This transcript has been edited for clarity.
Sparks: Welcome to Medscape InDiscussion. I'm Dr. Matthew Sparks. Today we'll be talking about CKD, CKD prevention, and how primary care physicians [PCPs] can have an impact on patients with chronic kidney disease [CKD]. Will the SGLT-2 inhibitors, the renin-angiotensin system inhibitors, and the mineralocorticoid receptor antagonists make a dent in CKD progression? With me to answer some of these questions is Dr. Ian de Boer. Ian is a professor in the Division of Nephrology at the University of Washington in Seattle. He's also an adjunct professor of epidemiology and director of the Kidney Research Institute at the University of Washington. He is a co-chair of the 2020 KDIGO Guidelines on CKD and Diabetes. Welcome, Ian.
de Boer: It's a pleasure to be with you here today, Matt.
Sparks: Let's just jump right in and talk about how we got to where we are. It's an exciting time to be working in the field of nephrology — and I think also for patients. Can you tell us where we are in the current state and how we got there?
de Boer: We really are at a time where there's a paradigm shift in our ability to take care of patients with chronic kidney disease. I trained as a fellow about 20 years ago and in my clinic, there was very little we could do to prevent progression of chronic kidney disease … to prevent the cardiovascular complications that we saw in patients with chronic kidney disease. But just in the last 5 or 10 years or so, there's been an incredible turnaround, with great new drugs that are available to treat people with chronic kidney disease, prevent progression, and prevent kidney failure. Now that we have these options, we're at a point where we need to implement them. We need to figure out who to treat and get those patients treated, so they can do better than they did when I started in this profession.
Sparks: I think that's a good point. Let's go ahead and just define what CKD is.
de Boer: Yes, that's very important. Chronic kidney disease is defined as abnormalities in kidney structure or function. What does that mean? Basically, that's a low estimated GFR [glomerular filtration rate; eGFR] — less than 60 milliliters per minute — or the presence of elevated albuminuria, and any signs of kidney damage or function that are present for at least 3 months. So, not an acute kidney injury but something that's been abnormal is confirmed and has been present for at least 3 months of time.
Sparks: Albuminuria is something that is not measured enough, which has been seen in study after study. When should a PCP measure albuminuria, and how do they do that?
de Boer: Everybody with type 1 or type 2 diabetes should be screened with an albuminuria test at least yearly. Also, people who have hypertension should be screened with albuminuria and eGFR testing, as should other high-risk groups, such as people of racial/ethnic minorities who are at high risk or those with family histories of chronic kidney disease. But that's a little less certain. It is quite easy to screen for albuminuria. You just urinate in a cup, measure the urine albumin-to-creatinine ratio, and there you go. It should be done along with eGFR testing. It's not being performed as frequently as it should be based on how simple it is — for example, in people with diabetes. While we test eGFR reasonably well — most people with diabetes get an eGFR check at least once a year — screening for albuminuria is, at best, 50% per year, and screening in people with hypertension is even less. It's a simple thing to do. It's absolutely necessary for diagnosing chronic kidney disease, and now that we can link that diagnosis to treatment, it has to be done.
Sparks: One of the other things that becomes a challenge is understanding all this terminology that nephrologists use. What is microalbuminuria and is the microalbumin test the same thing? Why do we have several names for the same test?
de Boer: Great question. There are 2 things we can measure in the urine … or commonly measure in the urine. One is albumin — that's the specific albumin protein. It's the most common protein in blood that gets filtered when there's kidney damage through the glomerular basement membrane, and it comes out in the urine. The other thing we can measure is total protein, which includes albumin but also other proteins that are naturally or unnaturally in the urine. That's always higher than albumin because it includes other proteins.
"Microalbumin" is a misleading term. It's not a small albumin; it's actually small concentrations of normal albumin in the urine. We realize that terminology is misleading. There's really a spectrum of urine albumin excretion, with higher being worse and lower being better. We've recoined those terms as "moderately increased albuminuria" or "severely increased albuminuria." The key is that anything other than normal urine albumin is abnormal and merits either diagnosis or treatment.
Sparks: Great. That's one thing I love to emphasize: albuminuria — we need to measure it more often. The other thing is that the kidney failure risk equation is a great way to look at a patient and say, "Should you have a nephrology consultation?" Can you talk about how you use the kidney failure risk equation in clinical practice?
de Boer: The kidney failure risk equation really is a useful tool. It uses a number of clinical variables to determine a person's risk for kidney failure in the next 3 or 5 years. So, that's something that's real to a patient. Patients, often understandably, find that it's a little bit abstract to understand what albuminuria is. But if you can translate that into a risk of kidney failure requiring dialysis or kidney transplant, that is a real piece of information that can motivate change.
Sparks: Okay, let's jump right in to the KDIGO guidelines. In 2020, you were the co-chair of these guidelines for diabetes. Can you talk a little about what guidelines PCPs should be looking at … what's coming in the future?
de Boer: The main kidney guideline organization is KDIGO, or Kidney Disease Improving Global Outcomes. KDIGO introduced its first guideline for diabetes and chronic kidney disease in 2020. The process actually started in 2017, when we were getting all these new data about new drugs for diabetes and trying to understand how to apply those to people with chronic kidney disease.
Sparks: Let's talk about SGLT2 inhibitors. We're all excited about these amazing outcomes. Every clinical trial seems to be positive. Can you tell us a little bit about how SGLT2 inhibitors are used in patients with CKD, both with and without diabetes?
de Boer: SGLT2 inhibitors really have been the major advance for treatment of chronic kidney disease over the last decade. These drugs have had so much more effect than just lowering blood glucose. We now have 13 large clinical trials that have been completed testing the clinical outcomes of SGLT2 inhibitors. These span trials of people with type 2 diabetes at high cardiovascular risk, people with chronic kidney disease who do and don't have diabetes, and people with heart failure who do have diabetes. These trials consistently show marked benefits of SGLT2 inhibitors for the kidney and for the heart — particularly for heart failure. That's really revolutionizing kidney disease care.
Sparks: Can you talk more specifically about when you should consider [introducing an SGLT2 inhibitor]? With what eGFR? Should you have a certain albuminuria? Then we'll talk a little bit about how to monitor a patient. So first, who's the right patient? If I'm a PCP, should I be doing this by myself or should I wait for a nephrologist?
de Boer: Great question. The most obvious and most important place to be using SGLT2 inhibitors right now is for people who have type 2 diabetes and CKD. That's where we have the most data. Those patients are at high risk for both kidney disease and cardiovascular complications of diabetes. It's abundantly clear now that SGLT2 inhibitors are effective and safe in that population. Who am I talking about specifically? I'm talking about patients who have type 2 diabetes and CKD — defined as either albuminuria of 30 milligrams per gram or more or low eGFR that's less than 60. Should primary care physicians be starting SGLT2 inhibitors? Absolutely. If we're going to get the improvements seen in these trials for all the patients who have these conditions, it has to be primary care who is prescribing the drugs.
So that refers to people with type 2 diabetes. Again, that's the population for which there is the most evidence right now. But those aren't the only patients who benefit from SGLT2 inhibitors. We have data from some of the newer trials that suggest other patients [benefit] as well, including people who have chronic kidney disease from other causes. These are people who have chronic kidney disease from high blood pressure or glomerular diseases, such as IgA nephropathy or membranous nephritis, who are stable. Those patients, if they have proteinuria of more than 200 or 300 milligrams per gram of creatinine, are at high risk for progressive chronic kidney disease. Those patients have also been shown in trials to benefit from SGLT2 inhibitors, even though they don't need the blood glucose benefit. These are not really [only] glucose-lowering drugs, in my opinion; they are kidney-protective drugs. Those patients with nondiabetic CKD and proteinuria also have better kidney outcomes from being treated with an SGLT2 inhibitor.
Sparks: Will we get to a point in time when we stop classifying these medications as antidiabetic agents? I especially want you to comment on the clinical trials, because when you look at the patients who don't have diabetes, the adverse events are almost nil. For instance, in the DAPA-CKD study, there was more hypoglycemia in the patients who received placebo, right?
de Boer: That's right.
Sparks: To me, one of the biggest issues we're facing now is reeducating nephrologists and primary care physicians and physicians in general that these are not just for diabetes. They're kidney-protecting agents. They are heart-protecting agents. How can we move beyond that?
de Boer: The clinical trials have shown us that they're not just glucose-lowering drugs. These drugs work across a huge range of glucose at baseline — from poor glucose control in diabetes to good glucose control in diabetes to no diabetes at all. The mechanism — we're still trying to figure it out — but it's clearly not through blood glucose. It's through direct effects on the kidney or other actions there. The guidelines have acknowledged this. In fact, in the KDIGO guidelines, we're now updating a 2022 guideline just 2 years after the original 2020 guidelines because we have so much new data. We've moved our SGLT2 inhibitor chapter from the glucose-lowering section to the comprehensive care section of the guideline because we don't consider it a glucose-lowering drug anymore; that's just not its main role. It does have beneficial effects for glycemia, particularly if you have a high eGFR and a high hemoglobin A1c, but its effects are really independent of the glucose-lowering effects.
de Boer: You're right. The clinical trials have shown that the efficacy in terms of kidney disease progression, heart failure, etc., is not dependent on glucose. The adverse effects in people who don't have diabetes are particularly low. There's no diabetic ketoacidosis, for example, in people who don't have diabetes. That's a population that we need to continue to examine in clinical trials.
Sparks: Before we move on to the renin-angiotensin system inhibitors, I want to talk about who should avoid these medications and where we should use a little caution. There are a couple of things I want you to talk about. One is polycystic kidney disease, two is issues with urinary tract infections.
de Boer: The most common major adverse effect is genital mycotic infections. These are fungal infections that are due to more glucose being in the perineum. They tend to be mild. They tend to be easily treated with antifungals. Often, people will restart SGLT2 inhibitors after treating a genital mycotic infection; sometimes not. Rarely, there have been reported cases of Fournier's gangrene. While this is generally a mild complication, we do need to be aware that it can happen. It does affect how we think about treatment for other conditions.
Bacterial UTIs, by the way, are not more common with SGLT2 inhibitors. That's a common misconception. The rates of bacterial UTIs are the same with SGLT2 inhibitors as with placebo in most of the trials. So, how does this affect other populations? And I'm going to add one or two to your list if you don't mind. One is type 1 diabetes. People with type 1 diabetes at high risk for chronic kidney disease or kidney failure probably, based on short-term trials, may have the same sort of kidney benefits as people with type 2 diabetes. However, they are at high risk for diabetic ketoacidosis [DKA], and SGLT2 inhibitors do increase the production of ketones and increase the risk for DKA in type 1 diabetes. So, until we have good efforts and good ways to detect and prevent DKA, type 1 diabetes is not a population where we should commonly be using SGLT2 inhibitors today.
Another population I want to add to your list, Matt, is kidney transplant recipients. That's a very controversial population as well. Probably, SGLT2 inhibitors could be very effective in that group. They're patients who have a single functional kidney. Based on what we know about the mechanisms of action of SGLT2 inhibitors, they probably will have benefit but we don't have data. There are just no trials in kidney transplant patients now. I was talking about the risk for genital mycotic infection. What happens to that with immunosuppression? We don't know. So far, I have not been treating my kidney transplant patients with SGLT2 inhibitors, because I don't know the adverse effect profile. I hope that will change and I hope we'll get more data in the near future.
You mentioned people with UTIs; so [that includes] people who have urinary incontinence. In my practice at the VA hospital in Seattle, I have patients who have indwelling Foley catheters occasionally. Those patients are not good candidates for SGLT2 inhibitors because of the genital infection risk. PKD was another population you brought up — polycystic kidney disease. There, we don't really know and I'm not regularly treating PKD patients with SGLT2 inhibitors either. Did I cover all the populations you addressed?
Sparks: I think so. I want to go back to urinary tract infections. I am aware that the clinical trials did not shown an increase in urinary tract infections. However, I want you to comment on the exclusion criteria of urinary tract infection. Is this a population of patients who already had a lower risk for urinary tract infection? If we have a patient who has several urinary tract infections a year, would you still give the patient the medication?
de Boer: I'd probably avoid [the medication in] that patient. You're right, Matt, that we need to be careful extrapolating clinical trial data to wider populations, so that's the sort of patient who probably would have been excluded from most of these trials.
Sparks: Okay. Let's move on now to an oldie but goodie — my favorite system, the renin- angiotensin system [RAS] blockade. Tell us about when we should consider this medication in patients with kidney disease.
de Boer: "Oldie but goodie" is a good description; I like that. RAS inhibitors have been around for decades now. It's been about 20 years since the seminal trials showed that they can slow kidney disease progression in people with diabetes. In fact, there have been trials showing that RAS inhibitors also slow progression of proteinuric kidney disease in people without diabetes. In that sense, they're a bit like SGLT2 inhibitors. The effects of SGLT2 inhibitors and RAS inhibitors seem to be complementary. They can be added together to get multiple benefits.
So, why do we prescribe RAS inhibitors? Well, generally, we prescribe them to people who have high blood pressure. There are multiple options for the treatment of high blood pressure. Why do we treat high blood pressure? It's not just all about the kidney. I'm a nephrologist; you're a nephrologist, Matt. We love protecting the kidney, but we need to recognize heart disease and stroke, and the fact that we want to reduce the incidence of those important diseases as well.
For people who have hypertension or kidney disease and hypertension, there are several classes of medications that can be used to reduce blood pressure and effectively improve cardiovascular outcomes and kidney outcomes. Those are RAS inhibitors, dihydropyridine calcium channel blockers, and diuretics such as thiazide diuretics. For many patients, you can choose any of those 3 classes — or most commonly a combination of those classes — because we usually need more than 1 drug to control blood pressure. There are some patients for whom a RAS inhibitor is clearly the best choice. Those are the patients with albuminuria, because if you do have albuminuria, that signifies increased kidney risk. In those people, kidney disease progression is a particularly important target, and that's where RAS inhibitors have their best effect. In the diabetes guidelines — and I think this is true for hypertension more broadly as well — the formula is this: If you have hypertension and you have albuminuria, you need to be on a RAS inhibitor.
Sparks: Can you tell us the exact definition of albuminuria?
de Boer: I view albuminuria as 30 milligrams or more per gram of creatinine — so, any elevated albuminuria. If you had higher levels than that, then you have an even more compelling indication for a RAS inhibitor. But even that micro range of 30 to 300 milligrams per gram of creatinine is an indication for a RAS inhibitor for your preferred treatment of hypertension.
Sparks: So, at 30 [milligrams], you're on the radar; you probably should take it. Get up to 200 [milligrams] and above, then you better be on a RAS inhibitor.
de Boer: That's right.
Sparks: So, same issue with this class [RAS inhibitors]. It's so interesting that SGLT2s and RAS inhibitors both affect intraglomerular hemodynamics and cause this increase in creatinine and decrease in eGFR. Is that just coincidence? Do we monitor both of them the exact same way — that is, SGLT2 inhibitors and RAS inhibitors?
de Boer: There's something special about intraglomerular pressure. In the pathogenesis of kidney disease, higher is bad and lower is better. In fact, there are lots of other drugs, too, that can lower intraglomerular pressure and seem to be beneficial. There are some similarities there, and I think it's not a coincidence. You're right that when you do lower intraglomerular pressure, albuminuria goes down and creatinine goes up. That can be considered a worrisome sign, but it's not; that's a sign of a response to the drug and generally not an indication to discontinue the drug. As with our discussion on SGLT2 inhibitors, it's reversible. So, if you stop the drug, it'll come back. You know that even with that short term looking bad, over the long term, you're going to get benefit.
Sparks: So, what is the number? Is there a number that they look for? I've heard 30% increase in creatinine. Is that a dogmatic approach to it built upon evidence or is that just kind of what we see? How would you describe this? I think that's where some PCPs might be a little bit nervous because you don't like to see the creatinine change … especially if you don't have any comfort in this. So, what can we tell our listeners about how to monitor creatinine when you start either a renin-angiotensin system inhibitor or an SGLT2 inhibitor?
de Boer: My short answer is up to 30% [increase in creatinine] is just fine; more than 30%, worry a little bit more about it. Think about other things going on — concomitant medications, fluid status, etc. — and do a little more of a workup. The longer answer is that we don't have great data on this. We have some observational data behind that 30% number, and that's what I use in clinical practice.
Sparks: You know, PCPs are really in a great place to make a large impact in CKD. I think if we look at implementing these medications in the right patients, over time, we'll see fewer individuals who have to go on dialysis but also see less cardiovascular disease, less stroke. So, I think these are really important areas to focus on. I know that the United States Preventive Services Task Force is currently discussing screening for CKD in the general population. Do you have any insight into that?
de Boer: They clearly recommend screening for people with diabetes and hypertension; I think all organizations do. Those are high-risk groups. Now that we have therapies that we can link to screening, that really makes us want to reevaluate the screening approach. We've learned a lot, and we've learned that when we can diagnose CKD, we can now effectively treat it. The most exciting thing in this field, in my opinion, is that because we have treatments, that should reinforce our desire to screen. So, it's not just screening for the sake of screening, it's screening that can be directly linked to therapies that directly improve outcomes — that's the winning formula for improving outcomes in this population.
Sparks: What do we have to look forward to in the future? What are the new drugs on the horizon? We also need to talk about mineralocorticoid receptor antagonists. But what else do we have coming?
de Boer: Well, it is a very exciting field, and there are all sorts of new things coming. You're right, mineralocorticoid receptor antagonists have some exciting trials, and they have a role already in people with chronic kidney disease. GLP-1 receptor agonists are out there, too; they show great promise. They work to reduce cardiovascular disease. They seem to have kidney benefits; there are ongoing trials, and we'll learn more about that in the next couple of years. I think they'll enter the guidelines in a bigger way in the near future. Then there are a lot of pipeline drugs. There are lots of mechanisms through which kidney damage occurs and kidney progression occurs, and many of those are being targeted. So, ultimately, down the road, we'll have more options. For now, what we have are a small number of really good drugs.
Sparks: That's great. Also, I'll leave our listeners with some fun facts that many of the drugs in these classes were derived from nature. I love to talk about this, because to me it's so interesting. The renin-angiotensin system inhibitors were first found in Bothrops jararaca, which is the Brazilian pit viper. I think it uses the substance basically to make the blood pressure drop in its victims. The SGLT2 inhibitor class was from the bark of an apple tree. So, the adage of "an apple a day" is very much in use. The GLP-1 receptor agonists were first derived from the saliva of the Gila monster, which is really interesting. That's how the Gila monster is able to survive by eating 10 meals per year, because they have a huge bolus of food that they have to tell their body to stop eating. That's how [humans] lose weight with those medications. It's really interesting that we have these drugs from nature that are really effective at diminishing CKD and adverse outcomes related to that.
With that, I will wrap up. First, we learned about albuminuria … the importance of measuring it. [We learned] what CKD is … what an estimated glomerular filtration rate is. [We learned] why it's important to check both [albuminuria and eGFR] in patients, especially those at high risk — those with hypertension and those with a family history of kidney disease or diabetes. We talked about the proper use of SGLT2 inhibitors. We talked about renin-angiotensin system blockers and how those are still a mainstay of therapy, especially in those who have hypertension and albuminuria. Finally, we talked about some new things on the horizon, including mineralocorticoid receptor antagonists and GLP-1 receptor agonists. We also now have a new combination of GLP-1 receptor agonist and GIP agonist. So, I think it's a really exciting time for all patients who have kidney disease and a really exciting time for nephrologists. We want to empower primary care physicians, because if we're going to make an impact, that's who's going to do it. Thank you so much, Ian, for joining. It's been a pleasure.
de Boer: Thanks for having me, Matt.
Sparks: Thanks for listening. I'm Matthew Sparks for Medscape InDiscussion.
Resources
Screening, Monitoring, and Treatment of Albuminuria: Public Health Perspectives
National Kidney Foundation: Albuminuria
KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease
SGLT2 Inhibitors for Non-Diabetic Kidney Disease: Drugs to Treat CKD That Also Improve Glycaemia
Glomerular Diseases: Emerging Tests and Therapies for IgA Nephropathy
Albuminuria, Proteinuria, and Urinary Albumin to Protein Ratio in Chronic Kidney Disease
KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease
Sodium-glucose Cotransporter 2 Inhibitors and the Risk of Severe Urinary Tract Infections
Euglycemic Diabetic Ketoacidosis
Sodium-glucose Cotransporter Inhibition in Polycystic Kidney Disease: Fact or Fiction
Management of Hypertension in Chronic Kidney Disease
Diuretics for People With Chronic Kidney Disease
What to Do for the Patient With Minimally Elevated Creatinine Level?
Screening for Chronic Kidney Disease: U.S. Preventive Services Task Force Recommendation Statement
From Snake Venom to ACE Inhibitor — The Discovery and Rise of Captopril
GIP and GLP‐1, the Two Incretin Hormones: Similarities and Differences
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Cite this: How to Manage Chronic Kidney Disease in Primary Care - Medscape - Aug 11, 2022.
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