. Intermediate values are considered a grey zone but most authors also considered these patients as affected by PA. The captopril test, which displays lower accuracy than the intravenous saline load test, should be used only when the patient is at risk for volume expansion.9 Once PA is confirmed, affected patients should undergo subtype differentiation.
All PA patients with a confirmed diagnosis should undergo subtype differentiation to be addressed to targeted therapy. PA is a wide spectrum of disorders comprising both sporadic and familial forms.10 Distinction between sporadic unilateral (aldosterone producing adenoma, unilateral adrenal hyperplasia and aldosterone-producing carcinoma) and bilateral (bilateral adrenal hyperplasia) forms should be made by thin-cut adrenal computed tomography scanning with contrast and adrenal vein sampling.11,12 A detailed description of subtype differentiations strategies is beyond the scope of the present review and is discussed elsewhere.11,12
Use of the RAAS assessment in essential hypertension
Most essential hypertensive patients are treated empirically with one or more antihypertensive drugs and display a marked heterogeneity of blood pressure response to different therapies, which is probably determined by the diversity in the pathophysiological mechanisms involved in essential hypertension.
At best, no more than 30–40% of hypertensive patients display controlled blood pressure levels and usually more than 50% are not controlled with a monotherapy. How does the healthcare professional choose among 10 classes (>60 compounds) of antihypertensive drugs? The European Society of Hypertension/European Society of Cardiology guidelines do not prefer a single class of drugs but leave to the clinician the choice of the first-line treatment for a single patient, from a group of preferred classes of drugs (CCBs, ARBs, ACE-Is, diuretics and β-blockers, BB).1 RAAS profiling has been proposed as a useful means to clarify the main pathophysiological alterations in the single patient and to guide the clinical decision-making process providing the most appropriate choice for a definite patient.13
Laragh’s hypothesis is based on the classical formula regulating blood pressure, which is determined by peripheral vascular resistances and blood volume. Patients are divided into two groups: low renin hypertensives (LRH) and normal high renin hypertensives (NHRH). According to Laragh’s hypothesis,13 LRHs are relatively more expanded in volume and therefore they will probably respond more to therapy with diuretics or CCB, whereas NHRH will probably respond better to ACE-Is, ARBs or BB.13 The cut-off for low renin is variable between studies, 7.8–12mU • L-1 if plasma renin concentration is used and 0.65–1ng • ml-1 • h-1 if plasma renin activity is measured. If blood pressure is still not controlled in monotherapy, renin can be measured again and a CCB or a diuretic should be added into the therapy if renin is suppressed, and an ACE-Is or ARBs if renin is high. The British Society guidelines use this theory in their recommendations: they suggest to use an ACE-I or an ARB as the first drug for patients younger than 55 years (excluding Black ethnics), a population with higher frequency of normal high renin hypertension, and to use a CCB or a diuretic for patients older than 55 years or Black ethnics (that are groups of patients frequently displaying low renin values) (www.nice.org.uk/guidance/CG127).
However, Laragh’s strategy has proved to be more effective than the therapeutic strategy following British guidelines or than thiazide diuretic therapy.14 In another study, renin-guided therapy improved control and reduced blood pressure better than a clinical hypertension specialist care (which is unavailable for most hypertensive patients), indicating that renin-guided therapeutic choice provides a reasonable strategy for treating hypertensive patients.15 In other studies, renin levels have been shown to be a strong and independent predictor of blood pressure response to BB, diuretics, ACE-Is, CCB and ARBs and is more reliable than any biochemical parameter, sex, age or ethnicity.16 It should be noted that the reduction of the number of drugs necessary to optimise blood pressure control largely exceeds renin measurement in terms of cost.13
The assessment of the RAAS activity by measuring renin and aldosterone levels should be considered as a routine evaluation in all hypertensive patients. Firstly, it is of fundamental importance to rule out secondary hypertension and in particular PA; the renin assay is also very useful to help the clinician in the choice of the class of drugs to treat essential hypertensive patients, resulting in a reduced number of drugs needed, reduction of costs and improved blood pressure control.
- ESH/ESC Task Force for the Management of Arterial Hypertension. 2013 Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens 2013;31:1925–38.
- Hannemann A, Wallaschofski H. Prevalence of primary aldosteronism in patient’s cohorts and in population-based studies -a review of the current literature. Horm Metab Res 2012;44:157–62.
- Mulatero P et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. J Clin Endocrinol Metab 2013;98:4826–33.
- Mulatero P et al. Mineralocorticoid receptor blockade in the protection of target organ damage. Cardiovasc Hematol Agents Med Chem 2006;4:75–91.
- Funder JW et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93:3266–81.
- Monticone S et al. Primary aldosteronism: who should be screened? Horm Metab Res 2012;44:163–9.
- Mulatero P et al. Diagnosis and treatment of low-renin hypertension. Clin Endocrinol (Oxf) 2007;67:324–34.
- Mulatero P et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004;89:1045–50.
- Mulatero P et al. Confirmatory tests in the diagnosis of primary aldosteronism. Horm Metab Res 2010;42:406–10.
- Mulatero P et al. Role of KCNJ5 in familial and sporadic primary aldosteronism. Nat Rev Endocrinol 2013;9:104–12.
- Mulatero P et al. Differential diagnosis of primary aldosteronism subtypes. Curr Hypertens Rep 2009;11:217–23.
- Monticone S et al. Adrenal vein sampling in primary aldosteronism: towards a standardised protocol. Lancet Diabetes Endocrinol. 2014 May 12. pii: S2213-8587(14)70069–5. doi: 10.1016/S2213-8587(14)70069–5. [Epub ahead of print]
- 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;24:1164–80.
- Schwartz GL et al. The role of plasma renin activity, age, and race in selecting effective initial drug therapy for hypertension. Am J Hypertens 2013;26:957–64.
- Egan BM et al. Plasma Renin test-guided drug treatment algorithm for correcting patients with treated but uncontrolled hypertension: a randomized controlled trial. Am J Hypertens 2009;22:792–801.
- Suonsyrjä T et al. Renin-angiotensin system and alpha-adducin gene polymorphisms and their relation to responses to antihypertensive drugs: results from the GENRES study. Am J Hypertens 2009;22:169–75.