ACE Inhibitors: Still a role for 40 year old drugs?

The For Kidneys Sake podcast series is brought to you by Imperial College Healthcare NHS Trust and North West London Integrated Care Board (NWL NHS)

In this episode, Jeremy Levy and Andrew Frankel discuss the role of renin-angiotensin-aldosterone system inhibitors (RAASi) in the management of chronic kidney disease (CKD), looking deeper into the mechanisms, benefits and practical considerations of using RAASi. 

They cover when to initiate these medications, the importance of maximum dosing, monitoring kidney function, and managing side effects like changes in GFR and potassium levels.

Key Takeaways:

1. RAASi Benefits Beyond Blood Pressure:
   • These drugs lower blood pressure, slow CKD progression, and provide cardiovascular protection through mechanisms independent of blood pressure control.
   • Maximum dosing is essential for optimal kidney and heart protection.
2. Monitoring and Managing GFR Changes:
   • A GFR drop of up to 25% after starting RAASi is not a cause for concern.
   • Clinicians should reassure patients and recheck levels to ensure stability.
3. Potassium Management:
   • Mild to moderate increases in potassium (up to 6 mmol/L) are common and generally not an emergency.
   • Careful monitoring, addressing potential contributing factors, and avoiding unnecessary panic are key.

This episode provides practical insights and actionable advice for clinicians managing CKD patients.

Resource Links:
NICE GUIDELINES [NG203] chronic kidney disease: assessment and management Overview | Chronic kidney disease: assessment and management | Guidance | NICE

Northwest London CKD guidelines for primary care Chronic kidney disease (nwlondonicb.nhs.uk)

The purpose of this podcast is to inform and educate health care professionals working in the primary care and community setting. The content is evidence based and consistent with NICE guidelines and North West Guidelines available at the time of publication.

The content of this podcast does not constitute medical advice and it is not intended to function as a substitute for a healthcare practitioner’s judgement.

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Transcript

The Rest is Kidneys makes kidney disease management easy.  The Rest is Kidneys is for primary care clinicians.  The Rest is Kidneys is nice, consistent, short and sweet. Welcome to the Restless Kidneys brought to you by the Northwest London NHS Kidney Care Team.

Jeremy Levy

Hello again, everybody. I'm Jeremy Levy, a Consultant Kidney Doctor at Imperial College Healthcare NHS Trust.

Andrew Frankel

I'm Andrew Frankel, a colleague of Jeremy’s, also at Imperial College Healthcare NHS Trust.

Jeremy Levy

Today we're going to talk a bit more about the drugs used in managing chronic kidney disease, and particularly about renin angiotensin system blockers, the RAASi, or the ACE inhibitors, or Angiotensin blockers. And this is the second of three podcasts focusing on the treatment of chronic kidney disease. The first one we talked about general approaches, about lifestyle and diet, general features of blood pressure control, and glycemic control. And on this occasion, we're going to think a bit more about some of the specific drugs and agents and medicines that we can use. We're going to focus on the Renin-angiotensin-aldosterone system inhibitors, the RAASi. Which you will be very familiar with, they've been around for almost 40 years now, but we know their importance in chronic kidney disease. We're going to think about when to use them, when not to use them, and how to manage some of the complications of these medicines, which are really, really important and we can now manage extremely well. So that's going to be the next 10 or 15 minutes. So Andrew, why don't you kick off? Why do we bang on about RAASi all the time, and why do we recommend them as sort of first line treatments in people with chronic kidney disease?

Andrew Frankel

So Jeremy, these drugs, the RAAS inhibitors, were of course, originally developed to treat high blood pressure, but it soon became apparent that they had an additional benefit over and above their blood pressure reduction effect, which was really about protection from cardiovascular disease, and also protection from chronic kidney disease progression

The exact mechanism by which RAAS inhibitors protect people against progression of chronic kidney disease, are probably multiple. But one of the key factors is that they have an effect on the blood flow within the kidney, and most particularly within the individual glomerulus within the kidney. And those changes in blood flow result in a reduction in the resistance to blood flow, as the blood leaves each glomerulus, dropping the pressure within the glomerulus, and that is believed to be the key to how they prevent progression of chronic kidney disease.

A side effect of this, if they drop the pressure in the glomerulus, is they also have an effect on filtration rate. But it's just important to understand the key message that RAASi have a completely separate, and unrelated effect on preventing progression of kidney disease, over and above their blood pressure effect.

There's one important subtle difference as well, in not just the renal, but the cardio protective effects of RAASi, over their blood pressure lowering effects, because as you increase the dose of RAASi in relation to blood pressure, you get a rather flat dose response curve. But the evidence from all the trials is that to get the maximal benefit of RAASi for Cardiorenal protection, you need to increase towards the maximal dose. Indeed, there's data to demonstrate that dose reductions of RAAS inhibitors below maximal dose leads to a significantly poorer outcome. And it's for this reason that we not only bang on, as you say, about RAASi, but we ask clinicians to try and maximise the RAASi dose as speedily as possible.

Jeremy Levy

That's really interesting, isn't it? And that important difference. It’s not just about blood pressure lowering. These drugs have effects that are beneficial for the kidneys separate from the blood pressure lowering. And I always remember some of the data that's, again, very old, about reducing scarring through all sorts of other pathways, completely independent of blood pressure.

So these pro scarring molecules, such as things called TGF-beta, are actually switched off by RAASi, so they are doing lots in the kidney that's not just blood pressure lowering, which is why we really want people on maximum doses, because those effects are really important in preventing progression of all kidney diseases, which we'll talk about in a second. And maximum doses can be, you know, seem quite high, but they're not inappropriate. Ramipril, 10 milligrams. Perindopril, 16 milligrams, Lisinopril, 40 milligrams, whichever one you use. None of us believe there are major class individual drug differences, any of the ACE inhibitors, any of the angiotensin blockers, all seem to be effective, but really getting people up to maximum doses is really important, isn't it. So are there particular people groups, patient groups, who you would particularly use them in, or just everybody with chronic kidney disease?

Well, I know I should be answering the question, but I'm going to be a politician here and make it a little bit easier for people. Which groups would we not be pushing RAASi, and really it is for all people with CKD, particularly if they've got cardiovascular disease. But you will sometimes get responses from us, either in clinic letters, or from the virtual clinic, or advice and guidance, where we don't push the RACI, and that is in a very small group of people with absolutely no proteinuria and stable CKD. In which case, getting the blood pressure right is probably the priority. But I would say to primary care and clinicians, always think RAASi, but if you are having difficulty, worry less about it if they have no proteinuria.

Andrew Frankel

And of course, the other thing is that, on average, people with chronic kidney disease need, sadly, two or three medicines to lower their blood pressure. It's pretty rare to get away with just one, even with excellent lifestyle changes, etc. So therefore, a combination of a RAASi with something else is likely to be what you need. You'd be lucky to have one drug. And therefore, a combination of RAASI with a calcium antagonist, or with a diuretic, can be very effective, combination medicines, can’t they?

Andrew Frankel

Correct. Absolutely. And I'm not sure what your second choice is, but to me, it doesn't really matter, so long as it does the job and the person meets the target.

Jeremy Levy

I completely agree. So practically, are there any considerations that you should think about when you're starting people on RAASi, in terms of their blood pressure control, and their chronic kidney disease? And are there any other tips and tricks about using these medicines that you generally think about?

Andrew Frankel

Yeah, so I think primary care has been used to using these agents going back now, oh gosh, it's probably about 40 years. So I've already described the fact that these agents have an effect on glomerular blood flow, and thereby an effect on GFR. And it's really important that we get across the message that a drop in GFR after starting a RAASi, is a physiological normal event. However, the extent of that drop is important, and that's why we recommend, and indeed NICE recommends, that kidney function, and indeed potassium, are assessed within one to three weeks of either commencing, or increasing, a dose of RAASi.

I mentioned the potassium, because RAASi can also have an effect on reducing potassium excretion and can increase potassium levels, potentially leading to hyperkalemia, or potassium above the normal range. So you check kidney function and potassium, and you check it about one to three weeks after starting the dose.

I would just point this out to you, the primary care is very busy, and if you are changing treatment levels frequently, it means extra consultations, extra blood tests. And because of those requirements, I think that makes it quite challenging for primary care. And quite often, because of this, people don't have their RAASi dose increased. A way of minimizing this (and I think this is something that we really want to get across in our guidelines, and indeed in the London Kidney Networks 3 in 3 guidelines, which is that you should be aiming to rapidly increase the dose of RAASi in people who are fit and relatively robust, not leave it over 6 months, 12 months, or 2 years, but actually try and get the patient onto a maximal dose within 4 weeks. There's no reason you can't do it. You can do it in two bites, far less blood tests, far less disruption for the practice, and for the patient. However, of course, if the person is frail, or multi morbid, then a more circumspect, incremental approach will still be required.

Jeremy Levy

So, Andrew, can I ask, does that mean your recommendation is starting on, for example, Ramipril, 5 milligrams and then doubling to 10 milligrams after four weeks? Is that the sort of route that you'd be recommending

Andrew Frankel

After even two weeks? Absolutely, I think if the person is a young (when I say young, I'm talking about, say, a typical 55 year old person with diabetes, blood pressure 142 over 95), you will find that as long as they are informed about maintaining their fluid intake, they're doing self monitoring of blood pressure, and they're taught about sick day guidance, I think it's perfectly safe to give them two weeks of 5, do the blood test, increase to 10, do the second blood test, and then they are done.

Jeremy Levy

That's exactly what I say as well. So we often see people, don't we, on sort of 1.25 milligrams of Ramipril, and they've been on it for 6 months, and it's sort of pointless. It's not lowering their blood pressure, but it's not protecting their kidneys and protecting them from future harms. So that's really important. So rapid titration - get people up to high doses as soon as we can.

You briefly mentioned about that GFR fall. Do you want to tell us a bit more about that, when you get worried, and when you don't get worried, because we do expect everybody to drop their GFR a bit when they start these drugs, don't we?

Andrew Frankel

Yes, and the GFR, for many clinicians may have at the back of their mind a historical fact of patients who have bilateral stenosis of their renal arteries, very rare, and they can get acute kidney injury. And that was actually the original reason that we did these tests. But we now recognise that you can still get this physiological drop, but that is exaggerated if the person is dry, if they have vascular disease, or if they're on concomitant medicine that might interfere with their GFR.

So what we recommend is a cut off of a creatinine rise of 30%, or a GFR fall of 25%. That doesn't mean you have to stop at that point, but I would say to you, if the kidney function tests are approaching those limits, you may want to repeat them, to ensure yourself that the individual has now got a new baseline. If they're above those limits, you may want to just bring that person in and just think about their fluid status, the medications they're taking, have they been taking on steroidals as well, and factors like this. And if they really do maintain that drop above creatinine of 30%, or GFR decline of 25%, you may want to seek advice through the North West London, CKD advice and guidelines, or ERS virtual clinic.

Jeremy Levy

That's a really helpful number. So for the GFR drop, 25%, so people with GFRs of 50, you know a drop to 40 is within those limits, is not unexpected. We would say, recheck it again at some point to make sure it's not continuing to fall, but you don't need to stop ACE inhibitors, angiotensin blockers if the GFR has dropped within that 25%, and don't need to frighten patients that this is a bad thing. And actually, there's good evidence isn't there that those people who do get a slightly bigger drop in GFR long term, seem to be protected more in terms of both progression of kidney disease, and cardiovascular risks. So actually, it's a good thing in various terms, for your GFR to have dropped, clearly, not very significantly, but really important. That's very, very helpful. And again, I think we're going to talk about this later, but you were going to mention something about potassium as well, weren't you?

Andrew Frankel

Before we do that, I just want to make a point to follow up yours, which, of course, is that we now have told all the clinicians about the GFR drop. You have to forewarn the patient, so they understand, because, particularly if there's someone very focused on GFR (which is not a bad thing), so they understand that it's their global kidney function. You start them, their GFR goes from 50 to 40, and they come back and say to you, ‘Well, what have you done?’ So I always warn the patients that there will be a drop, and that isn't a bad thing. And I give them the example that within their kidneys, they are born with each kidney having a million little, tiny filters that are filtering away, and that because they have chronic kidney disease, they've lost maybe 40/50% of those filters, and the remaining filters are working much harder, and that's what damages them. And what this drug, the RAASi does, is it calms it all down, so they'll see a drop, and then it stabilises. Now you asked about potassium.

Jeremy Levy

Go on, tell us about potassium.

Andrew Frankel

So as I've said, when you start a RAASi, you do see a reduction in potassium excretion, and you do see rises in potassium. Now, I appreciate that this can be quite alarming, because very high potassium levels constitute a significant risk to people, because of cardiovascular events. However, mild to moderate increases in potassium are not necessarily medical emergencies, particularly if the patient is well. And what we need to do is to expect it, to predict it, to try and think a little bit about, is the patient on any other drugs that might aggravate this, and try and hit it off before it occurs. So we do recommend you check potassium, and that you respond to that result.

Jeremy Levy

Give us a number Andrew, give us a number when you get worried, because I know that clearly for GPs, that the lab says, of course, it's abnormal above often 5.2 or 5.3, but you and I are not worried about a potassium at 5.4 are we when we start angiotensin.

Andrew Frankel

Absolutely not. And if the potassium goes up to say between 5.5 and 6, again, if the person is well, and it's just a routine monitoring, I would repeat it, because in the vast majority of those people, you are seeing a problem related not to real high potassium, but to the fact there has been problems in taking the blood sample or delaying collecting it.

Jeremy Levy

So you and I are not worried. Potassium is up to 6 and patients shouldn't be asked to run around their emergency departments to get rechecked. Let's say one last thing in this episode about Finerenone, this new medicine that's out there, but not yet widely used. You want to give us a sentence or two about that?

Andrew Frankel
Just very briefly, sorry to interrupt you there Jeremy, very briefly, Finerenone is a new mineralocorticoid receptor antagonist that's very specific for the mineralocorticoid receptor. It differs from Spironolactone and eplerenone in that specificity, and there have been studies now, a series of studies that have shown that it slows down progression of CKD, and NICE have now recommended that you add this to people with diabetes and persistent albuminuria that is not controlled on SGLT2 inhibitors or ACE or ARBs.

So what's this therapy?

Jeremy Levy

So going to be widely used, but not just yet. Andrew, I think that's been really, really helpful. So again, I think I'm remembering three things from what you've told us when we're talking specifically about Renin angiotensin blockers. These are great drugs. They not only lower blood pressure, but protect the kidney in all sorts of other ways that aren't blood pressure lowering. We need people on maximum doses of whichever of these drugs you want to use, because they have benefits over and above blood pressure lowering. We shouldn't worry about a GFR drop of up to 25%, and potassium is not really a problem unless it's over 6, and think about reasons for that. And with that advice, people should be maximally protected with this fantastic group of drugs, which neither Andrew or I have any shares in, and they're all generic, and they're all very cheap, and we should be using them widely in people with chronic kidney disease. I hope that's been helpful.