Dr. Mojola Omole:
Hi, I'm Mojola Omole.
Dr. Blair Bigham:
I'm Blair Bigham. This is a CMAJ podcast. So, Jola, today we're talking about hypertension and a cause of hypertension that maybe isn't as rare as people think. An article titled, “Screening for primary aldosteronism and primary care” has been published in CMAJ. And we're going to be focusing on how do we find these people who have primary aldosteronism driving their hypertension? Because as it turns out, and as the article points out, if you do have this as your cause of hypertension and your treatment is different, at least for the first, second, third, and fourth line, than other people who have essential hypertension.
Dr. Mojola Omole:
Yeah. And I think that after reading the paper, I just did not realize just how much primary aldosteronism is underdiagnosed and underappreciated as a cause of hypertension. Finishing medical school, I don't know, almost 20 years ago, it seems as if we're just learning more and more and which is the wonderful part about medicine, is that the amount of things that keep on changing, but also it's a bit daunting in terms of trying to keep up with everything.
Dr. Blair Bigham:
Well, all I remember from medical school about aldosteronism was that you had low potassium. But as it turns out from this article, even that's not necessarily sort of that flag for you.
Dr. Mojola Omole:
And I think for our family physician and primary care physicians, that this is a particular significance. Because we have a high percentage of the population who are affected by hypertension and that this is really a shift in terms of understanding the treatment algorithms to approach hypertension, especially looking at the role of aldosterone in it.
Dr. Blair Bigham:
Well, let's get into it with the author.
Dr. Mojola Omole:
Dr. Greg Hundemar is the co-author of the Practice paper in the CMAJ entitled, “Screening for primary aldosteronism in primary care”. He is a nephrologist and assistant professor at the Ottawa Hospitals. Greg, thanks so much for joining us today.
Dr. Gregory Hundemar:
Thank you so much for having me.
Dr. Mojola Omole:
So, just to start off, can you just give us the 101 on what primary aldosteronism is?
Dr. Gregory Hundemar:
Yeah, so primary aldosteronism a condition that's often overlooked and there's and part of the confusion is there's several different names for it. So it's sometimes called primary hyperaldosteronism, sometimes it's called Conn's syndrome. It all means the same thing.
Dr. Mojola Omole:
And so I didn't know that.
Dr. Blair Bigham:
I've heard Conn's.
Dr. Gregory Hundemar:
Yeah. And basically what it is it's an endocrine issue essentially, where your adrenal glands are secreting too much aldosterone and it's secreting aldosterone independent of its primary regulators, which are typically angiotensin II and potassium. And it's a common cause of hypertension. So we used to think that it was a rare niche form of hypertension, but the more and more research that's coming out, we now realize that it's 10% to 20% or maybe even more of hypertension that is actually due to autonomous aldosterone secretion.
Dr. Mojola Omole:
So what are the symptoms of it?
Dr. Gregory Hundemar:
So the classic findings are when you have too much aldosterone being secreted is you tend to hold onto sodium. So you get sodium retention, volume expansion, and that leads to hypertension. But with sodium being reabsorbed, you also get a concurrent excretion of potassium and acid. So the classic triad is hypertension, low potassium, and metabolic alkalosis. Now, not every patient manifests all of those, but that's the classic manifestations.
Dr. Blair Bigham:
Where does the metabolic alkalosis come from?
Dr. Gregory Hundemar:
It's because when your kidneys are holding onto too much sodium, they excrete different cations and potassium is one, but acid is the other. So you actually excrete too much acid in the kidney, which leads to metabolic alkalosis.
Dr. Mojola Omole:
Oh, look at the nerds. He's like, oh, what is that? So how serious is this when you have hypertension that's not responding to medication?
Dr. Gregory Hundemar:
Yeah, and that's a really good question. I think, what really got me interested in this field is we often think of hypertension as this one size fits all approach where we treat everybody the same. And it's really probably not the best approach because a primary doctrine is a specific cause of hypertension that has different treatments. So actually we have good treatments that it can actually target the action of aldosterone. And the reason it's important is rather than just throwing the typical blood pressure medications that we do to one of the mill hypertension is that patients with primary aldosteronism, there's a number of studies now that show that even independent of blood pressure control, these patients are at disproportionately high risk for cardiovascular disease. So they have much higher rates of stroke, heart attack, heart failure, AFib, as well as they have more rapid decline in their kidney function over time as well and higher mortality. And that's independent of blood pressure.
So the thing about this disease is it's actually modifiable. We have good treatments for it. Just we make the diagnosis far too late many times. And oftentimes the majority of cases we probably actually don't make the diagnosis and we miss these cases for many, many years.
Dr. Blair Bigham:
So how does the treatment differ then compared to regular hypertension or essential hypertension?
Dr. Gregory Hundemar:
So the treatment, it comes in two flavors. So again, the problem is the adrenal glands secreting too much aldosterone autonomously. And the treatments are really guided based on whether one adrenal gland is affected or both. So, when it's just just one gland affected, it's one of the rare forms of hypertension that you can actually cure because you can do a surgery to actually remove the problem adrenal gland, and a large number of these cases are actually cured of hypertension completely. And we know that their risk for cardiovascular disease and kidney disease and all sorts of other things comes way down after that. And they have excellent outcomes. Now, the majority of cases that's actually both adrenal glands are affected. In that case, obviously you wouldn't typically want to take out both adrenal glands, but we use medications that are targeted toward aldosterone.
So the common ones are mineralocorticoid receptor antagonists. So we often think of spironolactone or eplerenone and there's newer ones becoming available now that may be even better. But those really block the action of aldosterone in the kidney and elsewhere and can be quite effective when used properly to lower cardiovascular and kidney disease risk. Now with run-of-the-mill hypertension, we typically don't think of spironolactone until you're fourth or fifth line drug, but in these patients it should be their first line drug because we know it's really targeting their pathophysiology.
Dr. Blair Bigham:
Got it. So by identifying it, you're starting a different treatment that can really reduce mortality even if their blood pressure were controlled with something else?
Dr. Gregory Hundemar:
Correct. Yeah, because currently we don't even... If you look at the current screening guidelines, probably the most common reason to screen is when somebody has resistant hypertension. But to meet that requirement, they're often on four drugs already and that may have taken years or even a decade or more to actually reach that point and you probably missed an opportunity there to lower their long-term risk by diagnosing it almost too late.
Dr. Mojola Omole:
So you talked about the incidents in the general population being around 20%, which is quite high. How common within the population with hypertension?
Dr. Gregory Hundemar:
Yeah, so just in terms of hypertension itself, it's about one in four Canadians. So 25% of Canadians have hypertension, whether or not they're diagnosed or not, population-wide, that's what it looks like. It is kind of a spectrum. So if you look at severity of hypertension where you go from stage one or mild hypertension to more severe resistant hypertension, you see the prevalence of primary aldosteronism go from maybe 10% or so, to when you get to resistant hypertension, some of the studies show it's 20% and beyond. So it's actually pretty common. But some of the studies we've done where we actually looked at how many of these patients that actually meet these criteria to screen, it's actually very low. It ends up being less than two in a hundred, less than, so less than 2% that actually ever get screened, that should have been, at least according to guidelines. And some of the work I do is saying that, gosh, we should be screening a lot more people with hypertension for this because we often wait too late to actually look for this disease.
Dr. Mojola Omole:
So what are some of the key indicators or what are red flags that should promote a physician just to consider just to screen for this as a potential cause of someone's hypertension?
Dr. Gregory Hundemar:
Yeah, so according to the guidelines, some of the populations where it's recommended to screen is again, severe or resistant hypertension. So often on four drugs or somebody that has those very severe hypertension that is otherwise unexplained. Hypertension and low potassium is a common one just given how it works. And the low potassium, people are often confused because sometimes patients are already on several blood pressure medications which can lower their potassium like thiazide diuretics or loop diuretics. But that's actually oftentimes the hypokalemia is actually unmasked by being on those medications. So even if it's hypokalemia in the setting of say hydrochlorothiazide, that's still an indication to look for primary aldosteronism. Other times, if somebody has an adrenal nodule and hypertension, that's another reason to think of it because that adrenal nodule could be the source of where this excess aldosterone is coming from. So those would be some of the more common indications to test for this disease.
Dr. Mojola Omole:
If you're saying that maybe close to 20% of people with hypertension could have this, would it make sense to test anyone who comes in with hypertension or is that not, I guess, cost-effective?
Dr. Gregory Hundemar:
No, I think it's a really good point, and it's something that that's a lot of the work I'm doing is to say, gosh, we should be expanding this. Because you're right, 10% to 20% is a big number, when you think of one in four people have hypertension. And there hasn't been a whole lot of work in terms of how cost-effective it would be to screen everybody. But my guess is given the disproportionate amount of cardiovascular and kidney disease risk, I advocate for that. So I work in the hypertension clinic here, and actually anybody that comes through, and because of these recent studies showing the high prevalence, we test everybody for primary aldosteronism. And you'd be surprised by how many we actually pick up that were basically undiagnosed all along that we detect now.
Dr. Mojola Omole:
What's the workup? What are you sending off?
Dr. Gregory Hundemar:
Yeah, so the starting test is a screening test called the aldosterone-to-renin ratio. And so it's a simple blood test that you draw and you check aldosterone and renin. The classic hallmark of primary aldosteronism is you have high aldosterone in the setting of a suppressed renin. So very low renin. Sometimes it can be so low, it's undetectable. So usually typically with normal physiology, aldosterone and renin will travel the same direction. Where if renin goes up, aldosterone goes up and vice versa. Because that's how the renin-angiotensin-aldosterone system pathway works. But in this disease you have aldosterone being autonomously secreted, so it's high and it's causing you to hold onto sodium and your body gets volume expanded. And because of that you suppress renin. So it's an abnormal physiology where you have a high aldosterone and low renin. And so that's the classic hallmark we look for in the aldosterone-to-renin ratio.
Dr. Mojola Omole:
So do patients have to go up their blood pressure medications when you're testing for this?
Dr. Gregory Hundemar:
That's a really common question. It's a bit of a myth with this disease, I think some of the reason the screening rates are so low is I think it's a bit intimidating for many physicians to go down that pathway of testing these patients, because they think they have to take them off all their blood pressure medications. And these patients are often on multiple drugs, and it's often not safe to take them off all their medications because their blood pressure may be through the roof. So in reality, the way I practice, most blood pressure medications can actually be continued when you do this testing. The medications that I typically will hold are mineralocorticoid receptor antagonists, like spironolactone or eplerenone, and the other is amiloride. Those can give you false results in the testing. But for the vast majority of blood pressure medications like ACE inhibitors, ARBs, beta blockers, the vast majority of times you can just continue those medications and the testing will still be reliable.
Dr. Mojola Omole:
And then the other question is that, from what I'm trying to remember from medical school, is that would you necessarily have the low potassium or could you still have a normal potassium?
Dr. Gregory Hundemar:
Yeah, so the classic teaching is you have that triad of hypertension, hypokalemia, metabolic alkalosis, but actually the majority of cases actually don't have low potassium. And so that's a bit of a myth is that you have to have low potassium, and it often triggers you to think of it and it should, but you shouldn't come away thinking that you have to have low potassium in the setting. It's often over 50% of cases will actually have normal potassium. So you can't just rely on that clue.
Dr. Blair Bigham:
So you have somebody who doesn't really meet the classic rationale for testing, but you've sort of made the case that regardless of their blood pressure, you can spare them a lot of suffering in the future. Are there certain groups of people who if they walked into a family doctor's office you'd be like, oh, that's a slam dunk. You should definitely send off a renin.
Dr. Gregory Hundemar:
Yeah, so there are certainly some of those. And so the slam dunks are patients that are... The things I think of as a young patient with very high blood pressure, poorly controlled for unclear reasons. You should definitely be looking for secondary causes in that sort of instance. Again, they don't have to have low potassium, but if they do or they have an adrenal nodule, I mean that should be screaming to test for this, because there's a decent chance that number one, you might be able to cure their hypertension if they have one-sided disease, or two, you can get them on the right blood pressure medication where if you... These patients often when they finally get down that pathway where they get started on spironolactone or something that really targets what's going on with their body, their blood pressure after not being controlled on no matter what drug you threw at them, you get on the right drug and suddenly their blood pressure is way, way better, way controlled. They end up coming off a lot of the other medications. The problem is it takes us too long to get to that right drug.
Dr. Blair Bigham:
I want to go off on a little tangent here. Let's just say your renin came back normal or your aldosterone-renin ratio was normal. Is there a next diagnosis other than Conn's that would pop to mind like pheochromocytoma or one of those weirdo rare diagnoses?
Dr. Gregory Hundemar:
And so part of the reason in our hypertension clinical trial, I think I mentioned that we test everybody that comes new to us with an aldosterone and renal level, and that's not just to diagnose primary aldosteronism. It can actually be helpful to diagnose other forms of secondary hypertension. And so what we'll often see is I'll send an aldosterone and renin level and they're both sky-high. And that actually makes me think of things like renal artery stenosis. Where you're actually not perfusing your kidneys enough. And so you can see, you pick up on these patterns where aldosterone and renin are both high or one's high and one's low or both are low. And it does make you think about different disorders like Cushing syndrome is something that they'll classically both be low. So I think it's helpful in these, when you're thinking of secondary hypertension, I think aldosterone and renin are not just helpful for making the diagnosis of primary aldosteronism. It actually helps you diagnose other potential conditions as well.
Dr. Mojola Omole:
So we've done a lot of myth-busting in a very short amount of time. It's very fascinating. To what extent is that an indicator of how much our understanding of aldosteronism has evolved in the past decade?
Dr. Gregory Hundemar:
So things have, from my perspective over the last five to 10 years, it's really changed. And one of the directions where this is headed is when we define primary aldosteronism, it's defined by these discreet cutoffs where you go from whatever threshold you set for aldosterone and renin, where you go from not having disease to having disease. And that's really not how physiology works. It's really a lot of these diseases are a spectrum where it's this continuous spectrum of disease. And some of these thresholds we've set in medicine are arbitrary. So why is it one point below your aldosterone-to-renin ratio. Renin ratio is normal and above that it's one point above, it's abnormal. And so what we've been looking at is looking at the spectrum and saying that a lot of... I talk about 10 to 20% of patients meeting the criteria for what we classically call primary aldosteronism.
But we've been looking at milder subclinical forms that may not meet that criteria we've defined over time that's arbitrary. And looking at these more mild causes, and so my thought is that a lot of what we call essential hypertension now is actually subclinical forms of excess aldosterone production. And that's actually been proven in resistant hypertension. And that's why spironolactone has now become the top fourth line drug for resistant hypertension. When you look at those studies, it's because a lot of those patients secrete too much aldosterone. And I think in the future where I think we're heading toward realizing that that's actually true even in more mild forms of hypertension. And even at the first diagnosis of hypertension, a lot of it's aldosterone mediated. And we're just now starting to realize that more and more.
Dr. Mojola Omole:
Why do you think we're just starting to realize it?
Dr. Gregory Hundemar:
It's hard to know really. Because I think some of these things got set in stone over time, and Jerome Conn was the one who first... That's why Conn's Syndrome is named that. He discovered the disease many, many years ago in the forties and fifties. And everybody thought it was this rare disease, but he was just picking up these very overt severe phenotypes and now we're really realizing there's more milder and milder versions. And that's changing our thinking in that this really is a disease spectrum and not just this categorical disease as we've historically treated it as. And I think the other thing to bear in mind is that because of this, there's a lot of new drugs that are being developed in this field.
So there's better mineralocorticoid receptor antagonists being developed. So you may have heard of finerenone, which is becoming popular in treatment of diabetic kidney disease and it's been shown to slow diabetic kidney disease. And there's a newer class of medications called aldosterone synthase inhibitors, which actually blocks your adrenal gland's ability to produce aldosterone, which has a lot of potential of actually changing how we would treat these patients. And those drugs are becoming available. And here in the next 5, 10 years, you're probably going to see a pretty dramatic transformation in the arsenal of drugs that we have to treat this condition.
Dr. Mojola Omole:
It's probably challenging for primary care providers just to stay on top of these rapidly evolving fields. So what do you want the key takeaway to be, the one-liner for them to remember?
Dr. Gregory Hundemar:
Yeah, so I think, again, this affects a lot of people. So a lot of it is going to spill into primary care because given we think it's 10% to 20% of hypertension, it's going to be hard for a hypertension specialist to see all of these patients. Many of them will be in primary care. And so I think the takeaway is to think of it, because even the patients that we clearly should be testing for, it is not happening. So I think we have to learn that it is very common and we have to think of it and do the testing and get past some of these myths that the algorithm of taking this diagnosis is super-challenging. It actually can be simplified quite a bit.
And so I think the key is to really think of the diagnosis and go ahead and do the testing. And I think the goal here is to really individualize care for patients and picking, rather than treating hypertension as a one size fits all sort of disease and approach to it, you really need to individualize it. And I don't think it's going to be overly complicated. And I think over time we're going to be developing simpler and simpler algorithms for how to actually go about doing that.
Dr. Blair Bigham:
And all you have to do is send off an aldosterone and a renin.
Dr. Gregory Hundemar:
That's the starting point. Yeah.
Dr. Mojola Omole:
Well, thank you so much.
Dr. Gregory Hundemar:
Great. Thank you so much for having me.
Dr. Mojola Omole:
Dr. Gray Hundemar is a badass nephrologist and clinical associate professor at the Ottawa Hospital. Blair, what are your first thoughts?
Dr. Blair Bigham:
Well, first of all, I didn't know you could cure hypertension by removing the abnormal adrenal gland. I think that's so cool that you can cure what I thought was an incurable chronic disease just by sniping out the adrenal gland.
Dr. Mojola Omole:
As I always like to remind you, nothing cures faster than cold hard steel.
Dr. Blair Bigham:
And today you are right Jola. But otherwise, I just find this really interesting that I would've thought this was pretty rare. And we see a lot of people in the emergency department with hypertension and universally, unless they have organ damage, we are like, “ go see your family doctor”. But more and more often people are saying, "Well, I don't have a family doctor."
Dr. Mojola Omole:
For sure.
Dr. Blair Bigham:
And so I start hypertension management. It's actually against our national guidelines, but there's nowhere to send people for that. I can send them to the internal medicine clinic, but my GIM colleagues are like, "Our clinics are overwhelmed with people who don't have family doctors." And they're not able to see everybody. So I feel like everyone just needs to brush up on this type of stuff and be able to spot that patient who does need a different frontline agent for their hypertension. Because, it seems pretty inevitable that family medicine is no longer that safety net, because so many people in this country can't get a family doctor.
Dr. Mojola Omole:
And also that our patients are very complex and not just complex, but now we have a greater understanding of the variability in terms of what are some, whether it's genetic, secondary causes of well established disease processes like hypertension.
Dr. Blair Bigham:
And I guess I'm bound to order renin now, which is something I've never done. That's it for this week on the CMAJ Podcast. Please remember, we would love if you could or share our podcast wherever it is you download your audio. I'm Blair Bigham.
Dr. Mojola Omole:
I'm Mojola Omole. Until next time, be well.