Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk, Episode 117 I'm your co host, Dr. Kane, Dr. Khyati Patel 00:35 and I'm Dr. Patel, and in today's episode titled the yin and yang of ACE and ARBs. How do they really help or harm kidneys? We're going to dive more into the pharmacology of the ACE inhibitors the ARBs, particularly understanding, how do they help in preserving the renal function in patients who have CKD or underlying conditions that could eventually lead to CKD, but at the same time, they could actually harm the kidneys and cause something called kidney injury, or AKI Dr. Sean Kane 01:09 so Dr. Patel, when I teach pharmacy students in the second year, heart failure is one of the first topics that they learn about. And you know, these students also learn about hypertension about the same time they learn about ACEs and ARBs and how we have to monitor renal function and potassium. You know, a week or two after these agents, aces or ARBs, are initiated, because it can increase your potassium and make your renal function get acutely worse, as you said, called acute kidney injury. Later on in our curriculum, they learn about chronic kidney disease, and then they really get confused of how is it possible that these two drug classes can both help with chronic kidney disease but can cause acute kidney injury? It feels like it shouldn't be this opposite thing, that it should either be helpful for the kidney or harmful to the kidney, but it seems weird that it could do both, right? Dr. Khyati Patel 02:00 That's correct. And today is what we're going to take time to kind of break it down as to how exactly this happens, and how it is important for us as clinicians to really keep that balance, you know, and and what kind of strategies go behind in those clinical decision making. Dr. Sean Kane 02:16 So why don't we start with, like, the pharmacology, right? So how are these agents working? And then maybe that can inform how they could be helpful or harmful, right? Dr. Khyati Patel 02:25 And first and foremost, like talk about the RAS system, right? The acronym R, A, A, S, which stands for renin, angiotensin aldosterone system. We all know that a lot of different organs, especially the kidneys and the liver, is involved in this. But basically, kidneys produce renin, which is responsible for converting angiotensinogen into angiotensin one, and that's where our angiotensin converting enzyme ace comes in play. Ace is going to convert angiotensin one into angiotensin two. Now you're like, why do we need to know all those little steps? Because angiotensin, two, is that end product. That is the do all of all the evil stuff that can happen in terms of increase in pathophysiologic tone, increase release of, you know, catecholamines and decrease the reuptake of norepinephrine. So what are these catecholamines going to do? They're going to increase the sympathetic tone. They're going to increase the vasoconstriction. Again, it increases the water reabsorption in the kidneys via tubular sodium and chloride reabsorption. So again, this, this leads to more water retention and increased blood volume. So again, the net effect is increased blood pressure. Dr. Sean Kane 03:44 On top of that, we also have other systems within the renin, angiotensin aldosterone system, like aldosterone, right? So aldosterone, in itself, has similar effects in terms of increasing blood pressure. We also see that this net effect is that we have more antidiuretic hormone so if you just think of the word anti diuretic hormone, it's like the opposite of a diuretic, like the opposite of lasix. So then again, you have more water retention, increased blood volume, that increases your blood pressure. All of this stuff is going to promote vasoconstriction, increasing your blood pressure. And depending on the tissue type, like on heart tissue, for example, if you have someone with systolic heart failure as an example, this causes cardiac remodeling. It can cause hypertrophy of vascular smooth muscle. It can cause all sorts of like, longer term effects beyond just a higher blood pressure, right? Dr. Khyati Patel 04:35 And just like you mentioned, Dr. Kane, you know, depends on the tissues and so in lower extremities, for example, along with all this water retention, clinically, how that would be shown, one is obviously increased blood pressure, but there could be a visual sign of edema, water retention, Dr. Sean Kane 04:54 absolutely so. Dr. Patel, I assume that aces and ARBs are working on this pathway. So where exactly are they working? And. How can that be helpful? Dr. Khyati Patel 05:01 So kind of reminding a few seconds back, we heard about all the steps, right, how the renin converts angiotensinogen to angiotensin one. And then there is the ace enzyme, the angiotensin converting enzyme that converts angiotensin one to angiotensin two. So as the name stands, ace inhibitor, this inhibitors are going to block the ACE, the angiotensin converting enzyme, from converting that angiotensin one into angiotensin two. So basically, all these bad effects of angiotensin two, we learn the ACE inhibitor is going to basically stop the resulting effect. And what about the arbson? So the ARBs, as the name, stands there angiotensin receptor blockers, these are molecules that are going to sit at the receptors for where the angiotensin two would normally bind. So instead of angiotensin two binding to these receptors, the ARBs are already sitting there, so angiotensin two would not be able to bind and exerted effects. A lot of these receptors of interest are located in in the vasculature, smooth muscles as well as the kidneys. Dr. Sean Kane 06:08 You know, these are really, really common medications on the market, so aces and ARBs. There's many meds within those categories, and they're used for a lot of different things, ranging from hypertension, because they have a vasodilation quality, to treat systolic heart failure and for post‑MI care, because they can help with remodeling or hypertrophy of cardiac tissue. Also, because they drop your blood pressure, therefore they decrease what's called afterload, which is basically your arterial blood pressure, or how hard your left ventricle has to push in order to get blood to go from the ventricle into your systemic circulation. They're used for diabetics, right? So, Dr. Patel, where do you see this in diabetes care, which is interesting, because it doesn't really work on your blood sugar, right? Dr. Khyati Patel 06:49 Yeah, they do not obviously impact. These are anti hypertensive category agents, so, but we know diabetes, in the long run, could cause comorbidities, such as, you know, atherosclerotic cardiovascular disease, such as MI, as we just mentioned, or even nephropathy, these are diabetic nephropathy that happens after a long standing uncontrolled diabetes, usually leading to some glomerular changes, causing protein spilling, which we call proteinuria. And if that is left unchecked, it causes CKD. And so this is where we use the ACE and ARBs to help the progression of the nephropathy and even help with some of the ASCVD risk reduction. Dr. Sean Kane 07:34 And like you mentioned, we use it for CKD as well, right? So, and non diabetics that already have CKD if they're hypertensive, we can use it to help with blood pressure, proteinuria. We can use aces and ARBs to slow the progression of their chronic kidney disease, or in other words, make it so that their GFR goes down slower over time than it would normally. And also, we can use this in post transplant glomerulonephritis. It prolongs graft survival after kidney transplant. Dr. Khyati Patel 08:02 Yeah, and to our students who are practicing, you know, you may see in patients chart there is, you know, stage one CKD, or stage two, CKD. It's not until the stage three and further that arrives, where we start to see a lot of hepatorenal complications, cardiorenal complications, because that CKD is left unchecked. And so we know these agents have shown benefit on kind of halting that progression to advanced stages of CKD, halting the progression to end stage and progression to the hemodialysis, which we know can bring their own complications. Dr. Sean Kane 08:39 Oh, yeah, and if we just take a second to talk about that, preventing someone from having to go to a four hour session of dialysis three times a week alone, is a huge deal, let alone the infectious complications of having to go to a dialysis center being exposed to multi drug resistant pathogens. I mean, there's so many different things that are prevented by not progressing to end stage renal disease on hemodialysis, Dr. Khyati Patel 09:04 and this is exactly what you mentioned. Dr. Kane is going to be part of that shared decision making and the patient education conversation when we decide whether to add this agents in the patient's, you know, clinical care or not. Dr. Sean Kane 09:17 So before we get into a little bit more detail, we have to talk about the safety profile, right? So we're obviously talking about acute kidney injury today, but Dr. Patel, what are some other common and known adverse drug reactions to aces, ARBs, or both of them that anyone listening should know about? Dr. Khyati Patel 09:35 So by category, these are anti hypertensives, and so they're going to do their job of lowering the blood pressure. It's the most common side effect for both could be lower blood pressure, hypotension, or any of the symptoms that come along with that territory, such as, you know, feeling light headed, dizziness, hopefully not severe enough to cause syncopal episodes or falls, but definitely, some of this dizziness and lightheadedness can be noted so. Again, both of them are to same degree, responsible for causing hyperkalemia. We're going to talk about, you know, in a little bit, not spilling the beans ahead of time as to how that happens, and as well as both of them can cause acute kidney injury. Dr. Sean Kane 10:15 Now what's interesting is that those are kind of shared side effects that are more or less fairly similar in incidence rate between aces and ARBs. But aces on their own also have some unique side effects, like Ace induced cough, which is a bradykinin induced cough. And although both can technically cause angioedema, we see it more often with ACE inhibitors. Terms of ACE inhibitor induced angioedema that's primarily driven by an excess of bradykinin as well, correct? Dr. Khyati Patel 10:43 And I've always found it very interesting that, you know, they both kind of work in the same system, although ace have this like interesting side effect profile. But having said that, when patients have ace induced cough, or, let's say they have ace induced angioedema with some added monitoring involved, we could have patients use ARBs instead, and therefore we see a lot of interchangeability between the two agents. And obviously that goes into making sure that this decision of changing them from Ace to ARB is, you know, needed and appropriate, but some of the common two indications could be because they had this a specific side effects. Dr. Sean Kane 11:24 So, Dr. Patel, I feel like we've covered the pharmacology pretty well and kind of the rationale, let's go more to the pathophysiology of chronic kidney disease. So what is, in a nutshell, what is going on that potentially could be a drug target for aces or ARBs to slow that progression of chronic kidney disease. Dr. Khyati Patel 11:43 Yeah, and chronic kidney disease is interesting. Chronic kidney disease could be a lone standing condition, or it could be occurring in conjunction with some of the underlying conditions such as diabetes or hypertension or some sort of primary glomerular disease like glomerulonephritis and things like that. So if it is a conjoined condition, then you know the progression of this underlying disease is also going to progress the patient's CKD, right? They're going to move faster on that stage scale, in those who have long standing CKD, or even combined with underlying disease, we're particularly looking into a couple of different markers, if you were to say it. And those markers are how much protein is being secreted in the urine and how much GFR reduction are we seeing, right? Those are kind of like GFR reduction, basically, is like the defining factor when we talk about patient moving from one stage of kidney disease to another. And the idea here is that the increased proteinuria, which is the protein spilling, that is the biggest factor that's associated with rapidly declining GFR. And so if we can't halt that process, we can see patients moving quickly through that stage scale of CKD, progressing to the end stage renal disease and needing the hemodialysis. Dr. Sean Kane 13:05 And as we'll talk about, those patients that have progressive chronic kidney disease, that have excessive protein in their urine, that is the patient population that we're really interested in targeting with aces and ARBs, because evidence has shown that that is the best group in terms of benefit from aces and ARBs to slow that chronic kidney disease progression. Dr. Khyati Patel 13:25 That's correct. And that takes us right into talking about, how can they be renal protective in the CKD, right? And so, as we discussed, they are anti hypertensive by nature, so they decrease blood pressure and they also decrease proteinuria, and overall, the net effect is decreased progression of the CKD. And so really, now, diving into more of the pharmacology, we know aces and ARBs can cause vasodilation of the arterial. So if you look at structurally, we have our afferent arterial that takes the blood supply into the glomerul apparatus. That's where all the capillary, interglomeral Capillary structure is, and then you have the efferent arteriole that brings the blood supply out. Most antihypertensives are going to work on just the vasodilation of the efferent arterial, but the ACE and ARB are going to cause vasodilation of both. And what this does, it helps to decrease the the intraglomeral Capillary pressure, and so now the blood is not going through that much pressure into that capillary network. And if there is less pressure into that capillary network, then there is not whole lot of filtration of the protein that's occurring, and that kind of lifts up some of the burden that comes from the protein area. Dr. Sean Kane 14:52 So basically, what we're seeing here is that unlike a typical anti hypertensive where we just drop blood pressure generally aces and ARBs. And are able to kind of drop pressure more specifically in the glomerulus, so that you have less pressure means less damage that can be done, especially in those hypertensive patients, therefore, and we'll talk about this later, if you just look at blood pressure reduction, that's actually not the endpoint we're looking at. The main endpoint we're looking at is the amount of pressure reduction specifically in the glomeruli of the kidney. And it just turns out that aces and ARBs are able to do that a little bit better, correct? Dr. Khyati Patel 15:27 And the net effect is, obviously, you know, decrease in how much protein that's spilling. And if you look at ACE, we get about 30 to 35% decrease in protein spilling with ACE inhibitors alone. And we know that these agents work in normal tensive CKD patients to also prevent the progression through the stages of CKD. And that's where the other mechanism, and these mechanisms are obviously proposed mechanisms come in play that there is like some sort of a permanent improvement of properties of the glomerulus, because how they work right in that apparatus, there's some anti fibrotic effect coming along from these agents. And then some, some kind of correlation between how there is decreased protein area that means there is reduction in the lipids, and then decrease overall ascvd risk profile, which we know comes with the territory of having CKD. Dr. Sean Kane 16:21 So, Dr. Patel, you know the proposed mechanisms are wonderful, knowing the pharmacology is wonderful, but at the end of the day, it can only take us so far until we actually do those phase three randomized control trials to actually demonstrate that the proposed mechanism may, in fact, be the thing that matters in terms of a clinical endpoint. So certainly we've studied this from a clinical perspective to know that, in fact, Aces and ARBs can be helpful with chronic kidney disease, right, correct? Dr. Khyati Patel 16:49 And I think you emphasize the word clinical endpoint for a reason, because you can measure how much protein that is spilled with the these agents, without these agents, and kind of look at, okay, protein spilling, but that's really your surrogate marker. You what you're looking for a clinical outcome is that, did it do anything in terms of progression of the disease state? You know, did we prevent patients from getting on to hemodialysis or getting to, you know, losing all that GFR, basically? And so that's where we are looking at and so you will find multiple studies looking at just how much protein area reduction we got. Those are good studies. However, you're looking at a bigger picture here, and so there. There's quite a few studies out there, but we thought to summarize a meta analysis that was done in 2001 that looked at about 11 different randomized control trials. Now these trials included ACE inhibitors versus other anti hypertensive drugs or placebo. So it's not a direct control to control study. It's intervention to looking at placebo as well. About 1800 patients with chronic kidney disease were included in here. And in summary, what the study found patients who were in the ACE inhibitor treatment arm showed significant reduction in the rate of progression to the end stage renal disease. This was 7.4% for patients receiving ace versus 11.6% in those who received either placebo or other antihypertensive treatment. Dr. Sean Kane 18:22 That's a pretty big deal. That's basically a 30% reduction, a relative risk of point six, nine. Again, that's that's not nothing. When you're looking at just one single medication that's fairly well tolerated, that's very common medication, that's pretty impressive. Yeah. Dr. Khyati Patel 18:36 So that was the clinical hat. And then then they looked at, obviously, looking at the surrogate markers, such as, you know, what was the serum creatinine decline, or what was the protein area decline? And they also found significant reduction in the marker they used was the doubling of the baseline serum creatinine or ESRD. So kind of looking at both progression as well as the surrogate marker of serum creatinine decline. And this was pretty drastic, too. 13.2% of patients in ace inhibitor got this outcome, versus 20.5% patients in the other outcome. So that kind of reinforces the whole additional mechanisms really working here to prevent that progression. Dr. Sean Kane 19:20 It looks like they did do kind of some subgroup analysis to see which patient populations would benefit the most. It turns out that those with baseline proteinuria below 500 to 1000 didn't fare as well in terms of they didn't benefit as much versus those that had more proteinuria than that. So as we mentioned earlier, the key patient population that is going to benefit from this is going to be those with more proteinuria versus non or less proteinuria, correct? Dr. Khyati Patel 19:46 And one of the other surrogate marker they looked at was, you know, how large was the decline in blood pressure was, and this, this is not an inter-arm blood pressure decrease. This is just overall blood pressure reduction, as you would measure using a brachial cuff. And that wasn't a whole lot, 4.5 millimeter per Mercury reduction versus 2.3 millimeter per mercury in those who were in either placebo or other medication arms. So again, not a huge difference of blood pressure reduction here. But we know, like as we mentioned, some other mechanisms that come along with this agent are really helping in bringing the CKD rates down. Dr. Sean Kane 20:28 Yeah. And if you think about it, you know, one and a half of millimeters of mercury of systolic blood pressure, you wouldn't expect that to produce a 30% reduction in the risk of progressing to end stage renal disease. And again, the whole point of this is that we're not just reducing blood pressure. We're using these agents to reduce glomerular pressure and potentially have other mechanisms that are renal protective in patients that are at risk for progressing to a more advanced CKD stage right. Dr. Khyati Patel 20:57 And one of those questions I get in my clinic is whether this effect is dose dependent or not, as we know when we are using them for anti hypertensive perspective, yes, these are dose dependent. We do get dose dependent reduction in blood pressure, although, when it comes to reduction in proteinuria, it's not as a clear cut relationship, especially with the ace. We don't really know if there is a clear association between the dose and, you know, it's anti protein uric effect for the ARBs. We do have some evidence saying that as you increase the dose of ARBs, we do see greater level of proteinuria reduction. Dr. Sean Kane 21:38 A logical question at this point might be okay. So we understand that aces were well studied in this meta analysis, although ARBs potentially could have similar benefits. Is there a Preferred therapy between aces or ARBs in patients who are indicated because of proteinuria, chronic kidney disease, diabetes, whatever patient population we look at, is there a best one? Are they equally preferred? Dr. Khyati Patel 22:03 And so it's good to look at this question, Dr. Kane in terms of what do we have available from the studies, as well as what do the guidelines are saying? So if you look at the whole umbrella of, you know, randomized controlled trials and the meta analysis, it's seeming like Ace is more preferred or best proven in that protein, uric, non diabetic CKD patient. So like we're talking about proteinuria of, you know, more than 1000 grams per day when, when we look at ARBs, though their effects are actually best proven in patients who have diabetic nephropathy or have diabetes plus CKD alongside. But it's really important to kind of take a look at what the guidelines have to say. And so we have two different recommendations for us to discuss here. Dr. Sean Kane 22:51 So the first one is the 2012 kidigo guidelines. And this is the kidigo stands for kidney disease, improving global outcomes. And these chronic kidney disease that guidelines recommend an ACE inhibitor or an ARB, if patient has chronic kidney disease and they're a diabetic and they have a urine albumin of 30 to 300 milligrams per day, they also say that you can prefer either an ace or an ARB, and that CKD patient with or without diabetes if they have a lot of albumin area, so more than 300 milligrams per day. So terms of the 2012 kid ego guidelines, basically they say ace or Arbor preferred. The best evidence is going to be with those with more albumin area or more proteinuria and a little bit less evidence, or a little bit less preferred, and those that have kind of that micro albumin area. Dr. Khyati Patel 23:39 And the next one is obviously our diabetic nephropathy, or those who have diabetes and CKD together, we look at the ADA, the American Diabetes Association guidelines too, and as we know, those are updated yearly. There's a chapter on microvascular complications where the nephropathy related recommendations are housed. And what they're recommending is that if you have a patient with diabetes who have hypertension and has evidence for proteinuria, then you can use ACE or ARB and proteinuria or micro albuminuria, defined as the 30 to 300 milligram per gram creatinine excretion. They are strongly recommended for that higher proteinuria patients of the albumin creatinine ratio is above 300 or we are seeing more decline in GFR, so below 60. So again, differences in recommendation. One's recommended when you're looking at that micro albuminuria level 30 to 300 but strongly recommended if the albumin secretion is greater than 300 Dr. Sean Kane 24:46 and I think that this is an important point to kind of emphasize Dr. Patel, is that the presence of diabetes alone does not mean that you should be on an ace or an ARB. The guidelines in this section are pretty clear that you have to be hypertensive. First of all. So if you had someone with no hypertension at all, the perception is that they probably would not benefit from decreasing intra glomerular pressure. So we wouldn't do it in those patients. And we would like to see some degree of proteinuria, some degree of chronic kidney disease, or something along those lines, to kind of select out the patients that are most likely to benefit. So again, we're not taking the 35 year old normal renal function, no proteinuria, who happens to have diabetes. We're not going to give them an ace and ARB just for renal protection, because they don't really meet the criteria at that point. Dr. Khyati Patel 25:32 And that's absolutely correct. That's a point that we also try to drive really hard during the lectures and case discussions with students too, is that ace and ARB is not an automatic choice for anti hypertensives when you have a patient with diabetes, because if you look at the HA ACC guidelines, you know, hypertension plus diabetes, you can actually select any four of the primary agents that we should go with, right? But if when you start seeing that presence of microalbuminuria. That's when you narrow down your selections to ACE or ARB. Dr. Sean Kane 26:06 So Dr. Patel, if ACE or ARB are equally preferred, they work a little bit differently. It seems so logical to combine them both to get like Superman benefit in terms of prevention of chronic kidney disease. What does the evidence show for that Dr. Khyati Patel 26:22 great question, and I'm chuckling and laughing a little bit here, because I've had to fight this with some of my colleagues at the clinic to kind of show the difference, as we discussed earlier. One's a surrogate outcomes, the other one is a clinical outcome. So yes, plenty of evidence is out there when, when these two are combined, there is further reduction in proteinuria. We have a more recent meta analysis looking looking at 59 different studies and published in 2013 that showed that combining these two provided, wait for it, an additional 400 milligrams per day reduction in proteinuria. But what we have to see here as clinician is that, did it really translate into the long term outcomes? Did it really translate into us reducing the progression of CKD, preventing patients from going on hemodialysis? And the answer is no, there is no evidence to that this day that shows that combining these two really does anything to the overall progression of the disease in itself. Dr. Sean Kane 27:32 And we've really seen basically this same phenomenon and other disease states, like hypertension, heart failure, things like that, where we've studied combination therapy, and effectively, it doesn't do anything extra, and it causes more side effects. Dr. Khyati Patel 27:47 You're absolutely right, you know. So we're just inviting more side effects, such as maybe higher instances of AKI or hyperkalemia coming actually, there are few trials that have documented harm, and if I can be specific in terms of CKD patients, these harm was increased incidences of ESRD or doubling up the serum creatinine when these two agents were used together. So we have to be really careful and see how we want to use this to as our AIDS and not as our enemies. Dr. Sean Kane 28:22 So before we get into some of the issues with acute kidney injury, just to kind of wrap up the chronic kidney disease component. So Dr. Patel, you have your diabetic, proteinuric, hypertensive patient with risk of progression of chronic kidney disease, you start them on an ACE inhibitor. How do you know if it's working? Or how do you know if you need to go up on your dose or what is the approach in terms of treatment goals for that kind of a patient, right? Dr. Khyati Patel 28:47 And you know, you're looking at whether your patient with CKD and diabetes have hypertension or they don't have hypertensions. If they have hypertension, you're going to keep that hypertension or blood pressure goal in mind too, and that's where we're going to look at the AHA/ACC and the blood pressure goal of less than 130 over 80 millimeters of mercury is what we would go by. But let's say your patient has diabetes and CKD, pure CKD, but they don't have the hypertension part, right? So we're going to go off of their protein levels, and that's where the KDOQI guidelines, which is the Kidney Disease Outcomes and Quality Initiative guidelines, have put out a goal. And the goal is going to be, we're going to try to bring down that protein secretions to less than 500 to 1000 milligram per gram creatinine. And again, think about it. We said that these agents work best, or if they have the best evidence when we are looking at that proteinuric CKD, which that proteinuria is above that 1000 mark, and so bringing it down to less than that range, less than 500 would be the ideal goal. Dr. Sean Kane 29:54 So why don't we transition now into the whole point of the episode, which was, how is it that no. Think we've established it aces and ARBs are good to prevent chronic kidney disease. How is it possible that a drug that is good for the kidney can also be bad for the kidney in terms of causing acute kidney injury? Right? Dr. Khyati Patel 30:11 This is where the interesting caveat comes in. So we know when we add ACE or ARB we expect like a normal level of GFR decline, and it declines modestly after adding the agent, as we discussed, it decreases the glomerular pressure, and it therefore decreases that glomerular filtration rate, right? So again, we we have a good intention of lowering that pressure, because we want to lower the protein urea, but by lowering the pressure now we have also lowered the GFR. So that's that's some sort of like an expected outcome, however, that shouldn't be above a certain grade. Dr. Sean Kane 30:50 So what would that threshold typically be? Dr. Khyati Patel 30:53 So it's typically normal to see anywhere between five to 25% decline in GFR once we start these agents. But if we are looking at severe decline in GFR, and that's defined as more than 30% from the patient's baseline, that should catch our attention, and we should actually try to establish some sort of rationale to see whether we want to continue this agent or, you know, we want to maybe dose reduce, if there is room for dose reduction, keeping other underlying conditions in mind which CKD patients can commonly have, such as, we're going to have to keep a really close eye on that GFR. Dr. Sean Kane 31:34 So just to put a specific number to it, if a patient has a serum creatinine of one, we start an ace or an ARB for them, if their creatinine goes above or at 1.3 or higher, that'd be a 30% increase. That would be the threshold at which would say that they've progressed into this acute kidney injury. And we need to do something about that. And I think that, you know, it's important to realize why that's happening, right? So the reason why you're seeing this acute kidney injury is because we've decreased the glomerular pressure too much. The ace or the ARB has done too good of a job in dropping pressure in the glomerulus. And in order for glomerular filtration to happen, you have to have enough pressure. So it's kind of like a Goldilocks approach. If you have way too much pressure in the glomerulus, then you cause damage. You get proteinuria and progression of chronic kidney disease. If you have too little pressure in the glomerulus, because you've overdone it with your ace or your ARB, then there isn't enough pressure to have glomerular filtration, and you put the patient into acute kidney injury. So really, you want to have kind of this balance where you have kind of a normal pressure in the glomerulus, and hopefully we can accomplish that by picking an ace or an ARB at an appropriate dose and titrating at an appropriate rate so that we don't cause this 30% or more increase in serum creatinine for these patients. Dr. Khyati Patel 32:50 And this is where the entire episode Dr. Kane boils down, right like we need to have just the enough inhibition of the RAS system to promote that reduction in proteinuria, but not really cause the AKI by overdoing it. Dr. Sean Kane 33:06 And of course, along the lines of acute kidney injury, comes potassium problems. So you know, the vast majority of elimination of potassium in the body comes through the urine. So if your glomerular filtration rate changes, the amount of potassium that you can excrete can also change. And we we see that with really all of the renin–angiotensin–aldosterone system drugs – even spironolactone or other aldosterone antagonists, ACEs, ARBs – that they can cause hyperkalemia. And one of the main mechanisms for that is this drop in GFR correct. Dr. Khyati Patel 33:35 And we kind of discussed about how to treat some of the hyperkalemia in the previous episode, but one of the other dose limiting, or therapy limiting, side effect is hyperkalemia that we have to monitor. Dr. Sean Kane 33:49 So clearly, we have a balance here, right? Dr. Patel, so we have to figure out, how do we give just the right amount of drug, but not too much, so that we can accomplish our goal and not set the patient off into the wrong direction of what our overall intended goal is. So what is a typical approach for these patients, right? Dr. Khyati Patel 34:05 And this is where, you know, kind of combining whatever we talked about in terms of understanding the pharmacology, understanding the disease pathophysiology, understanding what the guidelines and the evidence have to say, and then creating this balanced clinical decision making, right? We're going to individualize it for the patient. We're going to assess the patient's risk and benefit at that point. I've actually seen for one example, again for a CKD patient, if their GFR and proteinuria are rapidly worsening, they would be taken off of the ACE inhibitors, because the end goal is to not have them be on, you know, cause some sort of an AKI, and then have them be on hemodialysis for the rest of their life. So that's, that's one example of how we decide whether they're helpful or not Dr. Sean Kane 34:53 helpful, you know, in terms of that shared decision making as well talking about risks and benefits and side effects and. You're going to monitor, right? So just like warfarin drug interactions, one of the easiest way to deal with a risk benefit kind of scenario is just more monitoring, so more monitoring of what the renal function is doing, and also monitoring potassium intake for these patients, so maybe some dietary changes related to eliminating or reducing potassium rich foods, so that they don't end up having a potassium problem on top of their acute kidney injury problem. Yeah. Dr. Khyati Patel 35:26 And this is really important if you know, we clinically want the patient to be on the drug that they may have to kind of eliminate, pretty much most sources of potassium where it comes from, and that it's easier said than done in reality. And then we have to look at other drug drug interactions, where the increased potassium coming in through right? We have patients who might be taking these agents because they have concomitant heart failure, or they could be on an aldosterone antagonist, which can cause hyperkalemia too. So really, that clinical decision making doesn't just focus on one condition and looks at the patient as a whole. Dr. Sean Kane 36:02 And of course, you know when you're thinking about initiating therapy for a patient, just like in heart failure, where you typically are going to start with lower doses of many of your initial therapies, because you're giving them two, three or four new medications that all drop blood pressure at the same time. Same is true here. So if you're going to start that ace inhibitor, if they're already on a diuretic, if they're a little bit dehydrated, if they're very elderly and maybe more sensitive to medications, you probably should pick a lower dose of your Lisinopril or Losartan than someone who is otherwise normal blood pressure, normal volume status, younger and you're giving it for hypertension and you're less worried about acute kidney injury for that kind of a patient. Dr. Khyati Patel 36:43 And what would be a good example of that, Dr. Kane, if you were to give in terms of, let's say, Lisinopril, Dr. Sean Kane 36:49 yeah, so like for that at risk patient, maybe you give Lisinopril two and a half or five milligrams a day. And normally, I would absolutely laugh at two and a half milligrams of lisinopril. It's like taking a little sprinkle of lisinopril and just shaving it onto their skin. But in this case, it actually makes sense, because now you can slowly titrate over a two to four week period, and it's okay. And that would be in contrast to, you know, Lisinopril five or 10 milligrams, where you're giving it just for hypertension, for a patient, for a typical younger adult patient, for sure, five or 10 milligrams would be perfect. But for that at risk patient, you're kind of asking for trouble if you are too aggressive with your initial dose or too aggressive in your dose titration. Dr. Khyati Patel 37:30 Yeah, and then keep, keep it in mind, you know, how soon are you going to have the patient come back to the lab to monitor the labs, and if, if they are not going to be able to come back like in the current situations of, you know, pandemic, for example, then we may have to be very conservative in choosing the dose that we choose for an initial therapy. And as we mentioned in shared decision making, you know, we are going to talk to patient about foods that contain high potassium, but we know that salt restriction has added benefit when it comes to decreasing the progression of protein urea and so that education should also be provided. Dr. Sean Kane 38:10 So Dr. Patel as part of our pharmacist, patient care processor, ppcp, our last step is follow up, monitor and evaluate. So monitoring is really important. After you implement a plan. What is our monitoring looking like for these types of patients? Dr. Khyati Patel 38:24 Yes, that's absolutely, very important to make sure that we have a closer follow up and monitoring for these patients, as we established earlier, some of the surrogate labs that you can look at would be amount of proteinuria. So a couple different ways it can be done more painful way, although more accurate way is the 24 hour urine collection, or more convenient way is the random creatinine spot check, basically, and I've seen lot of in lot of cases, that's what's occurring unless a patient is in the hospital where the 24 hour urine collection is more possible. That's when that lab is utilized. Obviously, if our patients are hypertensive alongside CKD or having diabetes, we're going to measure their blood pressure as well. This blood pressure can be obviously done in the clinic, or we can ask patients to measure it at home, called ambulatory monitoring. These two obviously were more of the efficacy related monitoring. We have to obviously worry about the ADR perspective of monitoring as well. Dr. Sean Kane 39:32 You know, we've kind of touched on this already, but that would be a BUN and serum creatinine renal function one to two weeks after you initiate or make a dose change. And if you see that serum creatinine going up more than about 30% you either stop the agent or you dose reduce with very close monitoring after that, and especially on those that are more advanced in their CKD or have more risk factors, you're going to be more conservative with them in terms of stopping versus just dose reducing, or how soon you see them after you make a decision, correct. Dr. Khyati Patel 40:02 And those patients who are on dialysis, sometimes they will get their potassium monitored twice, you know, a week, either like an alternating dialysis session. Dr. Sean Kane 40:12 And for the non dialysis patient, when you check your renal function, you should also be checking your potassium. So normal would be about 3.3 or three and a half to five and a half, and it depends on the lab what the normal range is. But if you're starting to see hyperkalemia, you probably should hold because it's a life threatening problem. So hold the agent until potassium normalizes, and then consider restarting at a lower dose. And if, despite that lower dose, they still have hyperkalemia, then it's time to just quit and do something different in terms of their chronic kidney disease. Again, hyperkalemia is a life threatening complication, so we don't want to mess around with that, right? Dr. Khyati Patel 40:50 And just, you know, Doctor Kane, you probably see more of the acute side of the hyperkalemia, I get to see more of the chronic side of it. And it sort of amuses me, the kind of foods that patients are eating. They have no idea how much potassium is in them. They're consuming it. And it gives rather a very good satisfaction to kind of point out and say, Aha, I caught the you know, the reason behind your hyperkalemia, we're going to stop you drinking an absorbent amount of orange juice, for example, or eating so much cantaloupe or watermelon, for example. And then hopefully, we will keep you on these agents that are obviously beneficial for a longer period Dr. Sean Kane 41:32 of time, for sure. Yeah. I mean, if you think about it, if you can tolerate some fairly minor dietary adjustments, again, by being on these agents, you drop your risk of going on dialysis by about 30% that's a really big reduction. Well, Dr. Patel, what are some of the key points that you'd like the listeners to take home from today's episode? Dr. Khyati Patel 41:51 Yeah, so kind of know that the ACE and ARBs work in our RAS system to inhibit the angiotensin two activity in the body, and the overall net effect is decrease in protein area, and clinically, looking at it, decrease progression of the disease, which is CKD. Dr. Sean Kane 42:10 And for me, you know, one of the things is the magic secret sauce of the aces and ARBs is that it's not just blood pressure reduction, but it's selective blood pressure reduction more than other anti hypertensives in the glomerulus, so we're dropping glomerular pressure better than other anti hypertensives, and that's probably the main mechanism of how these agents work. Dr. Khyati Patel 42:30 And as we know, you know, patients who have CKD, they're going to be at an increased risk of ACE or ARB induced acute kidney injury and hyperkalemia. And so we need to up our monitoring game and make sure that we are monitoring for adverse effects initially as well as as we change doses on a routine, ongoing basis as well. Dr. Sean Kane 42:52 And then finally, as attractive as it sounds to combine ace and ARB, we just shouldn't do it. So even though you have a potential surrogate benefit of less proteinuria, it does not translate into stopping the progression of chronic kidney disease, and in some cases, that actually causes harm, where we see more end stage renal disease and more doubling of the serum creatinine, which is the opposite of what we're trying to accomplish, let alone the side effects that we know will happen, like acute kidney injury and hyperkalemia. So with that, if you want to reach out to us, we're at HelixTalk.com we have episode notes for today's episode, Episode 117 we're on Twitter at HelixTalk, and we absolutely love the five star reviews in iTunes. We just recently got an extraordinary comment about our Pulitzer Prize winning commentary, which I don't think we quite deserve, but we definitely appreciate Dr. Khyati Patel 43:41 it, and I would second that remark, Dr. Kane, thank you. Dr. Sean Kane 43:45 So with that, I'm Dr. Kane Dr. Khyati Patel 43:47 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 43:51 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 44:02 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.