The Prevalence of Primary Aldosteronism and Evolving Approaches for Treatment

Abstract

Over six decades since primary aldosteronism was first described, much has been learned about its prevalence and optimal treatment. Estimates of the prevalence of primary aldosteronism have increased considerably over the years, even exceeding 20% in some populations of resistant hypertension. Even in patients with normal blood pressures, the prevalence of overt primary aldosteronism and dysregulated aldosterone production may be more common than appreciated. Emerging data support the concept that primary aldosteronism may be better characterized as a continuum of renin-independent aldosterone production, whose severity influences the clinical presentation and risk for incident cardiovascular disease. Mineralocorticoid receptor antagonists and adrenalectomy are the mainstay treatments for primary aldosteronism and have long been considered equally efficacious. However, recent data suggest that while surgical adrenalectomy can effectively reduce cardiovascular risk, mineralocorticoid receptor antagonist therapy may require a physiologic approach to optimize efficacy.

Introduction

Since primary aldosteronism was first recognized by Jerome Conn in 1954, our understanding of its prevalence and optimal treatment has evolved.¹ Once thought to be a rare and secondary cause of hypertension, primary aldosteronism is now recognized as a common endocrine abnormality that may play a major role in the pathogenesis of a substantial proportion of hypertension incidence. Recognition of its increased prevalence has mirrored the conceptualization of primary aldosteronism as a spectrum of dysregulated aldosterone excess, progressing from a subclinical state to an overt clinical syndrome.² Treatment of primary aldosteronism has historically viewed medical and surgical therapy as equally effective options. Some contemporary research has challenged this dogma, suggesting that under current clinical practice patterns, surgery may more effectively mitigate the excess cardiovascular risk in primary aldosteronism.^3,4,5,6,7,8 This review article will summarize a select collection of studies that have substantially informed our current and evolving understanding of the prevalence of primary aldosteronism and effective approaches towards its treatment.

Prevalence of Primary Aldosteronism

First Description of Primary Aldosteronism and Initial Estimates of Prevalence

In his presidential address to the Annual Meeting of the Central Society for Clinical Research in 1954, Dr. Jerome Conn described the first case of primary aldosteronism in a woman with severe hypertension, hypokalemia, and marked urinary aldosterone excess who was found to have a right adrenal tumor and was cured following adrenalectomy.¹ After this initial description, it was thought that primary aldosteronism was a rare disorder, occurring in no more than 1% of patients with hypertension.^9,10 Yet, Conn himself hypothesized that primary aldosteronism may be much more common, accounting for up to 20% of patients with essential hypertension.^11,12 His rather prescient rationale was that primary aldosteronism may originate in normotensive patients as a milder or subclinical form before it progressed to a more severe phenotype of hypertension and hypokalemia.

Defining primary aldosteronism – Use of the Aldosterone-to-Renin Ratio and Confirmatory Tests

The true prevalence of primary aldosteronism depends on how it is defined and what population is being considered. Primary aldosteronism is defined as a state of inappropriately high aldosterone secretion, independent of renin and angiotensin II, that is not suppressible by volume expansion (salt loading), and can induce elevations in blood pressure and increased cardiovascular risk.

Current clinical guidelines recommend use of the aldosterone-to-renin ratio (ARR) as the initial screening test for primary aldosteronism, having been found superior to isolated reliance on the aldosterone, renin, or potassium alone.^13,14 The most widely accepted criteria for diagnosis of primary aldosteronism are an ARR >/= 30 ng/dl per ng/ml/h with an aldosterone >/= 15 ng/dl and plasma renin activity (PRA) </= 1.0 ng/ml/h.¹³ Yet, these criteria are relatively conservative and may miss milder cases of primary aldosteronism, resulting in a risk of false-negatives. As an example, using a more permissive ARR screening cut-off of 25, Fogari et al confirmed a primary aldosteronism prevalence of 5.9% in a population of 3000 patients with hypertension.¹⁵ The prevalence would have been lower had a more conservative ARR threshold been used. As with any criteria designed to define a disorder that exists on a spectrum, more permissive cut-offs increase sensitivity at the expense of poor specificity (more false positives) whereas the opposite is true of more conservative criteria. Furthermore, the ARR must be interpreted with caution as several drugs and other factors may interfere with its interpretation.^13,16,17 If a patient screens positive for primary aldosteronism on the basis of the ARR, a confirmatory test is generally recommended. The recommended confirmatory tests are predicated on inadequate aldosterone suppression and include oral salt loading, saline infusion, fludrocortisone suppression, and captopril challenge. There are no data to suggest that one test is superior to the others and the choice of test is often based on experience, preference, and availability.^13,18,19 To further complicate diagnostics, although most confirmatory tests focus exclusively on suppressing or inhibiting angiotensin II to demonstrate inappropriate aldosterone production, many cases of primary aldosteronism may have substantial contributions from other secretagogues, such as corticotropin, that are not routinely accounted for.²⁰

The fundamental obstacle in assessing the true prevalence of primary aldosteronism is the lack of a universal gold standard or international consensus for defining the disease. The clinical improvement of blood pressure and hypokalemia following adrenalectomy is the nearest approximation to a potential gold standard; however, the majority of patients with primary aldosteronism do not undergo curative surgery and thus cannot be assessed with this metric.²¹ In the absence of a defined standard, measures of sensitivity and specificity, positive and negative predictive value, as well as the general efficacy of any screening or confirmatory test, must rely on arbitrary thresholds of success. Therefore, since the current diagnostic thresholds for screening and confirmation that we have become accustomed to are based on arbitrary definitions of primary aldosteronism, our estimates of prevalence are consequently relatively arbitrary as well.

Defining the Population

In addition to the interpretation of diagnostic tests, prevalence can also be modified based on the population where this testing is conducted. Prevalence statistics for primary aldosteronism are biased by targeting specific populations, whereas studies that have conducted more systematic diagnostic evaluations have provided a more unbiased perspective on prevalence. Current guidelines recommend screening patients with hypertension that is severe or drug-resistant (defined as three measurements greater than 150/100 mmHg on separate days, greater than 140/90 mmHg despite three conventional anti-hypertensives, or less than 140/90 mmHg on four or more anti-hypertensives), hypertension with diuretic-induced or spontaneous hypokalemia, hypertension with an adrenal mass, hypertension with sleep apnea, hypertension with a family history of early onset hypertension or stroke, and hypertension with a first degree relative with primary aldosteronism.¹³ Despite these recommendations to screen patients with a relatively high pretest probability of primary aldosteronism, current screening practices are not implemented effectively. In a recent study at a large academic medical center to determine how many patients with hypertension and hypokalemia underwent screening for primary aldosteronism, Ruhle et al found that of nearly 37,000 patients, only 2.7% were screened for primary aldosteronism.²² To add to this sober statistic, nearly 50% of these patients with hypertension required 3 or more anti-hypertensive medications, suggesting that despite having severe hypertension and hypokalemia, screening for primary aldosteronism was abysmal. Further, of nearly 11,000 patients with hypertension and sleep apnea, only 3% were screened. If the primary aldosteronism screening rate in a high-risk population is so low, one can imagine that even fewer cases of primary aldosteronism would be detected in patients with milder hypertension or even normotension who fall below the general threshold for screening.

Another caveat to keep in mind is whether the patient population is drawn from primary care or hypertension referral centers. Patients drawn from the latter are expected to have a higher likelihood of primary aldosteronism, but this is not always true. One meta-analysis from 2012 reported a primary aldosteronism prevalence of 4.3% in primary care versus a primary aldosteronism prevalence of 9.5% in a hypertension referral population.²³ A larger and more recent meta-analysis of 39 studies involving over 42000 patients found that the prevalence of primary aldosteronism ranged from 3.2% to 12.7% in primary care and from 1% to 29.8% in referral centers.²⁴ There was marked heterogeneity in this meta-analysis, forcing the authors to conclude that a large, prospective, international trial was needed to more accurately determine the prevalence of primary aldosteronism. With these limitations in mind, we will summarize several individual studies in the following sections that have reported the prevalence of primary aldosteronism in patients with both hypertension and normotension. It is important to note where studies have estimated prevalence from targeted population stratifications that may bias results, and where studies have attempted to estimate prevalence by conducting more systematic diagnostic testing to minimize bias.

Prevalence of primary aldosteronism in patients with hypertension

Among patients with hypertension, estimates of prevalence have generally ranged from as low as 1.0% in a hypertension clinic at a Brazilian university hospital to as high as 36% in patients with resistant hypertension at high risk for sleep apnea.^25,26 With the advent of the aldosterone-to-renin ratio in the 1990s, prevalence estimates of primary aldosteronism have increased, sometimes by as much as 5 to 15-fold.^27,28 In 2002, Rossi et al reported a primary aldosteronism prevalence of 6.3% in an Italian population of over 1000 patients referred to a hypertension clinic.²⁹ In 2004, Omura et al observed a primary aldosteronism prevalence of 6.0% in a similarly sized cohort of hypertensive patients at a general outpatient clinic in Japan.³⁰ Predictably, rates of primary aldosteronism are higher in patients with higher blood pressure. Mosso systematically evaluated 609 patients at a primary care center in Chile using aldosterone-to-renin ratios and confirmatory testing with fludrocortisone, and observed an overall primary aldosteronism prevalence of 6.1%, with prevalence rates of 2%, 8%, and 13.2% in stage I, II, and III hypertension respectively.³¹ In the PAPY study, Rossi et al found an overall primary aldosteronism prevalence of 11.2% in a cohort of over 1100 patients referred to several Italian hypertension clinics; 6.6% of patients with grade I hypertension had confirmed primary aldosteronism whereas 19% of patients with grade III hypertension were found to have the diagnosis.³² A decade later, Monticone et al published a primary aldosteronism prevalence of 5.9% among nearly 1700 Italian hypertensives; 3.9% had primary aldosteronism in the stage I hypertension group whereas 11.8% had primary aldosteronism in the stage III hypertension group.³³ The relatively low prevalence of primary aldosteronism in early stage hypertension was also seen by Williams et al who reported a prevalence of 3.2% in patients with mild to moderate hypertension without hypokalemia.³⁴

While most of the aforementioned studies relied on conventional diagnostic thresholds to define a positive screen and confirmatory test, in one study, conventional confirmatory testing was conducted following a liberalization of screening thresholds. In an effort to not exclude any true cases, Baudrand et al evaluated patients with stage I hypertension and considered a positive screen to include a suppressed renin with aldosterone values as modest as >6 ng/dL.^17,16,13 They subsequently eliminated false-positives by systematically performing salt-suppression tests using conventional diagnostic thresholds and reported a primary aldosteronism prevalence of nearly 20%, thereby highlighting how prevalence estimates can be modulated by changing the arbitrary diagnostic thresholds.¹⁷

Other studies have independently confirmed a primary aldosteronism prevalence above 10% in patients with the most severe forms of hypertension or with the highest pretest probability of primary aldosteronism. Strauch et al reported a primary aldosteronism prevalence of 19% in a Central European population of patients with moderate to severe hypertension.³⁵ In addition, Calhoun and others observed that 20% of patients with resistant hypertension had confirmed primary aldosteronism, with no difference in prevalence between white and black patients.³⁶ Thus, the prevalence of primary aldosteronism in resistant hypertension is approximately 1 in 5, yet even this figure may be an underestimate of the true prevalence since studies have indicated a spectrum of autonomous and renin-independent aldosterone secretion even below the current diagnostic thresholds.

For instance, the randomized, controlled trial PATHWAY-2 sought to determine the optimal fourth antihypertensive agent for patients with resistant hypertension who did not have primary aldosteronism.^37,38 Compared to bisoprolol, doxazosin, and placebo, spironolactone was the most effective fourth drug at lowering blood pressure. An informative observation was made when evaluating when spironolactone was most effective. Spironolactone lowered blood pressure the most among resistant hypertension patients in whom the renin was lowest and aldosterone was highest, highlighting a continuum of renin-independent aldosterone production that preferentially responds to spironolactone and exists below the conventional diagnostic criteria that are employed to recognize primary aldosteronism.

Prevalence of primary aldosteronism in patients with normal blood pressure

The possibility that primary aldosteronism may originate in normotensive patients was initially suggested by Conn in the 1960s and again prominently by Victor Adlin in the 1970s. In a study of 42 healthy patients with normal blood pressure maintained on an extremely restricted sodium diet, he observed that maximally stimulated plasma renin activity was inversely correlated with blood pressure.³⁹ Adlin hypothesized that patients with an inability to maximally stimulate renin, and hence a relative suppression of renin, may have mild aldosterone excess which could manifest with higher blood pressure even within the normal range. Further studies have confirmed these suspicions. In 2017, Adlin’s work was expanded by a large study that found that normotensive individuals with an inability to stimulate renin when sodium restricted had a higher ARR, higher urine aldosterone secretion when sodium loaded, higher blood pressure, and impaired renal-vascular function.⁴⁰

Longitudinal studies have perhaps provided the most robust evidence for a normotensive phenotype of primary aldosteronism. In a cohort of 1688 normotensive subjects in the Framingham Offspring Study, Vasan et al observed that normotensive participants with higher aldosterone levels had a higher risk of incident hypertension and elevations in blood pressure during a four-year observation period.⁴¹ An expansion of this work several years later further highlighted that the normotensive participants with lower renin values and higher aldosterone levels were at the highest risk of developing incident hypertension.⁴² Consistently, in a separate cohort study of normotensives from the Multi-Ethnic Study of Atherosclerosis (MESA), normotensive participants with a suppressed renin had a significantly higher incident rate of hypertension over five years.⁴³ Further, in the context of a suppressed renin phenotype, higher aldosterone levels were associated with a higher risk of incident hypertension. These longitudinal studies collectively describe a spectrum of renin-independent aldosterone production in normotension that is associated with a higher risk for incident elevations in blood pressure and development of hypertension. Thus, even below the current thresholds of diagnosing primary aldosteronism and attributing a categorical prevalence, these data suggest that primary aldosteronism exists over a broad continuum that may be better recognized by focusing on dysregulated aldosterone production rather than arbitrary cut-offs.

In light of the previous studies, perhaps it comes as no surprise that estimates of the prevalence of primary aldosteronism in normotension are quite substantial. In a population of normotensive individuals with suppressed PRA (< 1 ng/ml per hour), 14% of the 210 patients were found to meet confirmatory criteria for primary aldosteronism.⁴⁴ Markou et al reported a similar primary aldosteronism prevalence rate of 13% among a group of 100 normotensive Greek patients who were all subjected to fludrocortisone-dexamethasone suppression testing.⁴⁵ Importantly, patients in Markou’s study with a normotensive primary aldosteronism phenotype were followed for five years and almost all developed categorical hypertension. These studies suggest that primary aldosteronism is a continuum of renin-independent aldosterone excess that arises in normotension, may be biochemically overt even in normotension, and whose prevalence may be underestimated based on restrictive and inconsistently applied screening criteria.

Thus, the prevalence of primary aldosteronism is highly dependent on the population that is evaluated and the arbitrary thresholds employed to consider an ARR as positive or negative, and similarly the variety of confirmatory tests. Table 1 summarizes most studies reporting primary aldosteronism prevalence and organizes them in a manner to highlight the variety of selection biases that influenced the prevalence estimates, whereas Table 2 summarizes several studies that utilized a less biased approach of evaluating the continuum of renin-independent aldosteronism rather than categorizing the condition.

Table 1: The reported prevalence of primary aldosteronism, categorized by populations that evaluated normotensive versus hypertensive participants.

Studies are characterized by the selection bias in determining prevalence as a function of the populations studied and diagnostic testing employed (i.e. use of and type of screening or confirmatory test).

Screening criteria	Confirmatory test	Reported Prevalence	Study Population	Number of participants	Reference
Participants with Normotension
None	Fludrocortisone-dexamethasone suppression test	13%	Normotensives in Greece undergoing confirmatory testing regardless of screening ARR	100	45
None	Oral salt loading	14%	Normotensives in the U.S. with PRA < 1.0 ng/mL/h regardless of ARR	210	44
Participants with Hypertension
Post-captopril ARR >/= 35	Saline infusion	6.3%	Hypertension clinic in Italy	1046	29
ARR >/= 50	Saline infusion	19%	Hypertension clinic in Czech Republic; participants with moderate-to-severe hypertension	402	35
ARR > 25	Fludrocortisone suppression	6.1% total 2% stage I HTN 8% stage II HTN 13.2% stage III HTN	Primary care centers in Chile	609	31
PAC > 12 ng/dl and PRA < 1 ng/ml/h + furosemide upright test	Captopril suppression	6%	Primary care clinic in Japan	1020	30
ARR >/= 40	Captopril suppression	11.2% total 6.6% grade I HTN 15.5% grade II HTN 19% grade III HTN	Hypertension clinics in Italy	1125	32
ARR > 25	Oral salt loading	3.2%	Mild-moderate hypertensives in U.S.	347	34
ARR > 25	Saline infusion	5.9%	Hypertension clinic in Italy	3000	15
ARR > 25	Saline infusion	1%	Hypertension clinic in Brazil	105	25
ARR > 20 on high salt diet + PAC >/= 6 ng/dl and PRA </= 1 ng/ml/h on low salt diet	Oral salt loading	20%	Mild-to-moderate hypertensives in U.S.	241	17
ARR >/= 30	Saline infusion	5.9% total 3.9% stage I HTN 9.7% stage II HTN 11.8% stage III HTN	Identified by primary care providers, subsequently referred to hypertension clinic in Italy	1672	33
None	Oral salt loading	20%	Hypertension clinic in Alabama; all had resistant HTN	88	36
None	Oral salt loading	36%	Hypertension clinic in Alabama; all had resistant HTN + sleep apnea	114	26
Meta-analyses
Variable	Variable	4.3% in primary care 9.5% in HTN referral population	Hypertensive patients	>3500	23
Variable	Variable	3.2–12.7% in primary care 1.0–29.8% in HTN referral population	Hypertensive patients	42510	24

Table 2: Studies which support the concept of primary aldosteronism as a continuum.

Rather than employ categorical thresholds for primary aldosteronism, these studies demonstrated a severity-spectrum of renin-independent aldosterone production that was associated with higher blood pressure or a higher risk for developing incident elevations in blood pressure or hypertension.

Methods	Findings	Population	Reference
Measurement of PRA during sodium restriction	Maximally stimulated PRA inversely correlated with blood pressure	42 normotensive patients	39
Measurement of PAC	Higher aldosterone levels associated with higher blood pressure and more incident HTN	1688 normotensive patients in Framingham cohort	41
Measurement of ARR	Higher ARR associated with higher blood pressure and more incident HTN	3326 normotensive patients in Framingham cohort	42
Double-blind, placebo-controlled, crossover trial comparing efficacy of spironolactone, doxazosin, bisoprolol, and placebo in patients with hypertension despite 3 drugs	Spironolactone most effective fourth anti-hypertensive agent in resistant hypertension, especially in the context of lower renin and higher aldosterone levels	285 participants with resistant hypertension in the UK (PATHWAY-2 and substudy)	37, 38
Measurement of aldosterone and renin	In context of a suppressed renin, higher aldosterone levels associated with a higher incidence of hypertension	850 normotensive patients from the Multi-Ethnic Study of Atherosclerosis cohort	43
Measurement of PRA during sodium restriction	Lower PRA associated with higher blood pressure, lower potassium, and greater autonomous aldosterone production	663 normotensive and mildly hypertensive participants in the U.S.	40

Long-Term Treatment Outcomes of Primary Aldosteronism

Why we treat

There is little debate as to whether primary aldosteronism should be treated. Many studies have shown that patients with primary aldosteronism have a higher risk of adverse cardiovascular events and cardiovascular death when compared to patients with essential hypertension who have the same blood pressure.^46,47 This is thought to arise from the deleterious effects of excessive activation of the mineralocorticoid receptor. In a comprehensive meta-analysis focused on the cardiovascular effects of primary aldosteronism, Monticone et al confirmed higher rates of stroke, coronary artery disease, atrial fibrillation, heart failure, diabetes mellitus, metabolic syndrome, and left ventricular hypertrophy in patients with primary aldosteronism compared to blood-pressure-matched patients with essential hypertension.⁴⁸ There are even data to support that the aldosterone-to-renin ratio is positively correlated to several markers of the metabolic syndrome, including body mass index, blood pressure, low density lipoprotein, and microalbuminuria even in patients who do not have primary aldosteronism.⁴⁹

Dietary interventions

Dietary sodium restriction is an effective method to lower blood pressure in primary aldosteronism. Current guidelines recommend dietary salt restriction for all patients with hypertension, although this can be impractical to implement and patients with primary aldosteronism almost always require additional medical or surgical therapy.⁵⁰ Studies have shown that dramatic reductions in dietary sodium intake can substantially lower blood pressure and raise renin in patients with primary aldosteronism.¹⁷ Further, dietary sodium restriction has been shown to restore the normal nocturnal reduction of blood pressure in patients with primary aldosteronism.⁵¹

Medical interventions

Mineralocorticoid receptor antagonists such as spironolactone or eplerenone are first-line medical treatments for primary aldosteronism and are often employed in bilateral disease or in patients with contraindications to surgery. As seen in the PATHWAY-2 trial and its sub-studies, both spironolactone and the ENaC inhibitor amiloride are superior to other antihypertensives in lowering blood pressure among patients with resistant hypertension.^37,38 The effects are most profound with the highest ARR and aldosterone levels and the lowest renin values. Beyond effects on blood pressure, MR antagonists also ameliorate the adverse cardiovascular and renovascular effects of aldosterone excess. Treatment with spironolactone led to a significant decrease in left ventricular (LV) mass in a cohort of primary aldosteronism patients followed for a mean of 6.4 years.⁵² This significant decrease in LV mass with spironolactone was further confirmed in a much larger meta-analysis published eight years later.⁵³ Mineralocorticoid receptor antagonists have also been found to have positive effects on the kidney, leading to an improvement in urinary albumin excretion with preserved renal function over time.⁵⁴

Surgical interventions

Since primary aldosteronism was first identified by Conn in the 1950s, surgical adrenalectomy has been recognized as an effective treatment, particularly in the setting of a unilateral adenoma identified on cross-sectional imaging and confirmed with adrenal venous sampling. Surgical adrenalectomy has been shown to cure or at least significantly improve the hypertension and hypokalemia associated with primary aldosteronism and even lead to improved quality of life.^55,56,57,58 Surgical adrenalectomy is no worse than medical therapy at reducing left ventricular mass.^52,53 It also appears to be more effective than medical therapy at reducing the likelihood of atrial fibrillation.⁵⁹ The Primary Aldosteronism Surgical Outcome (PASO) study was an important international project to develop consensus criteria for surgical outcomes of adrenalectomy for unilateral primary aldosteronism.²¹ Complete, partial, and absent success of clinical and biochemical outcomes were defined based on blood pressure, use of antihypertensive drugs, plasma potassium and aldosterone concentrations, and plasma renin activities or concentrations. Using these parameters on an international cohort of 705 patients with primary aldosteronism who underwent surgical adrenalectomy, biochemical success as defined by normalization of renin and aldosterone levels was easier to achieve than clinical success as defined by normalization of blood pressure requiring no antihypertensives. An impressive 94% of patients achieved complete biochemical success whereas 37% achieved complete clinical success, with an additional 47% achieving partial clinical success. This persistence of hypertension despite high rates of biochemical cure has been noted by several other studies and is thought to be related to the duration of hypertension and vascular remodeling.^55,57,60 A recent clinical outcomes trial of unilateral adrenalectomy published by Vorselaars and others using an international cohort of 435 patients reported a clinical cure rate of 27%, defined as normotension without any antihypertensive medications.⁶¹ An additional 31% had clear improvement defined as normotension with lower or equal use of antihypertensives with a surprising 41.8% having achieved “no clear success,” although postoperative blood pressure and the number of antihypertensive medications still decreased significantly in this group.

Comparative efficacy of medical and surgical therapy

As we have summarized in the preceding paragraphs, both MR antagonists and adrenalectomy are effective treatments for primary aldosteronism. But, is one treatment more effective than the other? Although this is a basic question, it has been difficult to answer due to the inherent differences and biases in the patients who are selected for one treatment versus the other. Those who undergo unilateral adrenalectomy for an adenoma tend to be younger with more severe hypertension that has developed over a relatively short period of time. Those who are treated medically tend to have bilateral disease which presents in older patients who may have more prolonged hypertension and more medical comorbidities.

A recent large cohort study consisting of 602 patients with primary aldosteronism treated with MR antagonists, 205 patients with primary aldosteronism cured with surgical adrenalectomy, and nearly 42000 patients with essential hypertension who were matched by age and cardiovascular risk profiles, evaluated the risk of developing long-term adverse outcomes.^3,4 Despite having comparable blood pressures, the medically-treated patients had substantially higher rates of cardiovascular events (myocardial infarction, heart failure hospitalization, stroke), atrial fibrillation, diabetes mellitus, and all-cause mortality when compared to patients with essential hypertension. In contrast, patients with surgical cure had a lower risk for developing these incident events. Perhaps most interesting in these observations was the fact that the higher risk for adverse outcomes was driven by patients who had a suppressed renin activity (< 1 ng/mL/h) during treatment with a mineralocorticoid receptor antagonist. In contrast, patients treated with a mineralocorticoid receptor antagonist such that their renin substantially rose (>1 ng/mL/h), a biomarker of sufficient volume contraction, had the same risk for incident outcomes as matched patients with essential hypertension. These findings implicated renin as a biomarker of treatment efficacy by reflecting a contracted volume status and indirectly the efficacy of mineralocorticoid receptor antagonism in primary aldosteronism. Another study by Hundemer et al found higher rates of incident CKD and estimated GFR decline in medically-treated primary aldosteronism patients compared to blood-pressure-matched essential hypertension and surgical adrenalectomy patients.⁵ Similar to Hundemer’s findings, when other studies have found evidence of superiority of one form of treatment over the other, surgery is usually favored. Patients treated with surgery have been shown to require less follow up, achieve higher quality of life scores, and are less likely to develop type 2 diabetes than their counterparts treated with MR antagonists.^6,7,8

Overall, outcome studies suggest that the optimal treatment of primary aldosteronism is surgical therapy to eliminate or attenuate the source of inappropriate aldosterone production. If surgery is not feasible, then dietary sodium restriction, blood pressure control, and MR antagonist therapy to target a rise in renin as a proxy for sufficient MR blockade may be the most effective approach at mitigating incident adverse events. A major caveat of these aforementioned studies is their observational study designs which do not limit confounding and bias; randomized and prospective intervention studies to validate these findings are still needed.

Emerging treatments – radiofrequency ablation

Radiofrequency ablation (RFA) is an emerging treatment for primary aldosteronism caused by an aldosterone-producing adenoma. Although robust, large, and long-term data to support its efficacy are not yet available, the procedure is gaining in popularity at some centers. The procedure, performed by an interventional radiologist under CT guidance, leads to destruction of adenoma tissue via delivery of a high-frequency current through a percutaneously-inserted RFA needle. In an early prospective cohort trial of 24 patients, the technique was shown to be safe and effective, with an overall success rate of 95.8%.⁶² A similarly high success rate and similarly low complication rate were also found in a subsequent study involving a slightly larger cohort of 36 patients.⁶³ When compared to surgical adrenalectomy in a retrospective comparative study, however, RFA was associated with lower rates of clinical and biochemical resolution of primary aldosteronism.⁶⁴ One possible reason for this that needs to be critically examined is that even following lateralization on adrenal venous sampling, the culprit lesions of the inappropriate aldosterone production may not be the dominant adenoma; the culprit may be one or many small adenomas (not always distinguished on cross-sectional imaging), non-neoplastic aldosterone producing cell clusters, or a heterogeneous mix of inappropriate aldosterone synthase expression and neoplastic tissue.^65–69 These assessments could only be confirmed on histopathology, which is not available with the RFA procedure. Indeed, adrenal neoplasia is common and can often be incidental and unrelated to the underlying pathology of primary aldosteronism. As our understanding of the heterogeneity of primary aldosteronism improves, many more studies will be needed to adequately evaluate the comparative efficacy and specific indications of RFA before it can be recommended as a generally accepted alternative to surgical therapy.

Conclusion

Much has been learned about primary aldosteronism since it was first described by Conn over six decades ago. Conn himself posited that primary aldosteronism was more common than initially appreciated and may originate in a mild or subclinical form before it blossomed into the syndrome of dramatic hypertension and hypokalemia like that of his first patient cured with unilateral adrenalectomy. Prevalence rates are hard to define, but range from a low estimate of 1.0% to a high estimate of 36% of patients with resistant hypertension and sleep apnea. The prevalence may be substantial even in normotensive individuals, but these patients are not often screened for the disorder. Mineralocorticoid receptor antagonists and surgical adrenalectomy can be effective treatments for primary aldosteronism with favorable outcomes. Radiofrequency ablation is an emerging therapy with mixed data. More recent studies have demonstrated improved cardiovascular outcomes with surgical adrenalectomy compared to medical treatment, suggesting that the former should be chosen when possible. However, MR antagonist therapy at a sufficient dose to raise the plasma renin activity may approach the efficacy of surgical adrenalectomy.