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Clinical Endocrinology (2003) 59, 427 – 430
Commentary
Primary aldosteronism, diagnosed by the aldosterone to
renin ratio, is a common cause of hypertension
Pitt O. Lim* and Thomas M. MacDonald†
(n = 56, 161/98 mmHg to below 140/90 mmHg) of patients with *Department of Cardiology, Wales Heart Research mild hypertension with the ‘best’ monotherapy but only 39% Institute, University of Wales College of Medicine, when a random approach was adopted. Furthermore, it appeared Cardiff and †Hypertension Research Centre, that the plasma renin activity weakly but significantly predicted Department of Clinical Pharmacology and Therapeutics, the response to ACE inhibitors and β-blockers, and that older University of Dundee, Ninewells Hospital and Medical patients responded better to calcium channel blockers and diuretics. This important study suggests that if a better BP controlis to be achieved more widely, drug treatment should be tailored (Received 17 February 2003; returned for revision 3 March 2003; finally revised 20 March 2003; accepted 31 March 2003) individually according to the prevailing haemodynamics orneurohormonal status.
This article will focus on a simple diagnostic test, the aldosterone-to-renin ratio (ARR) as a marker of inappropriate Blood pressure (BP) control in hypertensives in general remains aldosterone activity in hypertensive patients. We believe that suboptimal, with less than a quarter of those treated having identifying such individuals allows tailoring of effective treat- controlled BP in western societies and even less in developing ment targeted at the neurohormonal abnormality. In other words, nations (Anonymous, 1997; Chamontin et al., 1998; Colhoun these patients with a high ratio have a form of primary aldos- et al., 1998; Joffres et al., 1997; Marques-Vidal & Tuomilehto, teronism (PA) that responds well to aldosterone antagonists.
1997). It is thus unsurprising that a recent report suggested that The ARR was first tested clinically by Hiramatsu et al. (1981).
hypertension remains a major modifiable risk factor worldwide It was then adopted by the Brisbane group (Gordon, 1994) contributing to global mortality (Ezzati et al., 2002). Importantly, who suggested (controversially) that the prevalence of primary it has been clearly shown that controlling BP offers significant aldosteronism in hypertension could be much higher than benefits. A 5-mmHg reduction in the population diastolic BP over previously suspected. Indeed, this group reported that, from 1987, 5 years is associated with a reduction in strokes of about 40% when the test was first applied to normokalaemic patients, the and cardiac events by about a quarter, highlighting the need for cases of PA diagnosed at their centre rose exponentially from less adequate BP control (Collins et al., 1990; MacMahon et al., than 10 per year to between 50 and 100 each year. Over the last 1990). There are many potential reasons why BP control is poor 5 years, numerous other centres worldwide have also reported in those diagnosed with the disease. This is not due to the lack a much higher prevalence of PA of between 5% and 32% as of anti-hypertensive agents as we now have an ever expanding compared to the traditional textbook PA prevalence of less than armamentarium of drugs that are better tolerated. We believe that 1% (albeit using different methodologies; Stowasser, 2001).
one problem with the current practice in hypertension manage- Plasma renin activity and aldosterone levels each vary markedly ment is that hypertension treatment is empirical, that the choice with posture and salt status. In theory, the ratio between the two, of drugs is dictated more by large drug trials based on populations the ARR, varies to a lesser extent. The ratio is derived by dividing rather than based on the individuals. There is thus a dissociation the plasma aldosterone level by the plasma renin activity. This between the underlying pathophysiology and drug therapy.
ratio capitalizes on the divergence between the two neurohor- The heterogeneity of hypertension as a disease has been well mones. In patients with PA, the plasma aldosterone level is demonstrated by Dickerson et al. (1999), who found that by a high and this, via a negative feedback system, suppresses renin process of drug rotation through the four major classes of anti- production, the level of which provides the denominator of the hypertensive drugs (ACE inhibitors, β-blockers, calcium channel ratio. Hence in PA the ratio puts into context any given aldosterone blockers and diuretics), they could adequately control 73% level. Thus the importance of a ‘high normal’ aldosterone isamplified by a low renin status. In contrast, subjects with a ‘high This paper has been presented as a debate in the Society for normal’ aldosterone and high renin are less likely to have PA, the changes in plasma aldosterone mirroring that of renin and Correspondence: Dr Pitt O Lim, British Heart Foundation Clinical Lecturer in Cardiology, Department of Cardiology, Wales Heart Research The ARR has been criticised by some who claim that the ratio Institute, University of Wales College of Medicine, Heath Park, is overly renin-dependent (Montori et al., 2001). This is because Cardiff, CF14 4XN, UK. Tel: +44 29 2074 7747, ext. 6060; Fax: +44 29 2074 3500. E-mail: pittlim@doctors.org.uk plasma renin activity cannot be accurately measured in many centres below a minimum value of 0·3 ng /ml /h. Some groups, without an adenoma (Lim et al., 2001). Although we and others including the Mayo Clinic group, have proposed interpreting have compelling clinical experience as to the efficacy of spironol- the ARR in conjunction with a plasma aldosterone threshold actone in patients with a raised ARR, as yet we do not have any to overcome this renin dependency (Young, 1999). Despite this properly randomized study to support our claim. There are, more stringent definition of PA, the Mayo Clinic group have however, two ongoing randomized drug trials, one in Scotland largely reproduced the Brisbane experience (Young, 2002).
and one in Cambridge assessing whether spironolactone offers Alternatively, actual renin concentration can be measured superior BP control over other diuretics in patients with a raised directly using immunoreactive techniques. However, at present there are no good published data on ARR using such total renin The use of ARR in hypertension management has raised many rather than plasma renin activity so the jury is out for now.
more questions about the ‘apparent’ epidemic of PA or those with Nevetheless, the predictive value of ARR used to signal PA is inappropriately increased aldosterone activity. Some authorities dependent on the threshold used; the higher is the ratio, the more use the ARR as the first step in a diagnostic pathway (Young, likely that PA is present. We now know from the PHarst study 2002). Until such time that we have clear support from rand- (Hood et al., 2001) that β-blockers (by suppressing renin) elevate omized drug trials, this whole area remains speculative except the ratio and that ACEI (by stimulating renin) suppress it. So a that the data from the PHarst study are quite convincing. Never- marginally high ARR in a patient taking a β-blocker should be theless, the next step would obviously be to explore the origin viewed with caution but a marginally high ARR in a patient of this inappropriate aldosterone activity, whether there is a taking an ACEI is likely to be diagnostic. Calcium blockers and genetic component and if there is an interaction with environ- diuretics do not appear to interfere with the ratio (Lim et al., 2002a).
mental factors. These are important questions, especially when Whether it is worthwhile looking for PA amongst hyper- one considers that at least 10% of hypertensives have a degree tensives, first and foremost it has to be demonstrated that such of inappropriate aldosterone production.
patients can be effectively treated. We have reported that in We have looked at a large cohort of hypertensives with regard hypertensive patients with a raised ARR alone, monotherapy with to aldosterone synthase genetic variation and how this relates the aldosterone antagonist spironolactone (low dose, 25 – 50 mg to the ARR (Lim et al., 2002b). Aldosterone synthase is the daily) can effectively control BP in nearly half of those who rate-limiting enzyme in the production of aldosterone. The gene previously had resistant hypertension or needed multiple drugs (CYP11B2) which encodes for this enzyme has a couple of for effective BP control (Lim et al., 1999). This observational genetic variants that have been reported to influence the activity study involved 28 hypertensive patients with a raised ARR ≥ 750 of the enzyme. One polymorphism affects a putative steroidog- and poorly controlled BP despite being on multiple drug therapy.
enic factor-1 binding site(-344 T/C) in the 5′-regulatory region, Spironolactone was added to their existing treatment regimen whereas the other marker reflects replacement of the intron-2 and they were followed up over a mean period 12·9 months.
from CYP11B2 with that from the neighbouring gene encoding Spironolactone significantly reduced the need for antihyper- 11 β-hydroxylase (CYP11B1; wild-type/conversion). We found tensive drugs by a mean of 0·5, as well as reducing the mean BP significant excesses of the SF-1 T and intron-2 conversion alleles by 15/8 mmHg. Hence spironolactone improved BP control and in patients with a raised ARR. Interestingly, we also found an at the same time also reduced the need for polypharmacy in these association between the number of such ‘deleterious’ alleles patients. The Cambridge group led by Morris Brown extended our present in each individual with the likelihood that a raised ARR observation that ARR could predict response to spironolactone was present (see Fig. 1). Furthermore, this risk of a raised ARR treatment. They conducted a large community-based study appeared to increase with age in individuals homozygous for such involving 529 unselected hypertensive patients and found that alleles. This raises the possibility that some individuals might 12·3% of the study population had ARR > 800 (PHarst study).
have genetic susceptibility to develop inappropriate aldosterone Consistent with what we have found, 70% of these patients with activity but that they require an environmental stimulus to a raised ARR responded (as defined by a BP fall of ≥ 20 mmHg) express this. Thus PA may be acquired in genetically susceptible favourably to 50 mg spironolactone treatment with a mean BP individuals (Lim et al., 2002c).
reduction of 32·3/12·7 mmHg. Whereas of those with an ARR In our PA case series (Lim et al., 2000), those without an of 400 – 800, only 40% dropped their BP ≥ 20 mmHg with adrenal adenoma on CT scanning predominated and indeed with spironolactone treatment. This is strong evidence that the ARR the use of ARR as a screening tool, the traditional ratio of three could be used as a guide for drug therapy in hypertension. A adenomas to one idiopathic hyperaldosteronism (IHA) for PA is recent literature review that we have conducted found that in reversed. In our experience therefore most patients with PA patients with demonstrable PA on dynamic tests, spironolactone diagnosed using the ARR have IHA. These are older patients with reduced BP by 16 –32%/17–31% (systolic/diastolic) and that this high plasma aldosterone level but not as high as can be found in drug was well tolerated even in the long-term in patients with or patients with an adenoma, who are usually younger. We propose 2003 Blackwell Publishing Ltd, Clinical Endocrinology, 59, 427 – 430
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Fig. 1 The relationship between the number of deleterious alleles and
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Hiramatsu, K., Yamada, T., Yukimura, Y., Komiya, I., Ichikawa, K., Ishihara, M., Nagata, H. & Izumiyama, T. (1981) A screening test toidentify aldosterone-producing adenoma by measuring plasma reninactivity. Results in hypertensive patients. Archives of International that IHA as a cause of PA is an acquired disease in genetically Mediciney, 141, 1589–1593.
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In conclusion, we believe that primary aldosteronism is probably a common form of hypertension. Such hypertension Lim, P.O., Jung, R.T. & MacDonald, T.M. (1999) Raised aldosterone appears aldosterone-driven, is identified quite easily by the ARR to renin ratio predicts anti-hypertensive efficacy of spironolactone.
and is effectively managed with appropriate treatment. There are A prospective cohort follow-up study. British Journal of Clinical
Pharmacology, 48, 756–760.
theoretical reasons as to why a relative excess of aldosterone in Lim, P.O., Jung, R.T. & MacDonald, T.M. (2002) Is aldosterone the itself may be deleterious (Rocha & Funder, 2002) but the most missing link in refractory hypertension?: aldosterone-to-renin ratio compelling reason for appropriate management of this form of as a marker of inappropriate aldosterone activity. Journal of Human hypertension is the much improved BP control achieved using Hypertension, 16, 153–158.
spironolactone in this subgroup of hypertensive patients who Lim, P.O., MacDonald, T.M., Holloway, C., Friel, E., Anderson, N.H., Dow, E., Jung, R.T., Davies, E., Fraser, R. & Connell, J.M. (2002) have been difficult previously to control.
Variation at the aldosterone synthase (CYP11B2) locus contributes
to hypertension in subjects with a raised aldosterone-to-renin
ratio. Journal of Clinical Endocrinology and Metabolism, 87, 4398–
Acknowledgement
Dr Lim is funded by the British Heart Foundation.
Lim, P.O., Struthers, A.D. & MacDonald, T.M. (2002) The neurohormonal natural history of essential hypertension: towards primary or tertiary
aldosteronism? Journal of Hypertension, 20, 11–15.
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2003 Blackwell Publishing Ltd, Clinical Endocrinology, 59, 427 – 430

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