Hyperaldosteronism 2025 guidelines

 Hyperaldosteronism 2025 guidelines

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Modest, Geoffrey (HMFP - Medicine)

​Modest, Geoffrey (HMFP - Medicine)​

 

a recent clinical practice guideline for primary aldosteronism was just published by the Endocrine Society: see aldosteronism practice guideline JClinEndoMetab2025 in dropbox, or doi.org/10.1210/clinem/dgaf284). this is a 43 page document, so i will present their major recommendations applicable to the primary care outpatient setting, with my commentary (thanks to Ian Huntington for bringing this to my attention)

Recommendations

-- All patients with hypertension should be screened for primary aldosteronism (PA) by measuring aldosterone and renin levels, and determining the aldosterone-to-renin ratio

    -- very little direct data supporting this (only one large retrospective VA study), finding that very few people were screened for PA (1.6%)

        -- international studies in Canada, Australia and several European countries confirm dismally low levels of screening

    -- observational studies have found PA in 5-14% of hypertensive people (see below for the cutpoints of tests defining PA )

    -- high aldosterone, especially with low renin, is associated with increased BP and cardiovascular events as well as chronic kidney disease (CKD) and microalbuminuria

    -- low renin levels, independent of the aldosterone level, are associated with higher cardiovascular risk than renin-dependent aldosteronism

    -- people in the ARIC study with subclinical PA (ie, the "dysregulated group" as in the prior blog: https://gmodestmedblogs.blogspot.com/2025/09/resistant-hypertension-are-diuretics.html) had increased cardiovascular dysfunction (including atrial fibrillation) at low renin levels and high aldosterone but with aldosterone levels that are below the PA cutpoints

        -- these guidelines also comment that "a systematic review and meta-analysis demonstrated that MRAs [mineralocorticoid receptor antagonists] are superior to routine antihypertensive therapy (eg ACE inhibitors, ARBs) in treating low-renin hypertension, which is the typical diagnosis given to individuals with suspected PA who do not meet diagnostic criteria for PA" (ie, they support the recommendations per the last blog), and that 20% of those with positive aldosterone/renin ratios but negative aldosterone suppression test (ie, a false-positive screening test) may develop PA over time

        -- though we all learned that hypokalemia is a hallmark of PA, its presence is not frequent (9%-37% of the time), and many people have totally normal potassium levels. Hypokalemia has been associated with more severe forms of PA and is more common in those who have lateralizing adrenal adenomas

    -- if the individual's initial PA screen is negative, it is important to see if there are factors that could lead to a false negative result: e.g. hypokalemia (needs to be corrected and normalized, or could lead to false negative) as well as medications such as being on mineralocorticoid receptor antagonists (should be off them for four weeks), diuretics (should be off them for four weeks), ACE/ARB (should be off them for two weeks)

-- individuals who have a positive screen for PA and a lateralizing adrenal adenoma should either have surgical therapy, or medical therapy with a PA-specific med (eg MRA), in those who are not candidates for surgery or are not interested in surgery

    -- the guidelines recommend surgery over medical therapy in those qualifying for surgery (unilateral adenoma). a recent article confirmed the advantages of surgery over medical therapy (see below)

-- it is reasonable to do aldosterone suppression testing (eg oral sodium suppression test, captopril suppression test, or saline suppression test; these are felt to be the three best tests of the ten that are available) when the screening results indicate an intermediate probability of a surgically correctable lesion

    -- several studies in different countries have supported that this regular screening of hypertensive patients for PA is cost-effective, even if patients receive the downstream testing/treatment (aldosterone suppression testing, venous sampling for aldosterone, surgery when appropriate), given the long-term benefit in decreasing complications associated with untreated PA

-- however, those having a high probability of accurate radiologic assessment of a lateralizing and appropriate surgical lesion (for example, those <35yo,  with adenomas > 1.0 cm on CT screening and hypokalemia are much more likely to have unilateral adenomas, though there are no RCTs to support this conclusion). so in that case there is no need for an aldosterone suppression test

-- the converse is also true: aldosterone suppression testing can be avoided if the likelihood of lateralizing PA is very low (normokalemia, serum aldosterone < 11 ng/dL (305 pmol/L)). 

-- in general, testing should include adrenal lateralization with both CT or MRI scan as well as adrenal venous sampling prior to the decision for surgical intervention

   -- typically, CT or MRI screenings by themselves are inadequate:

        -- people with PA considering surgery should have adrenal lateralization with CT scanning and adrenal venous sampling prior to deciding on the treatment approach, except in circumstances where the diagnosis of unilateral aldosterone or any aldosterone producing adenomas is so highly likely, as noted above

            -- For example, some patients with microadenomas on CT actually have hyperplasia, making  a unilateral adrenalectomy inappropriate; and some with unilateral adrenal micro/macro adenomas may have nonfunctioning adenomas, as is common in those over 35 years old

        -- the issue here is that the sensitivity and specificity of CT scans for determining  the presence of a unilateral adenoma is poor: a systematic review of 38 studies with 950 individuals having CT/MRI scanning as well as selective adrenal venous sampling (AVS) as the gold standard for lateralizing a functional adenoma, found that 37.8% of the time the CT/MRI misdiagnosed an adenoma

        -- and some patients with small unilateral adenomas may not be visible on CT scans

-- also, for individuals with PA and a radiologic adrenal adenoma, there should be a 1 mg overnight dexamethasone suppression test

    -- the issue is that there could be a concurrent Cushing's syndrome along with PA; a systematic review found a prevalence of both in 5% to 27% of 2862 individuals having an adenoma. It is also important to measure an early-morning cortisol following adrenal surgery given that there could be a period of possible glucocorticoid insufficiency. And, of course, it is really important clinically to detect and treat Cushing's syndrome

    -- and an abnormal dexamethasone suppression test may complicate the interpretation of adrenal vein selectivity and lateralization of aldosterone production

-- they suggest the use of spironolactone over other mineralocorticoid receptor antagonists given its lower cost and greater availability (agreeing with the prior blog: https://gmodestmedblogs.blogspot.com/2025/09/resistant-hypertension-are-diuretics.html) though other MRA antagonists can be titrated to achieve equivalent potencies

    -- though spironolactone certainly is associated with adverse effects, these can be minimized by commencing at low doses of 12.5 to 25 mg daily and increasing the dose gradually (e.g. every 2 to 3 months, sooner if clinically necessary)

    -- for those on MRAs, their renin level may be monitored; in those with hypertension that remained uncontrolled and their renin is still suppressed, the MRA can be titrated to higher doses to increase the renin level, though this can be more complex if patients are on medications that affect renin levels

         -- which, to me, brings up the unanswered question: they confirm, per above, that low renin levels are independently associated with higher cardiovascular events. so, should we be treating the hypertension with spironolactone to achieve normal blood pressure, or should we measure renin levels and continue titrating the spironolactone dosage to normalize circulating renin concentrations???

-- non-MRA meds, such as Epithelial Sodium-Channel Inhibitors (including amiloride, the best studied, and triamterene) have insufficient high-quality data, but it seems in some studies that the hypertension benefit of high dose amiloride is similar to high-dose spironolactone. The concern (untested) is that these meds are not MRAs, would not block aldosterone directly, and may not necessarily provide the same protection in aldosterone-specific end-organ injury

-- the cutpoints for defining PA are: 

    -- plasma renin activity (PRA) <= 1 ng/ml/h, or direct renin concentration (DRC) <= 8.2 mU/L

    -- aldosterone (immunoassay) >= 10 ng/dL (>277 pmol/L), or (LC-MS/MS) >= 7.5 ng/dL >=208 pmol/L)

 AND

    -- aldosterone-to-renin ratio (ARR):

        -- aldosterone (immunoassay, ng/dL)/PRA (ng/mL/h) >20 ,or aldosterone (immunoassay, pmol/L)/DRC (mU/mL) >70

        -- aldosterone (LC-MS/MS, ng/dL)/PRA  (ng/mL/h) >15, or aldosterone (LC-MS/MS, pmol/L)/DRC (mU/mL) >52

-- but it should be noted that aldosterone levels are influenced by individual variability, local laboratory assays, as well as other factors. And the interpretation of the results should involve a Bayesian approach by assessing pretest probabilities for PA

-- and, these specific cutpoints above are in a continuous biological spectrum, and differences between being minimally below that cutpoint or at the cutpoint may not really matter biologically)

-- also, medications that can lower renin and cause false-positive results include beta blockers and centrally acting alpha antagonists, and these should be withheld for two weeks prior to testing if it is safe and feasible (though if not feasible, having aldosterone levels of 7.5 to 10 ng/dL or 208-277 pmol/L suggest PA despite being on beta blockers)

-- if patients have renin suppression and aldosterone levels of 5-10 ng/dL (138-277 pmol/L), the test should be repeated on another day 

-- people with mild PA likely do not have lateralizing lesions, and are much more likely to have bilateral disease which is not surgically correctable

-- a recent article confirmed that when patients have a documented unilateral adrenal adenoma leading to primary aldosteronism, surgery had better outcomes than medical treatment. in the MATCH study, which included 17 studies with 1696 patients with 49% having had adrenalectomy and 51% being on MRAs (see htn hyperaldo surgery better HTN2025 or DOI: 10.1161/HYPERTENSIONAHA.125.25104), found:

    -- left ventricular mass was reduced, mean difference -3.5% (-4.9% to -2.2%), with p <0.0001 favoring surgery

    -- left ventricular hypertrophy was reduced 32% by surgery vs 19% with MRAs

-- other studies have found that 30-40% of patients with hyperaldosteronism do have unilateral adenomas

    -- surgery cures hypokalemia when present, and hypertension is cured in 35-60%; many of the remaining require fewer meds to control their hypertension

    -- quality of life has been found to be improved more so with surgery vs meds

-- other observational studies have found that those treated with medical treatment for PA versus surgical still require higher number of antihypertensive agents and higher doses of these agents

-- however, a systematic review did not find any statistically significant differences between medical and surgical therapy for ischemic heart disease, atrial fibrillation, major adverse cardiac events, and cardiovascular mortality. Observational studies, however, have found an increased risk of stroke with medical management alone

-- though medical treatment is cheaper and easier than surgical treatment, one analysis suggested that for individuals with a life expectancy of at least 25.4 years, surgery was calculated as the least costly strategy in the long term given the decreased risk of PA-associated adverse events

-- it is important to put these recommendations into perspective: the vast majority of the above recommendations, though they seem to be very appropriate, are not based on rigorous studies but have been developed based on Indirect evidence such as observational data (of which there is a lot). but many studies of the adverse effects of PA on the body (heart, kidney, etc), as well as cure of hypertension or at least easier-to-control hypertension, seem to be reversed by reversing the abnormal and deleterious hormonal changes associated with PA, best by surgery when appropriate or else with medical therapy.

-- It is also important to underscore that many of the tests recommended above are not true gold standards: for example the reliability of the aldosterone-to-renin ratio is fraught with its false positives and false negatives noted in the studies cited in the document, given the variability of its assays, inherent intra-individual variability, screening conditions, and the heterogenicity of the patient populations studied

so, pretty convincing argument that we should be routinely assessing aldosterone and renin levels and their ratio in pretty much all patients with hypertension. a few summary comments:

    -- this testing is particularly easy in patients who have not yet started therapy, since they are less likely on meds that would interfere with the assays (ACE inhibitors etc)

    -- we should definitely not rely on the presence of hypokalemia as a marker of primary aldosteronism

    -- from the last blog (https://gmodestmedblogs.blogspot.com/2025/09/resistant-hypertension-are-diuretics.html), we should try to avoid the typical diuretics (thiazides, chlorthalidone, and loop diuretics) as part of early anti-hypertensive meds, since they may make matters worse

    -- for most patients, we should preferentially try prescribing spironolactone as both a diuretic and mineralocorticoid receptor antagonist. adverse effects are minimized with a go-low (start with 12.5-25mg) and go-slow (augment when necessary, after a few months) approach. see this last blog for more information. but of course, the patients should be monitored for hyperkalemia and potential adverse renal effects (though it is common that there is an initial decrease in eGFR, this typically remits pretty quickly, and spironolactone seems to be renoprotective, especially in those with proteinuria

        -- there are limited studies i have seen, but one found that low-dose spironolactone monotherapy led to significant blood pressure decrease (https://pmc.ncbi.nlm.nih.gov/articles/PMC5777944/)

    -- i am not convinced that we should change blood pressure meds in someone who is on a stable antihypertensive regimen and has well-controlled hypertension (??maybe we should check renin levels??? those on ACE inhibitors or ARBs do have higher renin levels, but this is typically transient and reverses in several months. we would need more data on this...)

    -- it is increasingly clear that surgery is associated with the best long-term outcomes in patients with PA, and it should be pursued if the patient is willing and has a clear unilateral functioning adenoma (per CT/MRI plus selective venous adrenal sampling for aldosterone in most patients), with included dexamethasone suppression test as noted above

geoff

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