hyperaldosteronism: targeting renin level
a recent study found that patients with hypertension and aldosteronism benefit clinically by raising the renin as an important therapeutic target (see aldosteronism med therapy target renin LancetDiabEndo2025 , or doi.org/10.1016/S2213-8587(25)00263-3)
Commentary:
-- as noted in prior blogs, primary aldosteronism is the main cause of secondary hypertension, and it is associated with excess aldosterone production along with renin suppression
-- there are high prevalences of cardiovascular and renal damage with primary aldosteronism, as compared to patients who have essential hypertension
-- treatment for this condition involves surgery if there is a lateralizing adenoma, or targeted medical therapy with a mineralocorticoid receptor antagonist (e.g. spironolactone) or an ENaC (such as amiloride or triamterene)
-- of note, ENaCs can increase PRA, though mostly with short-term use, by blocking sodium reabsorption, and triggering the renin-angiotensin-aldosterone system. However, the PRA can normalize with long-term use
-- given the concern that ENaCs may lose their effect on renin over time, this would suggest that renin level should be checked more consistently in these individuals
-- and preferentially choosing spironolactone (titratable and more potent than eplerenone)
-- there are several guidelines that suggest targeting post-treatment renin levels, including from 2 Japanese medical societies and a Taiwanese medical society. This current meta-analysis also includes a reference from the US Endocrine Society supporting the recommendation that normalization of post-treatment renin is important, though I did not see that recommendation in this paper
-- i have mentioned in the past that it is not so infrequent that i look at a cited paper, and it does not have the finding cited in the paper citing it.... of course, i do not look up a whole lot of the references, but i do so when i think the researchers are making an important point that i think should be reinforced (eg, in this case, that there was a US recommendation to treat aldosteronism with meds that raised renin levels to a specific target, which i felt would reinforce their conclusions but wanted to be sure).
-- the reason that this current systematic review and meta-analysis was done is that there are many observational studies suggesting a favorable cardiovascular and renal outcome with targeted renin enhancing therapy, but there are also conflicting reports in the literature; this reinforces the importance of a more definitive randomized controlled trial (one of the papers stated that this was underway)
-- there were new clinical practice guidelines from the Endocrine Society recently, noting a few important items (https://gmodestmedblogs.blogspot.com/2025/09/hyperaldosteronism-2025-guidelines.html ):
--the importance of checking renin and aldosterone levels basically in all hypertensive patients routinely, to understand the best clinical approach to their control of hypertension
-- low renin levels by itself, independent of aldosterone levels, are associated with higher cardiovascular risk, and this is more so than in renin-dependent aldosteronism (eg Barrter’s syndrome)
-- another recent article suggested that patients with resistant hypertension who do not have primary aldosteronism by the traditional definition but do have suppressed renin levels with lower aldosterone levels than in primary aldosteronism (referred to this as dysregulated aldosteronism) found clinical outcome benefit from MRAs, and that furosemide (but not torsemide) and thiazides as well as chlorthalidone increased serum aldosterone concentrations and stimulated the sympathetic nervous system: these meds should not be used in these patients with dysregulated aldosteronism (and likely, by extension, the more severe form of primary aldosteronism: https://gmodestmedblogs.blogspot.com/2025/09/resistant-hypertension-are-diuretics.html
-- a small kerfuffle in the current study is that patients who had unsuppressed renin levels (i.e. they were given higher doses of spironolactone to increase the renin levels above the threshold) in fact had lower blood pressure
-- the systolic blood pressure difference between those who continued to have renin suppression versus those who had unsuppressed renin levels was -4.4 mmHg and the diastolic was -3.3 mmHg
-- a 2022 study found that of 344,716 participants from 48 randomized clinical trials and a mean age of 65, a 5 mmHg decrease in blood pressure was associated with a 10% decrease in developing major cardiovascular events (defined as fatal and nonfatal stroke, fatal and nonfatal MI or ischemic heart disease, or heart failure causing death or requiring admission to the hospital), without much difference in those who did have or did not have previous cardiovascular disease (it was 11% in the former and 9% in the latter), and there was a linear relationship over time in terms of cardiovascular events: https://pubmed.ncbi.nlm.nih.gov/35524880/
-- it was apparent from the above analysis, that the difference achieved in the group with unsuppressed renin levels was more than that 10% noted above
-- and the secondary outcome of blood pressure, as noted above, found that " the association with systolic blood pressure was higher in the group with a cut off plasma renin activity (PRA) of >1.4 ng/mL per h versus PRA 0.6-1.4 ng/mL per h", suggesting that a higher PRA may be reasonable
-- but, it would be useful to have a randomized controlled study that enrolled participants randomized into 2 groups, one with unsuppressed renin levels by MRA receptor antagonists and the other with other medications that do not affect renin levels but achieved equivalent blood pressure lowering. And then comparing cardiovascular and renal outcomes, preferably with a few different PRA cutpoints (eg 1.0 ng/mL per h and 1.4 ng/mL per h)
-- patients with unsuppressed renin, largely mediated by the use of MRAs (mostly spironolactone and often at increased doses), is associated with reduced risk of cardiovascular events and all-cause mortality, after 5 years of use
--renal outcomes, however, were not found to be significantly different in the targeted approach in the study, though this might be attributable to the relatively small number of patients evaluated (the 2 studies had fewer than 150 patients each) and one of these 2 studies had only one year of follow-up
-- of note, in a study of patients with hyperaldosteronism, 119 patients with renin unsuppressed PRA (1.7 ng/mL per hr ) versus 199 who were suppressed (0.5 ng/mL per hr) and followed for 3.91 years found a decline in eGFR that was less significant in those who were unsuppressed: https://www.ahajournals.org/doi/pdf/10.1161/HYPERTENSIONAHA.123.21096 . however this study was not included in the above systematic review because it did not report the incidence of renal events (only eGFR)
-- in the current study, they did achieve significantly lower blood pressure in the group who did have suppressed renin activity, which could explain the mild benefit in the eGFR , a marker of improved kidney function
-- though, I must reiterate for the thousandth time, eGFR based on creatinine is often much less useful as a predictor of major adverse clinical outcomes than one based on cystatin: https://gmodestmedblogs.blogspot.com/2025/12/test.html
-- it was also clear in the study that without checking renin levels after therapy would leave many patients undertreated, since there was frequent necessity to uptitrate the spironolactone to achieve a high enough renin level
-- one notable finding in this study is that their findings predominately had very low quality of evidence; this reflects the fact that these are all observational studies
-- another issue is that there are many meds/etc that can cause a pseudohyperaldosteronism: black licorice, carbenoxolone, abiraterone (may be part of prostate cancer chemotherapy), ketoconazole, itraconazole and posaconazole, glucocorticoids, and the mineralocorticoid receptor agonists deoxycorticosterone and fludrocortisone
-- so, patients having high aldosterone levels should probably be retested if they are on these things
Limitations:
-- this meta-analysis is based only on observational studies, eliminating our ability to determine causality: one can derive only an association in the results from observational studies because of potential residual and uncontrolled confounding
-- one issue is that other medications were not controlled for, and, for example beta blockers, decrease plasma renin activity and were used more frequently in the suppressed renin group than the unsuppressed renin group in one of the studies in the meta-analysis. In fact, one of the biggest limitations in the meta-analysis is that we have no information on the other meds (antihypertensive and otherwise) that might complicate the issue. several of the other antihypertensive meds affect renin levels (eg ACEi, ARB, b-blockers) and they also increase potassium levels, all of which affect renin targeting, especially since using/increasing spironolactone dosing may be impeded by the presence of hyperkalemia. torsemide might help some but does not lead to large potassium decreases
-- there is no assessment of treatment adherence, another potential problem in assessing their results
-- we do not have studies that were done for 2 to 4 years (one study in the meta-analysis was done only one year and did not have significant results, all of the others involved at least 5 years). We would need shorter term follow-up studies to feel more confident in evaluating and treating people using the renin-targeted approach if they had a shorter life expectancy than 5 years
--as a meta-analysis, the study did include quite disparate individual studies; for example one study evaluated only patients with unilateral primary aldosteronism (these individuals tend to have more resistant hypertension and hypokalemia) and included more patients on potentially interfering medications such as ACE inhibitors, ARBs, and beta blockers; this study also had an unusually high baseline PRA before treatment. Also there were some differences in the definitions in the studies of what the cutpoint was used for determining whether individuals were unsuppressed or not
-- this current meta-analysis found that spironolactone was more commonly used in patients with post-treatment unsuppressed renin levels (71%) than in those with suppressed post-treatment renin (57%). That raises the question that since spironolactone is significantly more effective than eplerenone or esaxerenone (the latter not approved by FDA), and that spironolactone can be titrated higher than eplenerone (recommended to max out at 50mg). so the med of choice seems to be spironolactone and the others not used unless there was a significant adverse effect from the spironolactone. so the results above may have been distorted by the use of non-spironolactone MRAs
-- renin levels do vary within individuals, so a single measurement may not reflect long-term levels or post-treatment levels, leading to misclassification bias both in initiating therapy and in assessing people post therapy
-- there is an ongoing study now to assess medical outcomes between renin-guided and renin-blinded groups that should clarify many of these concerns
so, this study validates and strongly suggests the following:
-- essentially all patients with hypertension should have renin/aldosterone levels assessed, in order to stratify therapy appropriately
-- my anecdotal experience oiver the past couple of months is that there are lots of people having low (surpressed) renin levels
-- in those with suppressed plasma renin activity (eg <1.0 ng/mL per hr), the principle medical therapy should be based on MRA receptor antagonists, with spironolactone being the leading candidate if tolerated
-- there is reasonable evidence suggesting that we should titrate this therapy to achieve a renin level >1.0 ng/mL per h (though the blood pressure response seemed to be higher with a level of 1.4 ng/mL per h)
-- the overall understanding is that surgery, when appropriate, has the best long-term outcomes in those with primary aldosteronism (https://gmodestmedblogs.blogspot.com/2025/09/hyperaldosteronism-2025-guidelines.html ). this blog reviews the data suggesting that, but most stuies compared surgery for aldosteronism vs patients with primary hypertension (and not aldosteronism), and the major benefit was quality of life with no good information on clinical outcomes
-- BUT is there really any benefit of surgery for a patient who is given renin-targeted therapy as above and thereby increases the PRA into the normal/acceptable range? it seems that the cardiovascular and mortality benefits noted above are quite profound.
-- As mentioned above and in these guidelines cited above, the primary driver of cardiovascular and other bad outcomes with aldosteronism is the low renin level. if we correct that, as in the above study, is medical therapy as good as surgical??? should we use the same cutpoint of 1.0 ng/mL per h?? or perhaps higher just to be sure??. Can we avoid invasive testing and potential surgeries to achieve similar results???? The older studies suggesting benefit from did not address the renin level......
geoff
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