#515 Primary Aldosteronism, A Deep Dive with Anand Vaidya, MD

Summary

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Podcast Summary: The Curbsiders Internal Medicine Podcast

Episode #515: Primary Aldosteronism, A Deep Dive with Anand Vaidya, MD
Date: February 23, 2026
Guest: Dr. Anand Vaidya, Chief of Endocrinology, Mass General Brigham
Hosts: Dr. Matthew Watto, Dr. Paul Williams, Dr. Mobin Ahmad

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Episode Overview

This episode explores the evolving landscape of Primary Aldosteronism (PA, or “Hyperaldo”)—its physiology, underdiagnosis, modern screening, pragmatic testing, management, and future therapies—with leading expert Dr. Anand Vaidya. Listeners are guided through a deeper, nuanced understanding of PA, its relationship to current clinical practice, and what might be just over the horizon.

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Key Discussion Points & Insights

1. What is Primary Aldosteronism? Why Does it Matter?

Dr. Anand Vaidya brings a fresh physiologic and evolutionary perspective to PA.

• Definition:
  PA is excessive aldosterone production by the adrenal cortex, autonomous from its usual regulators (renin/angiotensin II).
  • “Primary aldosteronism is a hormonal disorder where the hormone aldosterone … is produced in excess and independent of its classical physiologic regulators.” (Dr. Vaidya, 08:15)
• Evolutionary Physiology:
  Humans evolved high aldosterone in low-sodium, high-potassium environments; the modern diet is the opposite, leading to potential problems from "unneeded" aldosterone.
  • “You’re actually doing what we would call an oral sodium loading study on yourself every day if you’re an average human.” (13:00)
• Consequences:
  PA raises blood pressure, increases risk for cardiovascular disease, kidney disease, and is common yet vastly underdiagnosed.

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2. Who Should Be Screened for PA? Are We Missing Most Cases?

• Current Guidelines:
  • Endocrine Society: Screen all hypertensives at least once.
  • AHA/ACC: Most hypertensive patients should be screened.
• Why Not Just High-Risk Groups?
  It's no longer considered a rare, severe, hypokalemic disease; mild and moderate forms are much more common.
  • “Depending on which definition you use and which test you use, somewhere between 15 and 25% of people with hypertension have some degree of primary aldosteronism.” (14:29)
• In Practice:
  • Screening rates remain <1% even in major academic centers (17:00).
  • Barriers include complexity and perceived futility where resources are limited.

“The vast majority of people with primary aldosteronism are not going to get diagnosed.” – Dr. Vaidya, 20:27

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3. Practical Guide to Biochemical Testing

• Initial Labs:

  • Order Renin, Aldosterone, and Potassium immediately when you suspect PA; don’t get bogged down by ideal medication washouts.
  • “If you think about primary aldosteronism, if it even crosses your mind right then and there, you order renin, aldosterone, potassium. That’s it.” (23:21)

• Testing on Medications:
  Many antihypertensives (thiazides, ARBs, ACEi) increase renin and suppress aldosterone, so a positive test (low renin, inappropriately high aldosterone) is actually more convincing on these meds.

  • “If you test the patient on those drugs and they still have a low renin and renin-independent aldosterone production, they have proven to you they have primary aldosteronism.” (23:21)

• Beta Blockers/Alpha-2 Agonists:
  These can suppress renin, but do not typically lead to a “false positive” (26:57).

• What About Mild Elevations?:
  No strict cutoffs, but context matters; focus on inappropriate (not “high vs. low”) aldosterone for the sodium status (29:19).

  • “There is no high or low… there’s only inappropriate and appropriate.” (29:19)
  • Operationalize cutoffs for your practice (e.g., 10 ng/dL on immunoassay, ~7.5 on mass spec).

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4. Potassium: Still Useful?

• Role in Diagnosis:
  • Most PA patients have normal potassium—the “hypokalemic” phenotype is the minority.
  • Potassium helps interpret equivocal tests and frames severity.
• Key Pearl:
  • “Potassium is not a diagnostic. If you see it, it really does help your suspicion. But if you don’t see it, that doesn’t exclude primary aldosteronism.” (36:51)

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5. Destigmatizing & Simplifying the Workup

• Aldosterone Suppression (Confirmatory) Testing:
  • No longer recommended for routine confirmation due to lack of gold-standard and risk of excluding milder, real disease.
  • “The new guidelines do not recommend doing this for confirming or excluding the diagnosis.” (42:51)
• CT Scans:
  • Mostly used for procedural planning, not diagnosis or lateralization—absence of adrenal masses does not rule out PA.
  • “The point is actually quite limited. If you’re not going to pursue adrenal venous sampling or surgery… there’s no strong reason to get a CAT scan.” (67:29)

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6. Case Discussions: Application of Concepts

Case 1: Excess Aldo (45M, HTN, prior hypokalemia, equivocal PA labs on meds)

• Diagnosis: PA confirmed—renin independent aldosterone on meds that should suppress it.
• Management:
  • Refer to specialist for consideration of AVS and/or surgery, particularly in younger patients.
  • If not, start MRA (eplerenone preferred in men for fewer androgen effects).
  • Discuss options, patients can opt for medicine first; surgery remains an option down the line.

Case 2: AVS (30M, severe features, normal adrenal CT)

• Key pearl: Negative imaging does not rule out unilateral/curable disease.
• Next steps: Consider AVS regardless of imaging (unilateral microscopic foci can exist).
• Future: Emerging CYP11B2-PET tracers may soon enable non-invasive localization.

Case 3: Lois Kalma (66F, resistant HTN, prior hypokalemia, diabetes, no surgery desired)

• Management strategy:
  1. Counsel strict sodium restriction (“sodium is the fuel for primary aldosteronism”) (71:29)
  2. Start with low-dose spironolactone (12.5 mg), titrate up, monitor home BP, potassium, and ideally see renin “rises again” as a marker of effective therapy (Batman reference!)
  3. Try to wean off potassium supplements and excess antihypertensives.
• Clinical goal order: Blood pressure control first, then potassium normalization, then focus on renin.

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7. Drug Details & Practical Pearls

• MRAs:

  • Spironolactone: potent but causes more side effects (gynecomastia, ED), often for women.
  • Eplerenone: less side effects, needs BID dosing, preferred for men but more expensive.
    • Recent “wholesale pharmacy” options may improve access.
  • Hyperkalemia rare unless advanced CKD.

• Novel Agents (Future Directions):

  • Aldosterone synthase inhibitors (CYP11B2 inhibitors): Directly lower aldo, current trials promising.
  • Potential game changer: May one day treat undiagnosed PA by default (78:43)

• Finerenone: Not primarily studied for PA, might be used if CKD/diabetes present, but not yet standard of care for PA.

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Notable Quotes & Memorable Moments

• On the spectrum of PA:

  • “The risk for developing hypertension, for cardiovascular disease, for kidney disease, exists across this entire continuum… Any aldosterone production when renin is low is some degree of primary aldosteronism.” (29:19)

• On destigmatizing the workup:

  • “If you’re listening to this podcast and you want to test for primary aldosteronism, you cannot be wrong.” (42:51)

• On potassium's role:

  • “Potassium is not a diagnostic. If you see it, it really does help your suspicion. But if you don’t see it, that doesn’t exclude the possibility of primary aldosteronism.” (36:51)

• On trusting clinical instincts:

  • “Don’t be afraid, don’t be intimidated. You cannot mess up. The fear of messing up is such a barrier to doing the right thing.” (83:42)

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Timestamps for Important Segments

• Introduction and approach to PA
  • What is primary aldosteronism? — [08:15]
  • Who should be screened? — [14:29]
• Screening & Testing
  • Pragmatic testing philosophy — [23:21]
  • Beta blockers/medication effects — [26:57]
  • Interpreting mild elevations — [29:19]
• Role of Potassium — [36:42]
• Debunking Confirmatory/Suppression Testing — [42:51]
• Case 1: Application & Treatment Approaches — [51:03]
• Case 2: AVS and Imaging — [59:37], [67:29]
• Case 3: Long-Term Management — [71:29]
• Future Directions (Aldosterone synthase inhibitors) — [78:43]
• Take Home Points & Clinical Confidence — [83:42]

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Take-Home Points

1. Primary aldosteronism is much more common than previously thought and severely underdiagnosed.
2. Screen liberally: Order renin, aldosterone, and potassium for hypertensive patients without overthinking medication status; a “positive” test on meds is even more specific!
3. Don’t obsess over potassium or suppression tests: Most cases are normokalemic and guidelines no longer recommend confirmatory testing.
4. CT is for procedure planning, not diagnosis. Absence of an adrenal mass does not exclude curable PA.
5. When in doubt, treat with MRAs: Start low, titrate, monitor BP and potassium, and look for rising renin.
6. Future is bright: Non-invasive PET-scans and aldosterone synthase inhibitors could revolutionize diagnosis and management.
7. Trust your clinical instincts; don’t let complexity paralyze you.

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“If you’re listening to this podcast and you want to test for primary aldosteronism, you cannot be wrong… The fear of messing up is such a barrier to doing the right thing.”
— Dr. Anand Vaidya (42:51, 83:42)

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Transcript

[A]

Hey, before we get to the show, I wanted to remind you to check out our [e-mail] curbsiders if you haven't signed up yet, sign up now to get ad free episodes, twice monthly, bonus episodes and a whole bunch of other cool [e-mail] curbsiders Paul, I just watched a program about beavers and it was the best damn program I've ever seen.

[B]

I wish. I hope our YouTube viewers can see the series of contortions your face went through as you prep to read that joke out loud. The Curbsiders podcast is for entertainment, education and information purposes only and the topics discussed should not be used solely to diagnose, treat, cure or prevent any diseases or conditions. Furthermore, the views and statements expressed on this podcast are solely those of the hosts and should not be interpreted to reflect official policy or position of any entity aside from possibly cash like moral, hospital and affiliate outreach programs, if indeed there are any.

[C]

In fact, there are none.

[B]

Pretty much.

[C]

We aren't responsible if you screw up.

[B]

You should always do your own homework

[C]

and let us know when we.

[A]

Welcome back to the curbsiders. I'm Dr. Matthew Frank Waddo. A bit ashamed about that pun that I just told and I'm joined by my co host, my great friend, America's primary care physician, Dr. Paul Nelson Williams. Hi Paul.

[B]

Hey Matt, how are you?

[A]

I'm doing well because we just had a really fantastic eye opening discussion. We've talked about primary aldosteronism before, but our guest Dr. Anand Vaidya really just told us some new stuff. New, like fancy stuff. His approach is a little bit different than other experts we talk to, so I feel like it's really great. People are going to learn a lot and I'm excited for them to hear that. But Paul, before you introduce our co host and before we get into the bio, what is it that we do on Curbsiders? Why are we here? Paul, it's a new year. It's 2026. I think this is one of the first episodes we've recorded in 2026 and I just, I just don't remember why we do this still.

[B]

Yeah, it's our first recording of the new year. I refuse to be existential, but I will share that we are the internal medicine podcast. We use expert interviews to bring you clinical pearls and practice changing knowledge. And as you mentioned, we have an extraordinary guest today who sort of talks us through the management of Hyperaldo. But before we even get there, you also alluded to our excellent co host and producer of this episode, Dr. Mobin Ahmad. Dr. Ahmad, how are you?

[D]

I'm doing great. I'm ready to talk about some hypertension and kind of kind of change the world with this Aldosterone talk. Hopefully

[B]

before we change the world, why don't you share with our listeners who we talk to and how we got to world changing?

[D]

Of course. So today we have a fantastic conversation with our guest, Dr. Anand Vaidya. Dr. Vaidya is Chief of the Division of Endocrinology, Diabetes and Metabolism at Mass General, Brigham and Women's Hospital, including the Massachusetts General Hospital and Brigham and Women's Hospital. He is the Director of the center for Adrenal Disorders and Associate professor of Medicine at Harvard Medical School. He takes care of patients with complex adrenal disorders and leads an NIH funded translational laboratory that conducts human physiology studies, mechanistic clinical trials and population based studies investigating the role of adrenal disorders in health and disease. He teaches us a practical approach to the diagnosis and treatment of primary hyperaldosteronism today. So without further ado, let's get to it.

[A]

A reminder that this and most episodes will be available for CME credit for all health professionals through VCU [e-mail] and our guest for this episode, Dr. Vaidya did disclose that he's had relationships with two different companies that make Aldosterone synthase inhibitors, which we do discuss at the end of the episode as future directions. We don't show any brand preference and the discussion in general was fair and balanced on this episode. Anand so thank you so much for joining us. Really excited to talk about this topic. We've done a little bit on this in the past on the show, but there's new guidelines so we're excited to get into that. But first, the audience wants to know what's a hobby or interest that you have that you're currently enjoying outside of medicine?

[C]

Thanks for having me. It's great to be here. I have a lot of hobbies, but I would say my top one is cycling. I love to be on the bike. I bike to work as much as I can and bike on the weekends and I dabble in a lot of sports, but probably most of what I do is watch my kids play sports.

[A]

Yeah, that's a certain phase of life that I am also in watching the kids play sports. So cycling, are you clipped into your pedals and are you wearing one of these fancy riding outfits on the way into work or are you just kind of in Your work clothes with like a pant leg rolled up. What's the situation?

[C]

I'm clipped. I'm clipped in lycra, spandex, doubt and it's very cold. So I'm, I'm have multi layers and I'm going as hard and fast. It's, it's basically me cycling, enjoying the fresh air and working out at the same time. I have to take a full blown shower when I get to work because I'm, I'm sweaty.

[A]

So I'm sure your colleagues appreciate the shower. You know that you're taking the time to shower. That's good.

[C]

That's right.

[A]

Okay, Paul, you want to ask anything before we get to a case?

[B]

Sure. Let me ask my advice or feedback question. So something that we always like to hear about. Is there a piece of advice or feedback that you have received during your career training that was meaningful to you or one that you'd like to give out to your trainees that you feel is especially helpful and might be useful for our listeners?

[C]

Yeah, I like this question because of course we've all got great advice over the years. We have a family motto that's an amalgam of advice my kids got when they were in kindergarten. To advice I give mentees and it's a series of two word sentences which is be kind, dream big, work hard, don't complain and never give up. It's the kind of thing that they said to my daughters in first grade that makes kids feel good. Be kind, work hard. And you're like, you know, that kind of distills good advice down from when you're a child to an adult. And so we've over the years now my, my kids are teenagers, but be kind, dream big, work hard, don't complain and never give up. It kind of goes all the way from being a child to an adult and at a certain point in adulthood you want to be a child again. So it kind of goes full circle.

[B]

I love it. I had a colleague whose email sign off, it still is as far as I know is just do good, work hard. And like I just, it's, I just, it's so simple and so resonant. So that's great.

[A]

That's great. That's a good starting point. Let's get to a case from Kashlak. Mobine, would you do the honors?

[D]

All right, so the first case we'll talk about I think is something we commonly see in the clinic. The patient's name is Mr. Xavier Stevenson Aldo. So initials excess. Aldo is a 45 year old male with a past medical history of hypertension, hyperlipidemia and obesity. He presented to your clinic just for his annual checkup. On physical exam, he's noted to have a high blood pressure of 145 over 92 millimeters mercury and confirms that this is usually elevated at home. The rest of his physical exam is really only significant for a BMI of 32. Heart rate normal at 75, respiratory rate of 12 breaths per minute with no obvious signs of Cushing's syndrome. On exam currently he takes hydrochlorothiazide, 25 milligrams of sartin, 50, 50 milligrams amlodipine, 10 milligrams, and reports that he's adhering to his medication. On review of his labs, you see that he's had episodes of low potassium in the past of 3.2 milliquins per liter. However, his last few readings have actually been in the normal range around 3.9 to 4. So I guess, Dr. Vaidya, I guess the first question we kind of wanted to talk about is kind of, what is primary aldosteronism and why is it important to identify?

[C]

It's a million dollar question right off the bat. There's many ways one can tackle this question. So I'll start with saying primary aldosteronism is a hormonal disorder where the hormone aldosterone made by the adrenal cortex is produced in excess and independent of its classical physiologic regulators. That's kind of like a fairly official, non controversial statement. To really understand it, though, and I think our conversation today will get into this, you have to understand what aldosterone physiologically does. It is a hormone that's designed for terrestrial life, terrestrial mammals, meaning at some point millennia, millions of years ago, we crawled out of the ocean and onto land. And if you live on land like we do as humans or any other mammal, there's a ton of potassium. Every piece of living organisms, every cell, every vegetable, every cellular eukaryotic organism is full of potassium, but there's a dearth of sodium. Yet the main osmol of our blood is sodium, right? That's how we maintain a perfusion pressure, that's how we maintain osmolality. So there's a disconnect because if you eat, you're going to die of hyperkalemia and you're not going to ingest enough sodium to maintain all of this perfusion pressure and osmolality. If you look at a kilogram of vegetation, just take a Whole bunch of grass or hay, you're going to get 8, 10, 15 grams of potassium and only a few milligrams of sodium. I'm talking 20, 30 milligrams of sodium. Okay? So this is what aldosterone is for. It helps the kidney hold onto every atom of sodium in the distal nephron, and it helps it excrete volumes and volumes of potassium. And that's why we don't die of hyperkalemia. That's why we maintain our blood volume. And so then it gets to a second question, which is, what is our natural physiologic state? And that is to say, every terrestrial mammal except industrialized humans, Meaning if you go to a grocery store and buy something in a jar, package, can, or even if it tastes good, meaning it's flavored, it either has been preserved with something that has sodium in it, or flavored with something with sodium in it, or both. So unless you're eating raw meat that's unseasoned or unprocessed or just raw vegetables and fruits, you're eating a ton of sodium. You're actually eating probably 3 to 4 grams of sodium a day, if you're an average American, which is two orders of magnitude higher than what we were evolved to eat. And you're eating probably only a third of the potassium that our ancestors ate. Okay? So we were designed to have very high aldosterone levels. If you go measure aldosterone in wild mammals, or even ancestral humans, say tribal humans in the Amazon or in Papua New guinea, their aldosterone levels will be extremely high, higher than you've ever seen. Their renin and angiotensin II levels will be extremely high. Right. They're hypoperfused. Their kidneys say, whoa, we're hypovolemic. They'll raise renin, they'll raise angiotensin ii, they'll raise aldosterone, they'll have a vasopressor response, and they'll hold onto every atom of sodium. They're not hypertensive. Their blood pressure is 90 systolic. It's lower than even a normal person. That's a physiologic response to not die. So now we figured out how to satiate our sodium appetite. We figured out how to preserve food, we figured out how to make things taste good. The price to pay for that is now we've loaded ourselves up with sodium, we don't need aldosterone anymore. Okay? So that's the world we live in now. The world we live in now is we're all volume replete on any given day. Even when you don't have much to eat or drink on that day, I bet you're still days away from being volume depleted. So your renin and angiotensin II and aldosterone levels should be at their nadir. They should be very low. You're actually doing what we would call an oral sodium loading study on yourself every day if you're an average human. So you could see what I'm describing is in normal physiology, renin and angiotensin aldosterone all rise. And when you load yourself up with volume, get 2 liters of saline by IV or with oral salt, all of them go down. Renin, Ang to and Aldo all go down. They go up together, they go down together. Primary aldosteronism is a break in that system. Aldosterone is being produced either autonomously or without the classical signal from renin and angiotensin ii, which are low. So you have renin independent aldosterone production. That's the classic description of primary aldosteronism. Now I will just say we're learning more and more, or humbled more and more, because aldosterone is also regulated by many other ligands and receptors. Acth, lh, hcg, tsh, trh, serotonin, and on and on and on, as well as genetic mutations. So it's not as clean cut as what I'm saying. But the classic description of primary aldosteroneism is renin independent aldosterone production. And the reason it matters is because now you're sodium loaded and instead of being low, aldosterone is high. So it's going to precipitate an elevation in your blood volume which will trigger an elevation in your blood pressure. And over time that high, high blood pressure will become sustained. And aldosterone is toxic to many cells when you combine it with sodium, so it'll cause endothelial damage, myocardial fibrosis, kidney disease. So in short, primary aldosteronism causes high blood pressure, cardiovascular disease and kidney disease. And as we'll talk about, it's common and we can treat it. So that's the reason it's important. And I don't know if you want me to talk about it now, but it's very common and under diagnosed. So that these are all the public health reasons to be aware of it.

[B]

Well, I guess that begs the question of who should be screened. I think there's different guidelines to go by. I think some recommend to screening anyone with hypertension. I think the ACCAHA Update talks about if you have specific concerns. I think OSA is in there, interestingly, but also someone who's become hypokalemic or I think like young history of stroke, that kind of stuff. So what should our approach be? Who should we screen for? Who should be concerned about and chase this down?

[C]

Right. So there's about one and a half billion people with hypertension in the world. So just the scale of this is astronomic. The most recent Endocrine Society guidelines suggest that all hypertensive people be screened for primary aldosteroneism at least once. That's the official suggestion. The AHA ACC guidelines recommend almost all patients with hypertension be screened. So I think the answer to your question is that I think you might wonder, if you're an average clinician, you must see tons of hypertension every day. Can you screen all of them? Should you screen all of them? How did we get here? You know, originally in the late 1950s, primary Aldosteros was described as a disorder with severe hypertension and severe hypokalemia. It was first thought to be an extreme rare situation that's described by this extreme syndrome. Like most things in medicine are, you first see the most tip of the iceberg. And then over the last several decades, we found that there's milder forms, everything starts somewhere. There's milder forms, really mild forms, moderate forms. And it turns out that depending on which definition you use and which test you use, somewhere between 15 and 25% of people with hypertension have some degree of primary aldosteronism. If you liberalize that and say, how about inappropriate renin independent aldosterone production? How common is that biochemical phenotype? You can easily go between 30 and 50% of people in the United States. So then the question becomes like, who should we recommend testing on? And prior guidelines said, well, test anybody who has hypokalemia with hypertension, super high probability. Test anybody with resistant hypertension, super high probability. And they pick these high probability groups. But I will tell you that nobody does that. Okay? Actually, the screening rate at my academic medical center. At your academic medical center in Europe, in Japan and Australia, anywhere you go in the world, one of the most reproducible statistics is that the screening rate is almost zero. It's below 1% even in evidence based practices. So we've now taken new guidelines and expanded that to everyone. So it's a little bit unrealistic in the sense that if no one was testing before in the high risk groups, what's the likelihood that they will be receptive to educational standards and guideline standards and screen more. Probably not going to move the needle a lot, but it is showing the awareness that experts and guidelines have become attuned to that this is a much more common disorder than previously recognized and. And that's what where the guidelines go.

[A]

Yeah, I think Dr. Richard Aukus was the first one we had on talking about this and this was like 10 years ago or something and he was very passionate about this topic and was like, yeah, I'll come on the show. I don't usually do this stuff but I just feel so passionate about like making sure and primary care doctors need to know about this. So I think. Paul, you think our audience. The screening rate's probably 10%, right?

[B]

I would hope so.

[A]

It's gotta be higher than the national average because we have done a bunch of shows on this and I think this is important.

[B]

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[A]

I did notice in the guideline, the Endocrine Society guideline, there's like a caveat, you know, sort of like resource dependent. But maybe that's just to say, like, because if you can't do anything about it, if you're in a setting where you can't do anything about it, then maybe you're not going to and you could just treat with an mra. But how do you, let's say if someone says, I think I'm in a resource setting where no one's going to get an adrenalectomy, how would you counsel them?

[C]

Yeah, so it's a, you know, first. Rich is a friend of mine and like him, I'm very passionate about this. But there are multiple arguments that can be made here. You know, there's many right ways to think about this, which is there's many parts of the world with large populations. I'm talking India, parts of China, Southeast Asia, where there's billions of people and they cannot even reasonably order Arenin and aldosterone. So here we are, the United States and Europe writing guidelines where even in the United states you go 20 miles outside of Boston and people struggle to order these tests. And they have very good reason to question why a bunch of experts are recommending everybody test. You know, is that reasonable? Is it cost effective? Why can't we just treat everyone with hypertension, with spironolactone? All great comments. So I'll just say this is what the experts said. It's not based on really rigorous cost effectiveness analyses. It's not based on rigorous assessments of resources and the pros and cons. It was a suggestion, not a recommendation. And I think it could be reasonably debated. What I don't think is up for debate is how common primary aldosterosm is. So there's different ways to deal with it. The Other is you've mentioned how adrenalectomy. The vast majority of people with primary aldosteroneism are not going to get diagnosed. Of those that are diagnosed or recognized or suspected, most will have non lateralizing disease that will be treated medically. And we had discussed this a little earlier and maybe we'll discuss this later. The future of primary aldosteronism therapy is medical. The role of surgery is going to be narrower and narrower. And the only reason that message hasn't come across is because in medical school people learn it's either bilateral or unilateral, almost like they're equivalent. And if I told you that less than 1% of people are ever tested, a smaller fraction of that are ever diagnosed. And so now you can see this selection bias and referral bias. So you can imagine the people who ever get diagnosed are usually the most severe and most intense disease being picked up by some of the most aware doctors who then get referred. So now you're picking up that tip of the iceberg population where, yes, you'll be enriched for what's called unilateral or lateralizing disease, which is the more severe kind where you might perform more adrenalectomies. But all the cases that are undiagnosed tend to be less severe or more mild to moderate, and they will almost inevitably be treated medically because they're non lateralizing.

[A]

Let's get into what tests we might order for Mr. Aldo here and what to do with his medication because he's taken hydrochlorothiazide 25, losartan 50 and amlodipine 10. How would you handle the medications and what tests might you order?

[C]

So very pragmatic. If you think about primary aldosteronism, if it even crosses your mind right then and there, you order Renin aldosterone potassium. That's it. It don't think any more than that. Don't ask yourself any other questions or make your life harder. And this is an updated version. You know, there's differing opinions on this, but even the guidelines offer this suggestion. I'm very pragmatic, even though I have. You can do many sophisticated things and if you want to do more, you can, but you do not have to. I think this is one of the major barriers that has prevented primary care doctors and frontline physicians from testing or even thinking about primary aldosterone. The sheer intimidation. You know, endocrinology is a black box for most clinicians. Even I didn't want to go into endocrinology originally. I was Going to be a cardiologist. I didn't understand hormone physiology. I checked out in med school. When that area came along, I was focused on the heart and the kidneys. I just happened to run into an amazing adrenal mentor who changed my mind. But hormone biology is complicated. If you then superimpose on that all these stipulations on how the patient should be seated, which medications they should be on, telling primary care docs to stop an antihypertensive drug and substitute it, it's lunacy. And this is why the screening rates are so abysmal. So actually testing on medications is a benefit. This patient was on hydrochlorothiazide, a diuretic, which, if anything, will raise renin. Will raise renin. They were on an angiotensin receptor blocker, which, if anything, will block angiotensin II and raise renin and lower aldosterone. So they'll steer you away from the diagnosis. Okay. If somebody has primary aldosteronism and they have autonomous aldosterone production independent of renin and angiotensin ii, the effect of these drugs should be neutered. Right. If your renin and angiotensin II are low, the role of an angiotensin receptor blocker is kind of neutralized. If your volume expanded, a thiazide is not going to make you volume deplete to the point where your renin rises. So the value of doing the test on these meds is that if you test the patient on those drugs and they still have a low renin and renin independent aldosterone production, they have proven to you they have primary aldosterone. They're like screaming at you. Look at me. You tried to raise my renin and you couldn't. You tried to suppress my aldosterone and you couldn't. You actually are doing an aldosterone suppression test on the patient and a renin stimulation test. So most of the time, you'll get your answer. Now, is it true that some cases of primary aldosterone, particular milder ones, might get missed when you test on medications because they're so mild that the medication did interfere? Yes. So there's a small risk of false negatives. Okay. But we'll deal with that risk to just increase the number from almost zero to something. So if you highly suspect your patient has primary aldosteronism and the labs come back negative, then you can think about washing out medications, which is a big deal. And I will tell you, I only see adrenal patients. I see tons of primary aldosteroneism. I do not stop medications. It's only seldom that I stop medications and put a patient through that, put myself through that. It's a lot of work, it's a lot of effort, and it's usually not, not necessary.

[A]

I would like to mention specifically beta blockers and alpha 2, because I wasn't aware of what beta blockers do to renin and the guidelines specifically mention them. So can you talk about that?

[C]

Yeah. Okay, so I said, so I mentioned some drugs that raise renin, thiazides, ACE inhibitors, angiotensin receptor blockers, that this would steer you away from the diagnosis false negative. Then there are drugs that might lower renin and people say, well, that might cause a false positive. Okay, so if I lowered your renin and you didn't, let's say you did not have primary aldosterone and I lowered your renin, what would happen to angiotensin II and then what would happen to aldosterone?

[A]

You told us they all go in the same direction, so they should go down too.

[C]

So if you had physiologic renin, angiotensin aldosterone system activity and I lowered your renin, everything should decline with it. If you're on a beta blocker which can lower renin, particularly at higher doses, I'm talking 50, 75, 100 milligrams grams of Atenolol metoprolol equivalents and you still have renin independent aldosterone production. What is that? You think that's a false positive? I mean, sometimes that may happen, but I gotta tell you, false positive testing is not the problem in primary aldosteronism. Testing is the problem. It's the 1, 2, 3, 4, 5, 99 problem after that. Actually, false negative interpretations of test is the problem. People do the test and they say, ah, that's not primary aldosteronism because the aldosterone is not high enough, because the aldosterone is not high enough. So that's false positives. There's no epidemic of false positives and beta blocker use. I don't think I've ever seen somebody on a beta blocker where you think they have primary aldosteronism. And later you're like, whoops, they did not have primary aldosterone. So yes, they can lower renin, but they should not give you a strong phenotype of renin independent aldosterone production. So I don't want to dismiss that concern, but I think it's overhyped relative to the rest of the scenario. And the problem that we're in, I

[A]

think, because I have been testing for the past couple years. Mobeen and I work together in clinic and we would test and sometimes you do get some, like, you'll get like, arenin. That's kind of like borderline. It's not super low, or maybe it's suppressed. And then the aldosterone is like seven. And I find that I get a lot of more of the sort of like, I'm not equivocal testing than I do, like, the slam dunk positive testing. Can you talk about maybe why that happens or how we should troubleshoot that sort of thing? I think that's a higher level thing we haven't talked about before on the show.

[C]

Yeah. Okay, so we're going to get philosophical now. So, you know, we started off with what is primary aldosteronism? And I did not define it based on a cutoff. Okay? There is no international definition or gold standard for defining primary aldosterone. It's not like a biopsy. You do the histopathology and the pathologist says, this is breast cancer. And the pathologist in Italy and the pathologist in Kyoto, Japan, and the pathologist in Boston all say, yep, by this standard, by these criteria and these mitosis, this is breast cancer. We do not have such a standard in primary aldosterone. Not a pathologic standard, not a biomarker, none of that. Okay, we have the description I gave at the beginning of the podcast. It is a form of pathologic renin independent aldosterone production driven primarily by autonomous aldosterone or dysregulated aldosterone production from one or multiple foci in the adrenal cortex. Now you have to operationalize it. Now you have to operationalize it. And this is. It truly is philosophical because if you work in a clinic in Philadelphia or Boston, or if you work in a village in India or Russia or China, you might have a different way of operationalizing. And that's fine. This is not about right or wrong. It's just about what's the right thing to do for the patient in front of you in the clinical and geographic and regional context you're in. And there may be different answers to this question. So if the aldosterone is really high based on whatever you think high is, and the renin is really low. Easy, right? There's going to be a point where you start saying exactly what you said. I think you said 7 nanograms per deciliter. All right? And for those of you who are In a place listening with SI units. Just multiply 7 by 27.7. Okay, and you're saying that's equivocal? That's equivocal. What's equivocal about it? What's equivocal about it is. It's renin independent aldosterone production. But in your mind, you have a preconceived notion of high and low. And I'm an endocrinologist. There is no high or low. There's only inappropriate and appropriate. Okay, so if a patient. I'll give you a different example. If a patient's hypercalcemic calcium of 13 milligrams per deciliter, you check their parathyroid hormone, it should be undetectable. That's appropriate if the calcium is in the reference range. But high reference range, say 10 milligrams per deciliter. Sorry, if the calcium is 13 milligrams per deciliter high, but the PTH is in the reference range. Okay, the upper end of the reference range, it's not normal. It's still inappropriate. It's still primary hyperparathyroidism. And you can keep doing this to. The PTH is in the low end of the reference range, where is suppressed. You can keep making the argument it's primary hyperparathyroidism all the way down to a very low pth. So the same argument here with primary aldosteronism. And these notions stem from really, people, a few handful of experts who decided at some point in time, when we had older, say, radioimmunoassays, that 20 nanograms per deciliter was high, and everything below that just became essential hypertension or low renin hypertension. And the roads literally diverged. A group of people studied primary aldosteronism and they said it was rare because they were looking for these extreme cases. And everyone else said, hey, this is hypertension and low renin hypertension. And the group of people, and I'm talking 70s, 80s, who studied low renin hypertension noticed that Mr. Antagonists like spironolactone made it better. So we have clinical trials from the 1970s saying, hey, look at this. Low renin hypertension, it gets better with spironolactone. And now those roads are converging again where people are starting to say, I think this is all part of one continuum where any aldosterone production when renin is low is some degree of primary aldosteroneism, where the louder the signal, the more intense and obvious the diagnosis and the milder it is the bigger the conundrum. But we have cohort studies, very large repeated cohort studies, I'm talking Framingham Jackson heart, Eric Crick over and over that have shown that the risk for developing hypertension, for developing cardiovascular disease, for kidney disease, exists across this entire continuum, meaning renin. With an ALDO of 4, 7, 12, 20, 30, the risk of these incident adverse events just keeps going up. We also have studies that show that if you treat with an aldosterone directed therapy, the blood pressure reductions across this continuum are paralleled in magnitude. So to your question, if your patient has renin independent aldosterone production, whether it's 7, 12, 15, it's part of this continuum. What you have to do is operationalize it for that patient and for your clinical context. Okay? So I realize this is frustrating for people, so if you're the type of person that's just saying on this podcast, tell me the damn cutoff. Stop getting philosophical. For me, the cutoff is 10 nanograms per deciliter. You know why 10? You have 10 fingers. 10 is a nice round number. It's double digit. It's not controversial. So 10, okay, so it's come down from 20 to 15 to 10, but it's 10 on an immunoassay, an ELISA, if it's a mass spec assay. You know, mass. An immunoassay has to detect aldosterone using an antibody and differentiate it from cortisol. If you look at the structure of aldosterone or cortisol, just Google it after we're done. It differs by one oxygen atom. Take an oxygen atom and move it from here to here. That antibody has to be so specific that it differentiates aldosterone from cortisol and all the other adrenal steroids. So there's obviously some cross reactivity depending on the antibody and its specificity. And the number is a little bit inflated because it picks up some non aldosterone steroids. But mass spec does not. Right. Liquid chromatography, tandem mass spec, high throughput, available now in many labs, picks up just the mass of aldosterone. The peak is accurate. And in the United States, at least, most reference labs, I'm talking Quest, LabCorp, Mayo, et cetera, use mass spec. Mass spec levels will usually be lower to a lot lower. And so the guidelines say 10 for an amino assay. And they said, well, let's just make it 25% lower for mass spec. It's a nice round number. So it's 7.5 nanograms per deciliter. By mass spec. This is not precise, it's not validated, it's not calibrated. There is no gold standard. This is the experts coming together and say 10 seems like a reasonable number. We don't feel comfortable going lower, and then we'll just convert that to 7.5 by mass spec. So I'm not criticizing the experts. I was on that guideline as well. But that's where the consensus settled on what we feel comfortable with. We're liberalizing it, but we can't go further. But that doesn't mean that if you see a patient with seven, you said seven, that they don't have primary aldosteronism. They reside on that spectrum. The only question to you now as a clinician and as a patient is what do you want to do about it?

[A]

All right. Before we get into treatment, I think Paul has a question here.

[B]

I think it was the ACE guideline that made me laugh again. It talks about ordering the renin aldosterone and then potassium is also part of the workup. But every time potassium is mentioned, there's also this caveat that. But not for make the diagnosis. So I would just like to hear sort of broadly how you think about potassium and what to do with that in terms of the initial workup for Hyperaldo, because I feel like the traditional teaching is you almost expect it to be low if you suspect, but it turns out that's the minority of the time. So what are you doing with potassium? How do you think about it and how does it sort of guide management moving forward?

[C]

Correct? Yes. So great question. I think I did say, and I apologize if I didn't, that the test to measure if you suspected arenin aldosterone and serum potassium.

[A]

You did.

[C]

And the reason for the serum potassium is just in case. Serum potassium of 4.0, let's say that's what our body is tuned to. And each of us has a slightly different potassium stat. If you go slightly lower than that, aldosterone will be suppressed. And if you go slightly higher than that, aldosterone will be stimulated. Aldosterone is stimulated by extracellular potassium concentrations, and it's appropriately shut down when potassium gets lower. So if you suspect somebody has primary aldosteronism and they're potassium is 3.1, and their aldosterone comes back 5 or 7 and you start stroking your chin, wondering what's going on. If that potassium had been 4, it might have been 15 or 18 nanograms per deciliter, maybe making the diagnosis more obvious. So that's the Reason to measure the potassium. The other reason to measure it is if it's low, it makes you even more suspicious that this is all primary aldehyde. Meaning if you got a potassium of 3.1, a low renin and aldosterone of 7, you might say, that's good enough for me. What else could be going on? So the minority of patients with primary aldosteronism have a documented low potassium. If you just think about the physiology, as I mentioned earlier, aldosterone works in the distal nephron in the principal cell to exchange sodium and potassium. It absorbs sodium from the urinary lumen and kicks out one atom, one positive cation, either potassium or a hydrogen atom, proton. So that's why you get metabolic alkalosis and hypokalemia. But to do that, you have to deliver sodium to the distal nephron. Okay, so basically, if you eat a salt load and you keep eating high salt loads and you have very high aldosterone levels, your risk for hypokalemia starts going up. So the more severe the primary aldosterone is, the more likely you are to see hypokalemia. But even now, with the very low levels of diagnosis, it's only about 30ish percent of patients that have documented hypokalemia. If you look at that whole pyramid, that whole iceberg that's undiagnosed, it will be even lower. That fraction will be even lower. So the way to think about it is potassium is not a diagnostic. If you see it, it really does help your suspicion. But if you don't see it, that doesn't exclude the possibility of primary aldosteronism.

[D]

And Dr. Vaidya, I wanted to kind of touch on this before, obviously we get into treatment, but I think something that I think made me cringe as a resident was thinking about if I do get a positive screening test back, was aldosterone suppression testing. I remember it used to be a big thing. How do we set it up? How do we do it, especially in a primary care clinic. And I'm glad that the new guidelines have steered away from that. If you could just talk upon whether there is any role of aldosterone suppression testing as we thought of traditionally before. I know the guidelines mentioned that it may help with lateralization, but I know certain studies I don't haven't seen that, but if you could just kind of talk upon that.

[C]

Yeah. So I want to preface this by saying you said. What did you say? You said you felt squeamish or.

[D]

Yeah, it was cringe.

[B]

Cringe.

[C]

You felt cringe.

[B]

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[C]

So I really want to destigmatize this because I do think intimidation and fear has prevented so much progress in this field. If you're listening to this podcast and you want to test for primary aldosteronism, you cannot be wrong. The fact that you even just venture down this pathway, you're doing it right. And once you get the test, you're not going to mess up. You know, worst case scenario, you put your patient on some spironolactone and you've done them a huge service and you've moved the needle forward. So don't stress out. That's the key thing. I get emails from very smart clinicians who are absolutely right, doubting themselves and second guessing themselves, mainly because the guidelines had been written in the past in such a complex, intimidating, stern, kind of paternalistic way that very good clinicians doubted themselves. So really, don't doubt yourself. Trust yourself. You're already doing the right thing. In many aspects of endocrinology, not just adrenal and primary aldosteronism, we use stimulation and suppression tests. It's just a tradition in an endocrinology because many hormones used to be difficult to measure. We used to have radio amino assays and endocrinology is a biochemical specialty. We need to measure stuff to know what's going on. And once we could measure stuff, we realized, well, these hormones are going all over the place. Lh, growth hormone, cortisol, aldosterone, it's up and down. Sometimes it follows a pattern, sometimes it doesn't. So how can you measure something that that exists in picomolar quantities and goes from like super high to super low every 12 minutes or overnight or in the morning. And one way you can do that is to once you understand what regulates that hormone, which is a huge leap forward, is to stimulate it and then measure it at its peak or try to shut it down and measure it at its. Natalie Right. I'm sure you've heard about insulin suppression tests and cortisol stimulation tests and aldosterone suppression tests. It exists everywhere. So a lot of those tests were developed because assays weren't as good, because our understanding of physiology and biology wasn't that good, and because they were used as research instruments. And then, you know, at that time just carried right over into Clinical care. Okay. But that tradition now has persisted even as primary aldosteroneism has become common. And they got the name confirmatory test, which is, I think, even worse because it implies psychologically that this test is going to confirm or exclude the diagnosis. And I just kind of went on a mini rant telling you that there is no official international standard by which you can calibrate these tests. Right? So how can you make up a test that's now going to be dichotomized as positive or negative? Someone made it up. Up. The test itself makes complete physiologic sense, these confirmatory tests, generally speaking. And by the way, there's over a dozen of them. Over a dozen of them. The guidelines typically have recommended four, but in other parts of the world, they do other ones, almost every single one, intelligently and in very cool physiology, modulates volume, expands volume, typically sometimes contracts volume to modulate the renin angiotensin system or gives an ACE inhibitor, an arb, to interrupt the renin angiotensin system to try to interrogate. Is the aldosterone being produced autonomously? Does it shut off physiologically? But then once you get the test results, somebody says, well, I'm just going to say, you know, 10 is high and nine is low. And so that's the problem with these tests. They interrogate a physiologic system in a very wise way, but it's a lot of labor and a lot of work that, in the research setting, makes sense, but for the average busy clinician, it's a ton of work and intimidation. But then the actual readout is somewhat arbitrary. So the most recent guidelines acknowledged that this is a difficult test to do. It may not be necessary to operationalize how we diagnose and manage primary aldosteronism. And often you do all that work and you can actually erroneously exclude the diagnosis of primary aldosteronism. So the new guidelines do not recommend doing this for confirming or excluding the diagnosis. So, again, to podcast listeners, if you think about it, don't be afraid. Just go ahead and test on medication. Just with the renin and aldosterone, you can probably make the diagnosis or not, and if you're not sure, just repeat that. Just phlebotomy, Renin, aldosterone, potassium. So I think the second thing you said, mobine, is, well, should confirmatory test be used at all? Now, this is an area that's still kind of being flushed out, and I would say is nascent, which is the most recent guideline suggested. Well, maybe there is still a use because once you make the diagnosis, then you might want to know, should this patient be treated with a medicine like a mineralocorticoid receptor antagonist or. Or are they one of the minority of individuals who has one sided unilateral or lateralizing primary aldosteronism that might be amenable for surgery? And as you know, really the only reliable way of doing that is with adrenal venous sampling, a very technical interventional radiology procedure that most people in the world, even in the United States, don't have access to. And even if they have access to it, it's technically so complex that very few interventional radiologists get consistent results. So it's a major bottleneck. So one of the holy grails is can we figure out some biomarker, some circulating substance, some maneuver that lets us predict the outcomes of adrenal venous sampling without doing it? And we may talk about it. There are now new PET modalities that might actually succeed at doing that. But some people believe that if the primary aldosteronism is quite severe, it's more likely to be unilateral, which I think is generally true. And I've suggested that if you do a confirmatory test and it's positive, then you have predicted the likelihood of going down that pathway where you use those resources, whereas if it's negative, you can just avoid using those resources. Now, how accurate and robust are those data? I think that is debated because there are many studies that suggest that that might not be that accurate and a good use of time. And then there are some that suggest it might be. And so that's debated. I personally will tell you I do not use confirmatory testing for that purpose. I do probably 1000 a year on a research basis in human physiology studies, which is a major part of my career. But clinically for patients, I'm very pragmatic. And what I'm recommending here is exactly what I do in my clinic. Measure renin aldosterone potassium on medications, I interpret it, and then I talk to the patient about what they would like to do, what I have access to. I do have access to adrenal venous sampling. That's quite good. And I offer them what they would want to do. And many patients say, you know what, just treat me with the medicine. If it works, I'll go with it. Some patients say, get this thing out of me if you can, and we'll do the whole shebang. Some people can't do it, some people can do it. So if you, if you don't have access to adrenal venous sampling. This is a moot point. You just treat with medicines.

[A]

And in the guidelines, there's some figures in there that they mention. The probability of lateralizing primary aldosteronism. If someone has that hypokalemia, that's more likely. Or if they have a very low renin or a very elevated aldosterone, which we talked about is kind of all relative, they suggest some potential cutoffs in there, there. So we'll kind of take that for, you know, with a grain of salt.

[C]

That's an attempt to operationalize the severity of primary aldosteronism. And in some clinical settings, that might make sense. You might say, like, this is meeting the criteria of so severe and so likely to be unilateral before I give this patient a lifelong diagnosis and treatment. Let's see, let's see if they're open to it. Let's see if they have unilateral disease. But. But how that's operationalized in various clinical settings can vastly differ. So you have to take that as a suggestion and with a grain of

[A]

salt, let's get to the next part of this case, because I do want to get to the second case, too. So the patient is screened for primary aldosteronism with aldosterone renin ratio and metabolic panel. So aldosterone is 11 nanograms per deciliter. That's the LC Ms. Version. And then the plasma renin activity is 0.6 nanograms per milliliter per hour. So the ratio comes out to be 18, and the potassium is 4. So what would you make of that? We talked about some of these cutoffs. And what would you do next for this patient? This is our guy, Excess Aldo.

[C]

Right. And how old was excess Aldo?

[A]

He's 45.

[C]

Right. So I would say he has Renin independent aldosterone production. He has hypertension and renin independent aldosterone production. So he has a positive test for primary aldosterone. Further, those tests were done on a medication that should have raised renin and it was still low, and on a medication that should have raised renin and lowered aldosterone. So if there's any doubt, he really has primary aldosteroneism. So I would tell him you have primary aldosteronism. This is likely a major contributor to your hypertension. There are many other contributors to hypertension. Right. It doesn't have to be a monotonic relation relationship. It is increasing your risk for cardiovascular disease. And the objectives of your treatment are to block aldosterone control your blood pressure and mitigate your excess risk for cardiovascular and kidney disease. Given his age, he's 45 years old, he's young. Given where I work, where I have access to almost everything, I would say you can either take this medicine, mineralocorticoid receptor antagonist, for the rest of your life.

[D]

Life.

[C]

And you can get very good outcomes with it. Good blood pressure control, good reduction in other polypharmacy. But given how young he is, before we do that, would he be interested in doing a procedure that might determine whether he's eligible for a surgical adrenalectomy that might give him a more durable remission and disease, maybe even cure of disease that might be even more likely to reduce his cardiovascular risk. And then this is when the conversation gets really intertwined. And I would say this is a conversation that a specialist should have. So at this, by this point, you should refer your patient to a specialist because this does get nuanced. Patients start getting. Many patients get nervous. You're, what, surgery and a procedure before the surgery. So, you know, I explained to patients that an adrenal venous sampling is generally a very safe procedure. It's kind of like a colonoscopy. You get propofol or Versed and fentanyl. You don't remember anything. An hour later, you're awake. They cannulate, usually the femoral vein and go into the venous system. So it's not like a cardiac cath where you're in the arteries. Take samples from each adrenal vein, you wake up and you go home, and about a week later, you'll have the results. And if they lateralize deeply, lateralize to one side or the other, you would be eligible. And I would recommend a surgical adrenalectomy, which is done laparoscopically. Surgery is surgery. It's not something to sneeze at, but it's relatively low risk operation. And, you know, at 45 years old, I would probably tune up the intensity of that conversation so the patient truly understands. I'm 46, so I would probably tell this patient that if I were in your position, this is. I would choose this, but I would not pressure them to think that they must do that. You know, there are many patients who are not ready to make a decision like that. And I will just say if I get any feedback, don't worry, I'm going to start you on a medicine. You can always choose to get surgery at a later time or pursue adrenal venous sampling at a later time, but you cannot do A surgical procedure, right?

[A]

Yeah.

[C]

So I, I, I actually, I've taken this latter tact more and more because clinic visits are about 20 minutes. This is a conversation that sometimes is better had serially over time. Once a patient trusts you and gets to know you, so I would treat the patient if they had any, you know, without any knowledge and hadn't put a lot of thought into it, I'd give them the information, treat them, see them over time and maybe the treatment goes really well and they're not interested in doing anything further unless things change. And maybe with time and trust and more conversations, they, you know what, I'm ready to pursue adrenal venous sampling and

[A]

we'd do it then in your hands for a 45 year old like this guy. Spironolactone can have some sexual side effects, can have some gynecomastia like breast tenderness. And aplerinone is twice a day drug and can be a little more expensive. Can you talk a little bit about how that goes and what kind of doses are you typically getting to with either of those agents?

[C]

Yeah, so. Well, first it's important to know so I don't sound kind of like out of tune person. I practice in Boston, Massachusetts and I see patients all over New England. Because the states are very small, everybody typically has pretty good insurance. Okay, we have pretty good insurance coverage either from the state or from private insurers. I treat men with eplerinone. I do not treat men with spironolactone. Now I'm saying that because in many countries you cannot get a pleurinone. The national formulary only has spironolactone. In many parts of the world you cannot afford a pleuronone even though it's a generic pill. So I use a pleurinone and in women I'll use spironolactone. Spironolactone and eplernone are both mineralocorticoid receptor antagonists. Spironolactone is a steroidal. That is not specific to the Mr. And as you mentioned, it does have some off target effects, antiandrogenic effects, namely it is more potent so you can take it once a day and get a much more potent and durable response. Eplerinone is less potent and has a shorter half life, so you have to give it twice a day and usually at approximately twice the dose. But it'll get the job done. The reason I don't give it in men is at a certain dose, typically 50 milligrams and higher. Almost every man will have antiandrogenic effects. It's much more than the stats are because most men are not going to come to their doctor and say they have nipple tenderness and gynecomastia. Most men don't volunteer to their doctors that my sex life isn't great, my libido is low, my rectal function, if they do, it's pretty bad. You know, I've seen men with, you know, 10 or four breasts and you ask them and they say I'm fine. And then you're like oh man. On a physical exam they really don't want to complain about it. So I try not to give spironolactone. I go for a pleuranone and men but in my opinion you can get equivalent efficacy is you just have to deal with dose and frequency.

[A]

I'm looking up. You can get on a. I won't give them a plug by name but on a popular wholesaler that is a newer thing, not one of those coupon programs. The wholesale pharmacy that's online they have a plarinone for 50 milligram tabs. You can get 90 for $26.45. It says you're saving $383.95 by shopping there. So I hadn't looked it up on that site before. That's better than I've seen in the past with some of the other. So that's even if someone doesn't have insurance, they can go through there. All right, Paul, so this first case, let's say so we're putting this guy on a player known. And Paul, anything else you want to go through with this first case or you think we're ready to go on to the next?

[B]

I think it's time to move on.

[A]

On time to move on. Okay. Mobine, would you do the honors and we can go on to the next case. I think we have another great name.

[D]

Yep, of course. So the patient's name is Alexander Vincent Strong. He's got a long name so his friends call him AVs for short. They don't. I mean he's got. His friends are endocrinologists so I'll allow it.

[A]

They're endocrinology fellows.

[D]

Yeah. Basically he is a 30 year old male, has a past medical history of hypertension for the past two years coming for evaluation of his hypertension and also noted to have hypokalemia on blood work noted by the PCP on the physical exam his blood pressure is elevated. It's 147 over 90 millimeters of mercury, while the rest of his vital signs are normal. Otherwise, his physical exam is unremarkable. He's currently taking Losartan 25mg daily for his blood pressure workup. Was sent for primary aldosteronism and it was significant for the aldosterone being 16 nanograms per deciliter and his renin being very suppressed at 0.1 nanograms per milliliter per hour in the setting of having a low, potassium was 3.2 mill equivalents per liter. During this workup, he also obtained a CT scan of his abdomen without contrast, which did not show that he has a discrete nodule on either side. So I guess the big question with this case is the fact that since he does not have a nodule, would the patient still benefit from undergoing an AVS to try to lateralize where this Aldo might be coming from?

[C]

Okay, great case. So first, he has clear cut primary aldosteronism. He has an aldosterone of 16 nanograms, a very low renin, despite hypokalemia, which should have lowered the aldosterone despite the angiotensin receptor blocker. So clear primary aldosterone. And it's A young guy, 30, I would say, in this guy and even in the previous guy who I said was young, I would have also offered genetic testing. There are a few, four forms of familial primary aldosteronism. They're very rare. The likelihood you will diagnose familial primary aldosteronism in an adult that has gone through childhood life is low. It's not zero, but it's very low. But we have very simple ways of doing genetic testing right now. And if that were found, it might change management. Okay, I won't go in through familial forms of primary aldosteronism, but if you see somebody who's very young like this, you should mention it and work with a specialist to at least offer genetic testing. So do you need. The question you're asking is, does an adrenal mass have any meaning or value for primary aldosteros? So the answer is kind of no. And it's important here because I think in most people's mind, they think of an aldosterone producing adenoma or a cons tumor, because that was the original description and it has not died. The simple way to think about it is the presence of an adrenal mass doesn't imply that it is the source of primary aldosterone. The absence of an adrenal mass doesn't exclude the possibility of primary aldosterone. And the reason for that is that the majority of primary aldosteronism is caused by microscopic foci of aldosterone production that are almost all due to somatic mutations in the adrenal gland. This is a lot to digest, but just think about it this way. The adrenal glands, for reasons we don't fully understand yet, are predilected to developing somatic mutations that that pump out aldosterone. You don't need a tumor. And another way to think about this is adrenal incidentalomas are very common. Okay, if 100 people got a CAT scan at your hospital, somewhere between 4 and 10% will have an adrenal abnormality. So that pathology and adrenal growth lipid rich benign adenoma is common. Primary aldosteronism is common. I just told you. The somatic mutations that cause primary aldosterone is exist in somewhere between 15 to 30% of the hypertensive population. And sometimes these two common things happen on top of each other. You have an adrenal adenoma and within it you have foci primary aldosteronism. And that's an aldosterone producing adenoma. That's the convergence of two abnormalities. On the screen, Matt pulled up some slides of just some case representations just to give you an eye light. This is a case that we published in the New England Journal as a case report of a young woman with hypertension, hypokalemia, and primary aldosteronism. The CAT scan also showed no adrenal abnormalities. However, the adrenal venous sampling did lateralize to the right adrenal gland. And so she had a unilateral adrenalectomy and was cured. And what Matt is showing on the screen that I'm describing in words is the pathology. You look at the growth pathology. The adrenal is completely normal. There is no tumor, there is no hyperplasia. So this idea that there has to be an adenoma or hyperplasia, neither is seen. You look at the H and E stain. Normal. There is no hyperplasia. There is no tumor. The final picture shows immunohistochemistry for CYP11B2. CYP11B2 is the fancy name for aldosterone synthase. This is the enzyme necessary to make the final step of aldosterone that is expressed in what we typically call the zona glomerulosis. You stain this normal histopathology with the antibody for CYP11P2 and you see these little islands of staining? These islands are not tumors. These are areas where CYP11B2 is being expressed and it's being expressed. And if you dissected that out, which is not shown, and sequence it, you'll find a somatic mutation in there. So this is what primary aldosteronism looks like. It's little areas of abnormal or aberrant expression of aldosterone synthase. It shouldn't be expressed. Your hypokales, it shouldn't be expressed. Renin and angiotensin II are low, but there it is making aldosterone when it shouldn't be. That's primary aldosterone. I think if you go one more slide, Matt is an example. Yeah, here's an example of another young guy with primary aldosteronism. This time there was a tiny right adrenal nodule. So you might say aha. That's the cons. Tumor has a laparoscopic red adrenalectomy. Here's the gross pathology. It's a normal adrenal gland, but there, right in the middle is a little yellow adenoma. That's an adenoma. Is it an aldosterone producing adenoma? You stain it with immunohistochemistry for CYP11B2. It is. That is an aldosterone producing adenoma. It's the convergence of two abnormalities. Benign neoplasia and over expression of aldosterone. But then what should happen? If one area of an adrenal gland overproduces a hormone, the rest of the physiologic focal aldosterone production should be suppressed. Right, but there you look, on the ipsilateral adjacent adrenal gland are little micro islands of abnormal expression. So this patient's primary aldosteronism was caused by an aldosterone producing adenoma and multiple APMs. Aldosterone producing micro nodules. And if you have this process on one side, what's to say that this diffuse process won't happen on the other side? Alright, this guy lateralized to one side, but maybe it's asymmetric, maybe it's asynchronous. Maybe down the road, five, ten years from now, the other remaining adrenal gland might also start over producing aldosterone. So this is where we are right now in this field, starting to understand the pathology of this disease by physically seeing with our own eyes what it looks like. And if you go one more slide, Matt, this is a very recent development which is is a CYP11B2 specific, an aldosterone synthase Specific radio ligand. So this is a pet moiety labeled with fluoride 18F18 tagged to an aldosterone synthase inhibitor. So this radioligand will go to any place where aldosterone is being produced and light up on a positron emission tomography. So if you go to the next slide, there's a couple of cases that I'll just verbally describe. A patient with primary aldosteronism who has a CAT scan. The adrenals look normal, there is no nodule. You do the adrenal venous sampling, it does lateralize to the left. You do this special PET scan that is not widely available yet. This is a research study, but this might become available in the future. And it shows two areas light up. Now you say, is that just noise? Did this PET ligand just light up by accident? Because I don't see an anatomic correlate on the CAT scan. Patient gets an adrenalectomy, their primary aldosteronism is cured. And you actually look at the PET of the tumor. There it is of the adrenal gland, there are these two light ups. You do the immunohistochemistry, they match up perfectly. So what this CYP11B2 specific radio ligand can show is microscopic areas of aldosterone production. Aldosterone synthase expression are now visible on a PET scan. So this patient did have unilateral disease, but it was caused by multiple foci of aldosterone production. And the next slide shows the opposite. Here's a patient with primary aldosteronism whose CAT scan did show a nodule, a right adrenal nodule. And you might be tempted to say, well, aha, that's it. Adrenal venous sampling, lateralized to the right side. That's an aldosterone producing adenoma. But the PET did not light up. The adenoma is not expressing aldosterone synthase. If you go to the next slide, actually the aldosterone is coming from a different foci on the right and on the left. So this patient actually has bilateral multifocal, nonadenomatous primary aldosterone and also an incidental non functional adrenal adenoma.

[B]

All right, that's infuriating.

[C]

You have to disconnect. You might ask, then, what's the point of getting a CAT scan in a patient with primary aldosteros? The point is actually quite limited. If your patient is going to go to adrenal venous sampling, your interventional radiologist is going to want a CAT scan. It's Their map. If your patient is going to have surgery, your surgeon is going to want a CAT scan. It's their map. Map. But that's it. If you're not going to pursue adrenal venous sampling or surgery, which is. The vast majority of patients are going to be treated medically, there's no strong reason to get a CAT scan because an adenoma doesn't tell you that it's the source of primary aldosteros. One esoteric thing is sometimes the adenoma can make cortisol. A completely separate discussion, and that has other importance that we won't get into right now, but in terms of the primary aldosterone, it's. Its importance has been narrowed. So this slide basically just shows primary aldosteronism is not adenoma versus hyperplasia. It's microscopic foci of aldosterone production that sometimes collide with an adenoma.

[A]

I gotta rethink every. That kind of blows my mind there. And that's. Yeah, that's. So we just need to make this scan more widely available and then you will be able to see where it's coming from.

[C]

From. Yeah, it's a very exciting time right now because. So that scan, it not only lets you see it, but it, you know, if more robust studies come out showing that it can replace adrenal venous sampling, then of course, that would be a game changer. This is a. I'm showing you that study because the visuals are just so jarring. It was published in the New England Journal as a research letter because they haven't done the robust phase three studies where you kind of randomize people to AVs or not, but the correlation in that study, and I would recommend that study because they have an appendix where they just show every detail transparently of every case they studied and you see every permutation of it, and it's quite impressive. So I think if that type of modality or even newer ones that come down the road that are better than this one come out once you can see it with a PET scan and you don't have to do this bottleneck adrenal venous sampling, the process of managing and subtyping primary aldosterosism will get a lot easier here.

[A]

Anand. So let's say that AVS has decided that he does want to pursue surgery. He doesn't want to take medication for the rest of his life. So we'll plug him into that pathway. Maybe he gets in a research study and gets one of those fancy scans you just told us about and gets an adrenalectomy and does well. So let's move on to our third case, Mobine.

[D]

All right? Yep. So the third case is Mrs. Lois Kalma. She is a 66 year old female with a pass medical history of hypertension, hyperlipidemia, type 2 diabetes. Initially presenting to you for follow up of her type 2 diabetes, but on physical exam you notice that she is slightly hypertensive at 137 over 88 millimeters. Mercury and the rest of her vitals are normal. On a review of her medications, you notice that she's on quite a few antipertensives. Amlodipine, 5mg, Valsartan, 160mg, Chlorthalidone, 25mg daily and Metoprolol, 25mg. Importantly, she also was told to start taking potassium supplements many years ago when they noted that her potassium was low. After Screening her for PA, her aldosterone level is notably 11 nanograms per deciliter via LC Ms. And the plasma renin activity is 0.5 nanograms per milliliter per hour with an aldosterone renin ratio of 22 with a normal potassium level. After discussing with the patient, she decides that she wants to opt for medical therapy with spironolactone rather than pursuing surgery. So I guess, Dr. Vaidya, we start her on spironolactone and kind of, what is your approach to following up on these patients on medical therapy? What labs do you order and kind of what things do you monitor?

[C]

Great. So the patient has, I think, probably resistant hypertension and a history of hypokalemia. And on an angiotensin receptor blocker has these labs. So clear, primary aldosteronism wants medical therapy. That's great. So what I would do is the following. I would first talk to her about dietary sodium restriction. This actually should be counseled for every patient with hypertension. It's actually easy to say, but it's very difficult to do. Right. As I said at the beginning of this podcast, everything we eat from a grocery store that comes in a packaged jar or container has sodium in it. So somebody has to. And we're eating 3 to 4 grams of sodium a day. So to try to reduce that is very difficult. And how much do you have to reduce it? You know, aha would say 1500mg, 2000mg a day. It's difficult to do on a consistent basis. But sodium is the fuel. The substrate that fuels Primary aldosteronism. Actually, if you get rid of sodium in your diet and you go to an ancestral diet, you can kind of make primary aldosteronism evaporate, operate. It's just not sustainable for most people. This is a key point. If you get rid of sodium from your diet, if you can manage that sustainably, your primary aldosteros may not be visible anymore. It may just not manifest. It's there, but you just can't see it anymore. There's nothing for aldosterone to act on. How can you have the manifestations? So even some degree of sodium restriction will synergize with an Mr. Antagonist and give you a big greater efficiency. So what I would recommend is cut sodium to the best of your ability. And, you know, you can send them to a dietitian, nutritionist, give them some online resources, whatever you think might work. And I would start with a very low dose of spironolactone, 12.5 milligrams per day. I would just add it on to what she's currently on and then teach her how to measure her blood pressure at home. I would recommend a blood, I won't say the company, but an automated arm cuff. You sit down, you rest, show her the picture from the aha on how to measure blood pressure, rested blood pressure, and then do it in triplicate. Record it down on a piece of paper or on a spreadsheet and mail it to me every couple of weeks. And from there you can go at whatever pace is comfortable for you and your patient, whether you want to do it back and forth on an online portal or inpatient or in person visits. But the idea would be you start very low and see how much, much effectiveness you get. You might get a lot. And then over time, as necessary, you escalate the spironolactone dose with an ion, decreasing the other medications. So if this patient has primary aldosterone, spironolactone will be much more effective at lowering blood pressure than these other drugs. What are the goals to normalize blood pressure? Less than 130, 80 with the fewest number of antihypertensive medications. Number two, normalize potassium without the use of supplements. I think you said she's on a supplement. So my first goal would be get off the supplement, and then my next goal would be get off the angiotensin receptor blocker because you're on dual RAS inhibition. And then depending on how things go, you either increase the spironolactone dose further and maybe consider stopping some of the other medications. So blood pressure reduction and normalization is by far in a way causally related to reducing adverse cardiovascular outcomes. Outcomes. Getting rid of potassium supplements is a huge quality of life benefit. And then after that, if you think about the pathophysiology of primary aldosterone, it's renin independent aldosterone production. If you effectively block aldosterone and counter its deleterious effects, you should induce some volume contraction or normalization of volume and renin should rise again. Reminds me of Batman Rises, which is one of my favorite movies, the Dark Knight Rises. So renin rises again, it comes back into normal physiology. So it turns out that that rise in renin is associated with better outcomes. So if you just do what I said first, titrate the spironolactone up as hard as you can to get the blood pressure normal, lower the meds, most of the time the renin will rise. There's some debate about how much it should rise. Some people have cutoffs. I'm a kind of anti cutoff person. Any rise from baseline suggests that you're moving towards physiology and you've done a good job. And so that's kind of the main goals in a nutshell. I will say one other thing. I think you said she had diabetes. I can't remember if you said she had CKD. But as you may know, there's a new Mr. Antagonist called phenerinone, non steroidal Mr. Antagonist that was tested not for primary. Actually, there is a study in primary aldosterone, but its prime testing was in heart failure and CKD with diabetes. And it has remarkable cardiovascular and kidney protection. So this is a patient who might also, if she had gone to a cardiologist or a nephrologist, just have been started on phenerinone at a fixed dose. We don't know how good phenerinone is in primary aldosteronism. So if she had already come to me from a nephrologist on pheneronone, I probably would have left it if things looked good. But if it's me, I would have gone with spironolactone or eplerenone.

[A]

Paul, I don't know about you, but when he said ancestral diet, I was thinking of Liver King.

[B]

No, believe it or not, Matt, that's not exactly where we had.

[A]

That's not exactly.

[C]

Yeah, wrong podcast. Wrong podcast.

[A]

Yeah, wrong podcast. Okay, well, so that's interesting. Yeah. So phenerinone not yet studied for that. In your opinion, do you think that might work? If it's studied that it would work for this condition. I know it wasn't as good for blood pressure, but it did cause hyperkalemia just like spironolactone does. So I wonder.

[C]

Yeah, so I mean, the whole mantra with phenerinone was that it might actually have more predilection for myocardial mineralocorticoid receptor isomers than kidney. And that's why maybe the hyperkalemia risk is slightly lower. And so maybe that same thinking might be why it doesn't work as well in primary aldosteros. I think the jury's out because we don't have dedicated studies. I actually think there's actually a 24 hour blood pressure monitoring study with phenaris. Nocturnal blood pressure did go down. It actually had a decent effect. There's one randomized controlled trial from China where they actually compared phenerinone with spironolactone in patients with primary aldosteronism and showed that it did pretty well. It's just that the doses they used and the duration of time they used wasn't long enough for me to say that it's equivalent. But there's no reason to believe it wouldn't work. I bet it does work. The only question is, does it work as well? And is it necessary to pull out essentially a branded, difficult to obtain and expensive Mr. Antagonist when you have these, you know, 70, 50 and 70 year old Mr. Antagonist and spironolactone and a pleurinone with lots of experience and I think in the United States we might have this discussion. But this is a moot point almost everywhere else in the world, so I'll just leave it at that.

[A]

I like it. Paul, you had a question about future directions, I think.

[B]

Yeah, I mean, the treatment seems kind of shockingly simple. I mean, the workup is just so intimidating, or at least it was until we had this excellent education from you. But then the treatment, there's only a handful of drugs. I would love to hear sort of where you think we're going with this, especially since now that CT scans are not all that helpful in terms of localization, what does the future of treating primary hyperaldo look like just over the next five, 10 years, if you had to guess.

[C]

Yeah, well, I'm glad I made treating with spironolactoneplerinone sound easy. But as you know, most clinicians are terrified of giving Mr. Antagonist because they're terrified of hyperkalemia. And so it's one more point worth saying is most patients with primary aldosterone are not going to develop hyperkalemia unless they have pretty advanced ckd. That's not something you should worry about. But people are scared about hyperkalemia. So the future, you know, there's a lot of promising results. If you've been even perusing New England Journal, jama, Lancet and big journals like that in the last year, almost every couple of months there's a new blockbuster study featuring an aldosterone synthase inhibitor. I won't go through the individual names of them, but there's four aldosterone synthase inhibitors. These are drugs that inhibit CYP11B2, and they do it very specifically. They don't inhibit some of the other homologous enzymes like CYP11B1, which breaks cortisol and other adrenal enzymes. They just inhibit CYP11B2 with high specificity. So they essentially, unlike an Mr. Antagonist which blocks aldosterone and raises its level but tries to neuter its effect, they actually go straight to the source and eliminate aldosterone production. You can think about it as tamoxifen and letrozole, estrogen receptor antagonist and an aromatase inhibitor. When ER positive breast cancer was first treated with tamoxifen and error, our receptor antagonist, it improved survival and outcomes. It became like a workhorse medication. Then someone said, why block the effects of estrogen? Why not just inhibit estrogen production itself with an aromatase inhibitor? And that improves survival and outcomes even further. So you can think about aldosterone the same way. Right now, we're blocking its effect. But what if you could inhibit the production of aldostrone? That would be the holy grail. Then instead of doing a surgical adrenalectomy, you can do a medical aldosteronectomy. So what's exciting right now is in phase 2, 2b and early phase 3 studies, there are four aldosterone synthase inhibitors that have shown excellent specificity for inhibiting the production of aldosterone. And they have been tested in resistant hypertension, uncontrolled hypertension and primary aldosteronism, all relatively short term studies. But they beautifully reduced blood pressure by large magnitudes through the mechanism of lowering aldosterone. So this year, 2026, there's a bunch of phase three long term studies that are going to go on and when they pan out at the end of this year and early 2027, we'll see whether this might be a new antihypertensive class of agents that automatically treats aldosterone. And so one of the excitements is we've Been talking about primary aldosteronism. And so specialists say, well, I can use one of these agents to treat primary aldosteronism. But, but if they get approved for hypertension and one day frontline clinicians use them as antihypertensives, unknowingly, they'll be treating undiagnosed and unrecognized primary aldosteronism. So the exciting thing is all the stuff I just said could all be moot and my entire career could involute because I'm not needed anymore. Because most primary aldosteros will be treated one way or the other without, without the clinician even knowing about it. And that's what primary care doctors probably want. They're busy, they're dealing with a lot of issues. They don't want to think about hormone biology. They want to give the agent, treat the blood pressure, and if there's some hormonal mechanism behind it, it's automatically taken care of. So the, you know, again, I'm speculating a little bit, but if everything goes smoothly in multiple phase three trials and there's an FDA approval, this new antihypertensive class of agents would treat aldosterone mediated diseases in a way that's unprecedented. So that's exciting.

[A]

All right, so for Ms. Lois Kelma here, you said we were going to put her on spironolactone 12.5, have her monitor her blood pressure. We would be following her. You said we'd be following basically her potassium, her. You don't follow aldosterone anymore, do you? Once they're on the medicine, you just follow the renin. And we want to, want to see the renin start to come back up. Don't really need a specific cutoff, but we want to see a nice jump in the renin there and the blood pressure be controlled and try to peel off some of the other medications. And that can be a great outcome there.

[C]

Yep. But I just, I would change the order of what you said. Blood pressure, blood pressure, blood pressure, potassium, renin. You know, I just, I get a lot of emails from people who've done a beautiful job. The blood pressure is 110. The potassium is normal, but the renin hasn't moved the way they wanted. And they're stressed out. Like, you've done a beautiful job. Blood pressure is the number one priority. Got it. And the priority is important. Okay. It's blood pressure first, then pat yourself on the back, and then maybe you can optimize the situation a little bit more. But that prioritization in Your mind is important.

[A]

All right. I think this is a great spot to get some take home points for you and this has been great. Thank you so much for your teaching. But what are a couple take home points that you want the audience to remember?

[C]

You know, for me, I've, I've spoken to audiences a lot about this and I'm at the point in my career and speaking people where I really want clinicians who care about this topic to know that they should trust themselves. Just the fact that somebody is listening to this and interested in implementing this with their patient, I just want them to know, don't be afraid, don't be intimidated. You cannot mess up. The fear of messing up is such a barrier to doing the right thing. I think clinicians should know you're not going to get criticized or be made fun of and there's not going to be an M and M about you. Test. Trust your instincts based on the physiology we talked about and you'll almost certainly do the right thing. And if you're not sure, you can always email and ask for help. The bigger problem is not doing the next step or erroneously excluding things in a kind of confident, absolutist way.

[A]

All right, Paul, you got that? Are you, you feeling confident?

[B]

I mean, you know me, Matt. I'm gonna be terrified until I die. I will be less scared of actually testing things.

[A]

All right, have a great night and thank you so much.

[C]

Thanks for having me.

[B]

This has been another episode of the Curbsiders bringing you a little knowledge food for your brain hole.

[D]

Yummy.

[B]

Thank you mabeen for preempting that session thing holes. Still hungry for more? Join our Patreon and get all of our episodes ad free plus twice monthly bonus episodes at patreon.com curbsiders you can find our shownotes thecurbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsider side just which recaps the latest practice changing articles, guidelines and news in internal medicine.

[A]

And we're committed to high value practice changing knowledge. And we want your feedback. So email [e-mail] a reminder that this and most episodes are available for CME credit for all health professionals through VCU Health at curbsiders.vcuhealth.org Special thanks to our writer and producer for this episode, Dr. Mo Binamad, and to our whole Curbsiders team. Our technical production is done by Podpaste Elizabeth Proto. Does our social media Jen water runs our Patreon. Chris the Chew Manchu moderates our discord. Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto.

[D]

I've been Dr. Mulbina Moth.

[B]

And as always, our main doctor, Paul Nelson Williams. Williams. Thank you and goodbye.