Activity Transcript

Donald E. Wesson, MD: Hello, I'm Dr Donald Wesson. I'm president of Donald E. Wesson Consulting in Dallas, Texas, and professor of medicine at Texas A&M College of Medicine. Welcome to this program: Metabolic Acidosis: What's the Latest? Joining me today is my colleague, Dr Navdeep Tangri, from the University of Manitoba. Welcome, Nav.

Navdeep Tangri, MD, PhD: Thank you, Don.

Dr Wesson: Happy to have you join along with us. Nav, you and I have been treating folks with metabolic acidosis (MA) for a long time. But recent research supports that we've got some new information to talk about that really affects how we treat our patients with MA. We recognize that it's common, but now we recognize that it is a contributing cause to its progression, which makes it a bit distinctive with respect to the complications of MA. About 37 million adults in the United States have CKD. And about 3 million of those with stage 3 to 5 are affected with MA in the United States. Nav, we've got a case that we can base our discussion on. If you'll take it from here.

Dr Tangri: Don, I think it's really great that we both get a chance to talk about this because not only do we both treat patients with acidosis, I find that we're really coming at the problem from 2 separate angles. My approach has really been very much grounded in the epidemiology, whereas your approach is very much grounded in the pathophysiology and the physiology of acidosis. So hopefully, as we talk through this case, our viewers can get some insights from both perspectives. So I think it's always good to anchor these stories in a case, so why don't we start with that?

Dr Wesson: All right.

Dr Tangri: I've got a 60-year-old man in my practice, and he's got stage 3b CKD. His GFR is about 35 mL/min. He's got a potassium of 4.9 mE/L. He's got diabetes, so he's got an HbA1c of 7.5%, but his bicarb is 20 mEq/L, and his ACR is 351 mg/mmol. He's got progressive disease, high risk, and he has got acidosis. He also has coronary artery disease (CAD) and he's on an ACE inhibitor, a statin, insulin, beta blocker, aspirin, loop diuretics. So, 6 or 10 medications, similar to most of our patients. Tell me, why do you think MA is important in this patient's progression? Come at it from the pathophysiology, like you do so well.

Dr Wesson: Well, from the pathophysiologic standpoint, we've recognized over the years how the kidney actually excretes acid, particularly when it has been challenged with an increase in acid load. It excretes acid in the form of buffers, and we've recognized that for a long time. Ammonium being, quantitatively, the greatest part of that net acid excretion. We've recognized that ammonium in high concentrations in the kidney actually stimulates complement and causes kidney injury that reduces kidney function over time.

In addition to that, there are other cytokines in the kidney, most notably, endothelin-1 and components of the RAAS system that are up-regulated that in the short term, helps the kidney get rid of that accumulated acid. But in the long term, Nav, measured over years, those internal cytokines inside the kidney actually cause fibrosis and inflammation, most notably in the interstitium of the kidney. Over time, that can reduce kidney function that gives us that insight that the kidneys' response to MA in the short term is helpful, but in the long term can be harmful. Hence, the reason to treat MA and reduce that kidney's maladaptive response to the accumulated acid.

Dr Tangri: Yes. I think what I find striking is that we've known about this as a complication of CKD for a long time. We've known about its maladaptive effect on not only the kidney, but other organs as well. And yet, it doesn't get a lot of attention from nephrologists, right? I think that it's a shame, because compared with some of the other complications such as anemia or hyperkalemia, which are not disease modifying -- they're complications that are important -- but they don't really change the trajectory of CKD. Yet, acidosis probably does. And yet, it's still so underdiagnosed and undertreated.

To that note, I want to share a recent study we did, which really looked at this from a very comprehensive angle and looked at real world diagnosis and treatment rates in 86,000 US patients. We used this data set from a company called the Symphony Integrated Dataverse. This has been used in multiple studies in nephrology involving transplants, and in many other fields. It's a really well validated and connected data source with both labs and medications and claims. What we found really was that only 21% of patients had a diagnosis code of acidosis. And more importantly, only 15% ever received treatment with oral alkali. To our knowledge and your knowledge, other than diet which you have taught us for years is invaluable, the only medication treatment that's been available has been oral alkali. The treatment rates are dismal.

Dr Wesson: Absolutely.

Dr Tangri: And then, I decided that we should probably look at this in our province. I work in Manitoba, Canada, as you know. We have universal healthcare and a central database that captures all prescriptions. We said maybe Symphony, even though it's very good, is missing some scripts, and let's look in our universal healthcare system. To my surprise, only a small percentage of patients were ever treated with oral alkali, even in our universal healthcare system. The biggest thing was, that even the ones who were treated in Symphony and in our dataset, they were stopping treatment very early. We did a nice little experiment where we compared the adherence over time to statins, because statins are commonly used in patients with CKD. Statins are a reasonable example, muscle aches aside, pretty well tolerated drug. We said let's compare sodium bicarbonate to statins and see what the adherence profile is. I'd say about a year out, 6 months to a year out, half of patients who start oral alkali, stop it. Not only are only about 1 in 6, 1 in 7, ever get treated, it's probably 1 in 12 that are staying on treatment. I think we have a big diagnosis gap and a big treatment gap. Like you, I spent a lot of time thinking, why aren't people paying attention and why doesn't this get treated? It's a complex thing, right?

Dr Wesson: It is. It is.

Dr Tangri: CKD care is hard. The patients have many competing priorities. You've got to manage diabetes, you've got to manage hypertension, you've got to manage all the complications. How much time does a nephrologist have in their office to really say, "Okay, today we're going to tackle acidosis."? I think until you really show convincing data, and that's what we're going to get to later on in this talk, you get convincing data that there is an effective treatment. And that not only does the treatment treat acidosis, it can improve, let's say, physical function or CKD progression. That might be what's needed to move the needle and get more physicians interested.

Dr Wesson: The other thing, Nav, I think it's interesting is that when you and I see patients, we typically focus on other concerns for kidney patients -- their potassium, calcium phosphate, the anemia -- all of those things that we have very good algorithms as to how to treat. But as you alluded to, we don't have very good algorithms for treatment of MA. Even though KDIGO and KDOQI has told us in recent years that this chronic MA needs to be treated, I think the uptake has been rather slow. I think that's one of the contributing reasons for the data you've presented to us, that relatively small percentages of folks with CKD who should be treated and the most common treatment available being sodium-based alkali, are not being treated.

As you mentioned, our laboratory has looked at the effectiveness of diet, but only a small percentage of our patients in our laboratory, 10% or less, are able to sustain the type of treatment through diet that effectively treats MA. Certainly, part of the reason of this undertreatment is the lack of effective interventions that patients can sustain and tolerate over a long period of time.

Dr Tangri: Don, one thing I wanted to touch on, which you really alluded to, the fact that sometimes there's this perception that the acidosis we're seeing in outpatients is mild. Right?

Dr Wesson: Yes.

Dr Tangri: But work from you and others have shown that it's kind of like a tip of the iceberg phenomenon. Right? Because by the time you get to 21, 22, you've already exhausted a lot of the buffering capacity of the other organs, as well as I know citrate has been proposed as a marker of earlier acidosis. Would you tell us a little bit about in the patient who's sitting at 20 or 21, what has already happened?

Dr Wesson: Yes, I'm glad you brought that up, Nav. I like the iceberg analogy. Because what we've recognized is that before the serum bicarbonate starts to decrease to a measurable amount, we in our bodies have already accumulated a bunch of acid. The good news is that we've got very good systems that can combat the effects of accumulating acid, such that we don't have a significant decrease in bicarbonate concentration. However, that acid is still there. Once we start seeing a decrease in the serum bicarbonate concentration, that means we've already accumulated a bunch of acid there.

The next question that you can ask is, well, if it's not decreasing the bicarbonate concentration, is this acid causing harm? Well, our animal studies and patient studies suggest that the answer is yes. In that, if you treat this accumulated acid with sodium-based alkali or with diet in the way that I described, you can reduce the complications that are related to that accumulated acid. Most notably, the more rapid progression of CKD. This so-called mild MA that we've been talking about for many years is really our looking at that tip of the iceberg, but we're missing that part that is underwater that we can't see. And so, that tells us then that even mild MA needs to be treated.

Dr Tangri: I think we talked a lot about the kidney outcomes. As you remember, we've spent almost a decade now since Drs de Brito-Ashurst and Yaqoob did a study that first showed that if you treat acidosis, you can improve kidney outcomes. I think recently, there's been really great work showing that acidosis associated with cardiovascular (CV) complications and fractures and falls, and there's been multiple RCTs showing muscle outcomes, different muscle outcomes. But I tend to remember that our colleagues in pediatric nephrology were probably attuned to this a long time ago. When you look at patients with RTA and the treatment rates for acidosis in pediatrics are north of 50%, because they recognize that untreated acidosis impacts growth.

Dr Wesson: Absolutely.

Dr Tangri: I wonder if we're seeing adults are obviously fully grown. But are we seeing muscle and bone effects in adults, whereas what we would see in children, the same process would produce growth deficiencies?

Dr Wesson: Wow, Nav, that's a very good point. When adults are fully grown, and of course their bones aren't growing anymore, the effect of this accumulated acid may not be as obvious as our pediatric colleagues have known for decades, because that accumulated acid is slowing bone growth. They saw the need for treating these kids with chronic MA decades ago. It may well be as you're suggesting, that we adult nephrologists are finally catching up to the bone injury that's related to the chronic MA that is less obvious because it's not inhibiting growth. But we're recognizing that accumulated acid is inhibiting bone formation, reducing the structural integrity of the bone and increasing the risk for falls and fracture, as you suggest. So we're catching up with our pediatric colleagues. Another reason yet to treat chronic MA, is the ongoing threat to the bones that is occurring, even in adults.

Dr Tangri: I think there's this big crosstalk between bone and muscle, and bone and muscle work together to prevent you from falling and breaking. I saw some really cool data recently from, I think, Bab Roshanravan, which showed that acidosis affects the mitochondria and muscle. The muscles don't work as well, don't contract as well. I can't belabor that there's been tremendous observational studies associating it with all of these outcomes and all-cause mortality, but I think that there is a sound pathophysiological basis. I'm glad that you see and you agree with that every one of these observations that we're seeing in the data has real pathophysiology behind it. In a lot of cases, we have studies that show that if you treat, you can actually impact these endpoints. I think we've got quite a sound basis there.

Dr Wesson: Absolutely. Now we nephrologists, we love pathophysiology. We've known about the pathophysiology of increased protein catabolism for a long time causing muscle decrease in size and even decrease in strength. But now, we're recognizing that that pathophysiology that we've known for a long time is really translating into a detriment in overall physical functioning. And very importantly, treating that MA can then improve the physical functioning. Now there's yet another example of this good pathophysiology that scientists have come up with over the years translating into having clinical applicability.

Dr Tangri: Yes, I think with that in mind, I want to go through very quickly the current treatment options, and then I want you to highlight for us data from your study that was published in Lancet. Let's start a little bit with oral sodium bicarbonate. You can neutralize acid. But really, in my practice, most of my patients need at least a gram 3 times a day to get started.

Dr Wesson: Absolutely.

Dr Tangri: A lot of them are going to need 2 grams 3 times a day to get really into the normal range, so that's 6 to 12 pills a day. We discussed with my case earlier: one, that patient's already on 6 to 10 pills a day, so doubling their pill burden. The second part is, I think, lots of us have seen edema and worsening of shortness of breath post-- in some cases, worsening shortness of breath -- but edema, very commonly with high doses of sodium bicarbonate.

Dr Wesson: Yes.

Dr Tangri: The biggest thing that my patients complain of honestly, is the gastric carbon dioxide, that GI discomfort. I don't think we need to get into all the reasons. We can just look at the data, because the data show that 50% of the patients stopped taking it within 6 months. And it's not the patients, because the same patients keep taking their statin. I think there's real limitations to oral alkali.

Now I love the diet piece -- I think it's really wonderful. I love the fact that I don't eat meat personally, but I'm really happy that for the first time in decades, we have a lot more plant based products out there, right?

Dr Wesson: Yes.

Dr Tangri: There's tons of options now than ever used to be. But the reality is, as you know, plant-based products unfortunately are still more expensive than their alternatives, and just not accessible to 8 out of 10, 9 out of 10 of our patients.

Dr Wesson: Yes.

Dr Tangri: I'd love to have more of my patients eat more plants because I think even a little bit helps, and every little bit helps. But I can't see it yet being the bridge to full correction of acidosis.

Dr Wesson: I agree with that. I mean, even someone from my laboratory who has really pioneered some of these plant-based studies and showing the effectiveness, it just is not accessible to the great majority of patients, particularly a great majority of patients that I see that are very poor and live in food deserts and have less access to those foods. So that's a concern. The sodium-based alkaline, most commonly, sodium bicarbonate as you mentioned, if given enough, can increase the serum bicarbonate concentration, but that requires a significant amount of bicarbonate being given a day. Like you said, 6 to 12 650-mg tablets of bicarbonate. If you give 6 of those tablets per day, Nav, that gives you about a gram of elemental sodium.

Dr Tangri: Yes.

Dr Wesson: You look at the KDIGO guidelines, they suggest that we restrict the sodium intake to 2 grams a day. So if you're treating a MA with the minimum amount that looks like it gets a reasonable increase in serum bicarbonate, you've already given them half of their sodium load. And not to mention the challenge that it gives in terms of reducing the effectiveness, the CV protective effectiveness, and the kidney protective effectiveness of the ACEs and ARBs. So there's a lot of reasons to avoid this high dose of sodium that comes with the most common way by which we have to treat MA today.

Dr Tangri: Yes. I think effectively, high sodium loads are undoing the therapeutic benefit of a lot of our interventions, a lot of our best interventions.

Dr Wesson: Yes.

Dr Tangri: As you alluded to, RAAS. There's a high sodium load, lots of great data showing that they decrease the efficacy of RAAS inhibitors. And probably, emerging data suggest that a lot of the benefit of SGLT2 inhibitors is volume mediated, right?

Dr Wesson: Yes.

Dr Tangri: If you look at, your hematocrit goes up and that's a big mediator of SGLT2 inhibitor efficacy. I wonder if maybe you're actually taking some benefit away there as well. With all of that in mind, it's probably a good time to talk about newer strategies and strategies that are really novel. A lot of our audience may not have heard of veverimer, which is a completely unique mechanism of action (MOA). It just sort of binds and removes acid and takes it away permanently. Veverimer is orally administered once a day, directly binds acid with very high affinity in the GI tract, and then you get rid of it in the stool. There's been multiple randomized trials showing that it works within 24 to 48 hours, and that its efficacy is sustained over a year. Now, you led the phase 3 studies, the 12- and the 52-week study. And recently, I understand that you examined some data from subgroups from these studies. I'm wondering if you can walk us through some of those data.

Dr Wesson: Sure. Nav, you've already alluded to this. But if we think about MA as being too much acid on board, then conceptually, we can think about treating it by eliminating the amount of acid that is taken in by diet. By neutralizing it, is the way we've described with sodium-based alkali, or by removing it from the body. Physiologically, as a physiologist, I like the idea of removing acid from the body. That's a very attractive mechanism that veverimer gives us. It removes acid from the body, increases the serum bicarbonate in that way. And in the phase 3 studies that looked at 2 weeks, 12 weeks, and now a total of 52 weeks of treatment, we get sustained increases in serum bicarbonate. It says that 61% of folks get a net increase of 4 mEq/L or more. And we nephrologists treating MA, if we can get an increase of 4 mEq/L, that's our hallelujah time. We really are happy about that.

But more importantly than simply increasing the serum bicarbonate showing the effectiveness of treating MA, it yields the outcomes of improved physical functioning measured subjectively by our survey, and objectively by the sit-to-stand chair test. As you mentioned, Nav, that is a way by which we can actually improve how our patients feel and function. We nephrologists have been looking at an intervention for decades that actually has our CKD patients feel and function better. Treatment of MA in these 2 studies in Lancet shows that treatment of MA does that.

You might think, all right, does that work for all patients with CKD? What about those who have particular subgroup problems, like heart failure? What about those that have diabetes? And so, when we examine those subgroups of those who have heart failure, you might think: well, is it as effective in increasing the bicarbonate in folks with heart failure? The answer is yes. Is it effective and improving their physical functioning, measured both subjectively and objectively? The answer is yes. The veverimer treatment of MA increased and improved the way patients feel and function in those who had congestive heart failure (CHF).

The other disease you might think about is diabetes, because that in and of itself can be associated with poor physical functioning. You might ask: well, can the veverimer help such patients when they are treated, when their MA is treated? Well, again, answer is yes. In the subgroup of patients who had diabetes, they had a similar increase in their serum bicarbonate in response to veverimer. And very importantly also, both subjective and objective improvement of their physical functioning.

This, for us nephrologists, is a game changer because we're not only making our patients feel and function better, but as you know Nav, how patients feel and function is one of the criteria we use as to when we are going to recommend long-term dialysis. If we can delay that long-term dialysis, our patients are happier and our overall costs to treat CKD is reduced because we put off the need for that expensive dialysis treatment.

Dr Tangri: That's incredibly valuable. I was listening so intently to what you said and my key takeaways are: one, am I that surprised? No, because the mechanism is direct binding. Right? If the mechanism is so simple and it binds, why should it matter if a patient has diabetes or heart failure? I think it's important to show. I agree with you, it's important to show. Because half of our patients have diabetes, and heart failure can lead to fluctuations in volume status and contraction, alkalosis, and all of that. It's important to show these subgroups, but it's not surprising that it doesn't matter, because the drug works just by binding acid in the gut, right? If you bind acid in the gut of a diabetic, you should be able to bind it in the gut of a non-diabetic, right? So I think that's really neat. I think to touch on your point about how patients feel and function, it's underappreciated probably in the community, the value of that.

Dr Wesson: It is.

Dr Tangri: Yes. It's really consistently ranked as a high patient priority. You ask patients, what are your priorities for CKD care? They want to be less tired, they want to be stronger. They want to be able to do that activities that they want to do. I think that's an important message that treatment of acidosis has this potential to impact QOL, physical function, and CKD progression beyond just treating the lab measure of bicarbonate.

Dr Wesson: Yes. Nav, from my standpoint as a physiologist, this is particularly gratifying to me in that basic physiology that many of us have been studying for years and years has now translated into a clinically meaningful benefit. And so it's all the more reason for us in nephrology to continue that connection between understanding of basic physiology and how that translates into our management of patients.

Dr Tangri: Yes. To bring it full circle, I think it's also gratifying for me because sometimes we see things in the data in epidemiology that suggest that if you treat this risk factor, you are going to get a benefit, but they don't turn out to be true. I think we all remember the TREAT trial, which was motivated by people with low hemoglobin tend to do worse cardiovascularly. But when you treated them, then they didn't do better. This is also a really nice case where the epidemiological data suggest that MA is common, it's harmful, it needs to be treated. But then you also have randomized trials, well done randomized trials, that show that treatment of acidosis is associated with improved outcomes. I think both of us need to keep working on research to spread the word that treatment of acidosis is important and show that there are real meaningful excellent treatment options out there. And hopefully, clinicians can move that needle way north of 1 in 6, to 1 in 12.

Dr Wesson: I would say, even before some of these new treatments that are being tested come onto the market, what these data tell us is that we should pay more attention to chronic MA. That in addition to the potassium, the calcium, the phosphate, and the hemoglobin, we should put that bicarbonate a little higher on the list as we're looking at patients. And then look at ways by which we can even now intervene in a way to improve the MA with the thought that this is going to not only improve the lab that we're seeing, but it's going to improve things that the patients can see as an improvement in their overall well-being.

Dr Tangri: Yes. I think the hierarchy of evidence will strongly support that. When you look at the pathophysiology, the epi, and the trials, bicarbonate should probably be ahead of a lot of those other lab measures that we treat. Thank you, Don. This has been great. Thanks for the great discussion.

Dr Wesson: And thanks for the great work that your group has done, Nav, that has helped to point out that this is a concern that has led to a lot of the work that we interventionists have done over the years.

Let me thank the audience for their participation in addition to thanking my colleague, Nav Tangri, for his contribution to this discussion. And please continue on to answer the questions that follow, and complete the evaluation.

This is a verbatim transcript and has not been copyedited.