Time Stamps

  • 00:13 Reviewing CKD Classification!
  • 04:20 What’s wrong with how we estimate GFR?
  • 06:50 Why is creatinine flawed as an estimator of GFR?
  • 10:52 Enter new contender…Cystatin C!
  • 16:16 Importance of the A Stage!
  • 20:21 Which patients should you measure proteinuria in?
  • 22:10 Treatments for albuminuria!
  • 24:27 Summary and Closing



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Show Notes

Welcome to the “Stage”: GFR and Albuminuria 

Reviewing CKD Classification!

  • Kidney Disease: Improving Global Outcomes (KDIGO) introduced a dual-staging criteria for chronic kidney disease (CKD)
    • eGFR Staging (G-Stage)
      • eGFR between 60 – 120 ml/min/1.73 m2
        • NOT clinically significant CKD
      • Stage G3
        • Stage G3a
          • 45 < eGFR < 59
        • Stage G3b
          • 30 < eGFR < 44
      • Stage G4
        • 15 < eGFR < 29
      • Stage G5
        • eGFR < 15
    • Albuminuria (A-Stage)
      • Measured by albumin-to-creatinine ratio (ACR) in mg/g.
      • The gold standard definition for staging albuminuria involves checking 24 hour albumin excretion.
        • However, in practice, we make the assumption that all human excrete 1g of creatinine per 24 hours and this allows us to check a spot urine test  
      • Stage A1
        • 0 < ACR < 30 mg/g
      • Stage A2
        • 30 < ACR < 300 mg/g
        • Moderately elevated (previously “microalbuminuria”)
      • Stage A3
        • > 300 mg/g  ACR
        • Severely elevated (previously “macroalbuminuria”)
  • Both the G-stage and A-stage are independent risk factors for cardiovascular and renal events! 

What’s WRONG with how we estimate GFR?

Assessing Qualitative Renal Function using A-Stage! (Albuminuria)


Dr. Cary Blum: Hi, I’m Cary Blum! I’m a primary care doctor. 

Dr. Greg Katz: And I’m Greg Katz. I’m a cardiologist, but I also like to think of myself as an internist. 

Dr. Cary Blum: And welcome to mind the gap on CKD staging!

Dr. Greg Katz: So CKD it’s one of those topics that when I start talking about, I very quickly bore myself and my eyes glaze over because, you know, CKD can feel like there’s a lot of alphabet soup of letters and numbers with staging and there’s estimates, and there’s all of these different things that don’t always translate immediately to clinical interventions. And so, Cary, I’m really looking forward to learning from you. I could be a little bit less bored by this topic and how I can figure out a way to translate it more directly to things that may change my perception of my patients. 

Dr. Cary Blum: So, you know, Greg, I think you’re not alone in terms of, just immediately feeling a little bit bored when you hear the term staging. I think in general, that’s our natural instinct. But, honestly, I’ve kind of discovered for myself over the years that it’s really the boring stuff that matters the most. Right? So much of medicine is accumulation of risk factors over so many years until finally, something bad happens. And we have an opportunity to to help really before that bad thing. So you gotta care about the boring stuff and that’s really why the CKD staging matters. Not only that, but it’s really an opportunity to improve our practice. I think that there’s a lot of ways that we do this incorrectly. I think that, just like sometimes people just look at the eGFR and the BMP and they sort of take that at face value. Give the patient a stage and kind of move on and don’t realize why it’s important. But, one, eGFR is really just an estimate. It’s really inaccurate in a lot of patients. So I think it’s important for us to identify those patients. I also think that we do a really bad job, honestly, at thinking about the other half of staging, which is not the GFR, but whether there’s albuminuria.

Dr. Greg Katz: So that’s a really good point. Back in 2018, KDIGO, the Kidney Disease Improving Global Outcomes group changed the CKD staging to include both a G stage and an A stage. Cary, what do each of those stages mean? And why does KDIGO think it’s so important to add the A stage in there to our understanding of kidney function?

Dr. Cary Blum: So G stage stands for GFR and, in the rest of this episode, just to make things easier, I’m just gonna call it G stage. Right. And that’s broken up in the exact same way that it used to be the new staging system hasn’t changed that at all. So if we wanna put some numbers on there for the listeners, stage G5 is a GFR of less than 15, 15 to 29 is G4, 30 to 44 is stage G3B, 45 to 59 is stage G3A. And and that’s basically you know, the patients that we identify because anyone with a GFR of over 60 is generally not considered to have CKD, unless there’s some other abnormality that we’re identifying. So that’s the G stage. A stage stands for albuminuria right. And, and for the rest of this episode, I’m just gonna say A stage just to keep things simple. The breakdown there is that anything from 0 to 29 in terms of milligrams of albumin per day is considered normal. 30 milligrams to 299 milligrams per day is stage A2, which is considered moderately increased albuminuria and anything of 300 milligrams or more per day is stage A3, which is severely increased albuminuria. 

Dr. Greg Katz: So the G stages go up to 5 and the A stages go up to 3? 

Dr. Cary Blum: That’s right! Yeah. So, you know, the, the highest stage that you could have for kidney disease is stage G5, A3. And it’s both the G stage and the A stage are independent risk factors. They’re both independently important. Not only that, but as we all kind of know as internists knowing our patient’s GFR is important in terms of medication dosing. The lower someone’s GFR is the more likely they are to experience complications of CKD. So you really need to be on top of monitoring for those, counseling about those, and probably most important, right? So identifying a patient with proteinuria really provides you an opportunity to turn around the natural history of CKD using medications that are really helpful in patients with proteinuria or kidney disease. Yeah. So, I hear you, Greg, it sounds boring, but in reality we have a lot of work to do, and I hope to convince you by the end of this, that we should be more excited by this topic. 

Dr. Greg Katz: And so what’s wrong with how we’re measuring G stage? 

Dr. Cary Blum: So in order to answer that question, I really honestly think better to start with just an understanding of what GFR is and what would be a perfect way to measure it, and then compare that to what we do in real life. So GFR, you know, the name tells you everything, Glomerular Filtration Rate, right? It’s the amount of serum flowing through the glomerulus into the filterate per unit time. So the best way for us to figure that out would be to inject a molecule into our patient’s vein, which is fully filtered in the glomerulus, enters the filtrate, and then once that happens, it’s not reabsorbed or secreted into the tubule. And then you could either measure that molecule in the urine, or you could take serial measurements of it in the serum. And you could identify how quickly that patient is clearing the molecule. That would be the perfect way of doing it, right.

Dr. Greg Katz: That’s not what, that’s not what we do. 

Dr. Cary Blum: No, not at all. In an ideal world, in order to measure GFR, we would have to have a molecule that is in our patient in an exact known dose. Gets freely filtered. And then once it’s in the tubule nothing happens to it. It is not reabsorbed and not secreted. And unfortunately it is, there’s just no molecule like that that’s produced in equal quantity and every individual. And because of how cumbersome it would be to inject everybody with a certain dose of a biomarker, we end up using something endogenous, which is creatinine, which is often helpful, but often really poor estimate. 

Dr. Greg Katz: I’ve certainly noticed on the electronic medical record that there’s a lowercase ‘e’ before GFR. And so I guess I should take that to really force home the point that this is estimated and it’s not measured directly. 

Dr. Cary Blum: Yes. That’s huge teaching point, honestly, for me with my internal medicine residents. And honestly, just to illustrate that, let me give you a few numbers. The 95% confidence interval for a patient with an eGFR based on a creatinine only formula GFR of 60, that 95% confidence interval actually ranges from about 35 to 85. 

Dr. Greg Katz: That’s like, that’s a massive, massive difference.

Dr. Cary Blum: It’s huge. Right? And so if we can figure out which patients are estimated correctly and which patients are misestimated by that creatinine formula we may be able to help our patients more sort of either downstage the ones who think they have CKD and don’t, or actually for the other side of the coin potentially assign a lower GFR than we think the patient has. 

Dr. Greg Katz: Okay. So talk to me more about the, the limitations of the current biomarker that we use. Like what’s wrong with creatinine? 

Dr. Cary Blum: So creatinine is made in skeletal muscle, right? And we all have different amounts of skeletal muscle. And because of that, we use age and we use sex as sort of a way of trying to adjust for skeletal muscle mass. But that’s really not a perfect surrogate for skeletal muscle mass, as we both know. Like for example, I have a lot less skeletal muscle than a 34 year old guy in the NBA. And he would have a higher serum creatinine because he has more creatinine production. Even though his glomerular filtration rate may be exactly the same as mine. So increased creatinine production is one thing that can boost the creatinine level in patients with bulky skeletal muscle.

Dr. Greg Katz: So, in general, if you have a lot of muscle, your creatinine levels are high and that will make your kidney function look worse.

Dr. Cary Blum: Or, you know, the same thing on the other side. So a patient with decreased skeletal muscle mass will have a really low creatinine cause they’re not producing very much. And that will falsely reassure you that their GFR is fine, but if you think about them critically and you realize that their baseline creatinine really should be 0.4 and not 0.7, then you may recognize that this patient, has CKD.

Dr. Greg Katz: Yeah. It’s just one more reason why we need to be concerned about our frail patients. And you know, we have so much evidence that frailty is a risk factor for a lot of different things. And what I’m getting a sense of is that if I’m just looking at someone’s creatinine, who’s fairly frail, I’m going to get a false reassurance that their eGFR is in the normal range when actually it’s not. So the first flaw with creatinine as marker of GFR is the impact of skeletal muscle on what the levels in the serum are, but there are other problems with creatinine aren’t there?

Dr. Cary Blum: Yeah, there’s actually a host of other problems. I mean, the biggest one honestly, is the fact that creatinine is actually secreted in the tubule. So it breaks that rule that I told you, that the perfect molecule would have to be not secreted or reabsorbed. And that secretion of creatinine can actually be influenced by a variety of processes. So it can be blocked by drugs. And the most common one that we see is bactrim, the trimethoprim portion of that actually inhibits the secretion of creatinine into the tubule. And also it can be enhanced in certain situations. So in patients with a GFR, that’s sort of in that abnormal, but still not too bad range, like I would say in the 50s or so there is a compensatory increase in the secretion of creatinine in the proximal tubule, which will lower the serum creatinine level, despite the fact that the patient’s glomerular filtration rate is not doing so hot. So that, that actually is one way that we can miss relatively early stage patients by looking only at creatinine. 

Dr. Greg Katz: Right, I think you’ve persuaded me that the flaws with creatinine as an estimator of GFR have to do with both the fact that it’s present in muscle mass and so is gonna be dictated by the patient’s body habitus and and distribution of skeletal muscle, but also that the fact that it’s not just perfectly filtered and it’s also secreted into the tubule and that’s gonna be impacted by the stage of of renal dysfunction that we have. And then, you know, one of the most recent changes in this formula has to do with the removal of race. Can you educate me on why that was done and how I should be thinking about that? 

Dr. Cary Blum: Yeah. So historically this, you know, this race factor was added to the equation because it was observed in sort of empirical studies that for a given serum creatinine in African American patients the GFR was actually a bit higher. So this was thought to be potentially related to increased skeletal muscle mass. But as we’ve sort of gotten a better understanding of what race is, and where this comes from, we’ve eliminated that factor, which under staged African American patients and potentially made them more vulnerable to missing CKD. So I think that was definitely a move in the right direction for our profession as a whole. Kind of removing that social construct from the way we think about a biological process.

Dr. Greg Katz: And so if creatinine has flaws, is there something else that we should be using for our patients who we’re not sure we’re getting a great estimate on that eGFR? 

Dr. Cary Blum: Yeah, Greg! So you walked right into that one. There actually is. It’s called Cystatin C. Have you heard of this one before? It’s pretty new. 

Dr. Greg Katz: I’ve heard of it. I scan some New England journal articles that had that in the title. And so I know it’s hot and I’m supposed to know more about it, but frankly, my dumb cardiology brain has not equipped me to, to fully understand the nuances of Cystatin C. 

Dr. Cary Blum: All right. So this, this is a perfectly timed conversation. I think maybe you’re gonna love it. So, first of all, Cystatin C it’s not made an only skeletal muscle. It’s made in every nucleated cell. So in that way, it kind of gets around this skeletal muscle mass being a complicating factor. It’s also freely filtered, just like creatinine. So it does have that characteristic that we’re looking for. And unlike creatinine, it is not reabsorbed or secreted at all in the tubules. So in that way it’s much better than creatinine for certain folks. Now, let me backtrack a little bit because it’s probably not perfect. You know, new studies keep coming out, showing that other processes can influence the statin C levels. For example, inflammation, potentially diabetes as well. And just like creatinine, sex and age do play a role. So there are corrective factors for sex and age when you use a Cystatin C based estimate for GFR.

Dr. Greg Katz: So who’s the right patient to measure a Cystatin C in and when does it offer me useful information above and beyond what I can glean from a creatinine.

Dr. Cary Blum: So first, let me just say on a population level, it provides you a more accurate GFR estimate when combined with creatinine. So there’s new CKD epi formulas, which were just published in 2021, which you alluded to that removed the race coefficient. And the nice thing about these 2021 formulas is that there’s actually several for us to choose from. There’s the good old creatinine only based formula. There’s this Cystatin C based formula. And then there’s one that actually combines both variables. And if you look at large populations, the one that combines both variables, time and time again, outperforms either of the first two formulas. So, just in general checking a Cystatin C will give you a better estimate of GFR. Now with that said, I don’t check it in everybody. Right. Honestly, I think it would be just a little bit too much testing. There is some cost associated with it. So what I do is I think about my patient. I think about them critically. I think about their skeletal muscle mass. I think about their medication list I think about their risk factors for CKD and where they may live sort of in the natural progression of that disease. And if I think that there’s a chance they may be early stage CKD, I do check it. So there’s a lot of situations where it’s helpful. And one actually comes to mind that happened recently in clinic. So I had this patient who actually, unfortunately several years before I met him, had an above the knee amputation. So, most of his skeletal muscle in the right low extremity was missing. And then also he had diabetes, he had relatively poorly controlled hypertension. And to me, this is the guy who sort of would classically have CKD, right. He was in his mid fifties. And he was coming to me for the first time. I check urine albumin and low and behold his was high. And so that sort of confirmed my suspicion that he may actually have some degree of CKD. And that’s what I decided, let me check a Cystatin C! Right? Like he’s got a couple risk factors for me, potentially under staging his kidney disease, right. The amputation, and also the potential early G stage. So I checked one and using the Cystatin C only formula, which I felt was the most accurate one for him, his GFR was bumped down from what was considered normal or above 60 down to 50. Right. And now this patient carries the diagnosis of of CKD stage G3a and since his albumin level was increased, he was stage A2 as well. 

Dr. Greg Katz: What I love about this case is that you used your brain to identify a patient who you thought was vulnerable. And then you ordered the confirmatory testing, knowing the flaws with our current methods of analysis that actually enabled you to objectively identify the fact that this patient had low GFR. And that’s gonna change your cardiovascular risk assessment. That’s gonna change some of the medicines that you would put them on. That’s gonna change your threshold for nephrotoxic agents. And so I love that this forces us to change the way that we’re going to evaluate some of their risk factors. 

Dr. Cary Blum: That’s why I love practicing medicine! Because we get to think critically and identify ways to help patients, that other folks may have not recognized before. Yeah. And, for him, like you mentioned, he was on very high dose Gabapentin for diabetic neuropathy. And I had to think a little bit about dropping his dose to adjust it for his GFR. I also bumped up his dose of statin just because I was really worried about him from a cardiovascular perspective. And I think I’m gonna be more aggressive with him overall, just in terms of blood pressure lowering and, and other things. I’ve also seen other situations where, you know, a patient may drop from stay stage 3 to stage 4. And that’s where I may be calling my friendly nephrologist to say, ‘Hey, can you be involved in this patient’s care?’ Because we need to start preparing them for dialysis. And so this stuff actually does matter. It matters mostly to primary care doctors and nephrologists. But I think that every, specialty may have some connection to this, to be honest. 

Dr. Greg Katz: So to summarize all of this. In a patient where there’s any uncertainty about the degree of their renal impairment, those are patients that getting a cystatin C might be helpful to better understand their kidney disease. The pros of  Cystatin C is that it’s not affected by skeletal muscle mass the same way that creatinine is, and it’s not secreted  in the tubules like creatinine, which can also affect the levels in the blood.

Dr. Cary Blum: But, you know, in terms of potential drawbacks, we do know based on some relatively nascent literature that certain conditions such as inflammatory diseases, diabetes, and thyroid disease seem to increase Cystatin C levels a bit. But, you know, the impact of that and how that should change interpretation is really unclear at this point in time.

Dr. Greg Katz: So I think that you fully persuaded me that. Doing better job of estimating the amount of flow through the kidney is really, really important and often changes management for our patients. But when you were talking about the patient before, who had the discordance between creatinine and Cystatin C-based GFR, you also referred to the albuminuria and that kind of gets to this idea of qualitative versus quantitative renal function. And so GFR, to me, is a measure of how much is being filtered through the kidney and how much each nephron is actually doing. But I also care about the quality of the work that our kidney is doing and the quality of work performed by each nephron. And I think that gets to the A stage. And so how are we measuring this? Do you measure the A stage for everybody? And how should I be thinking about the importance of proteinuria. 

Dr. Cary Blum: So, let me just start by giving you some definitions before I answer those questions. But first thing we should know are the actual ranges for the stages. So any urine albumin to creatinine ratio of 29 or less is considered normal and that’s stage A1. Stage A2 is this category called moderately increased albuminuria and that’s a patient with a urine albumin creatinine ratio in the range of 30 to 299. And then anything of the ratio of 300 milligrams of albumin per gram of creatinine is considered severely increased and that’s stage A3. So those are the categories. The reason this matters, well, you know, I was thinking about this in the shower and, the beautiful thing about the kidney is that the endothelium actually comes adjacent to the outside world. Right. And so we have an opportunity to measure a body fluid, urine in this case. That is in great proximity to the endothelium. Something that we really truly care about a lot, because we know that endothelial dysfunction is at the root of a lot of cardiovascular disease.

Dr. Greg Katz: Yeah. And we talk about endothelial dysfunction all the time in the cardiovascular realm, but there are no fluids in cardiology that we’re able to directly measure. 

Dr. Cary Blum: Yes. So the nephrologists win on that one! And, the thing is, that when glomeruli are not functioning appropriately, albumin gets into the urine. Right. We have to go back to med school and kind of remember what the glomerulus is supposed to do. It’s a…

Dr. Greg Katz: Please don’t say the word podocyte, right now! 

Dr. Cary Blum: I’m not gonna say podocyte, but you did! So anyways you know, it’s, to put it simply, right? The glomerulus’s job is to let certain things through and not others, right? No cells are allowed through, no large proteins are allowed through. And albumin is a large, negatively charged protein. If there is endothelial dysfunction or any other part of the glomerulus, maybe the podocyte, that’s not working, then protein will get in the urine and we can check that. Right. And so next logical step is, proteinuria provides us a snapshot of how our kidneys doing right now. Which GFR does not. GFR sort of shows us what has happened to our kidneys so far and how much damage the glomeruli have accumulated to the point where they’re no longer able to even filter. But the dysfunction of allowing albumin through happens way, way before the sclerosis and the failure to filter. So, you know, it shows us where our patient’s at and gives us this opportunity to identify high risk people who need more aggressive intervention. 

Dr. Greg Katz: So do you check proteinuria for all of your patients or just those who you suspect may have some degree of CKD?

Dr. Cary Blum: The latter, honestly, because if I were to check a urine albumin in every patient, I’d be swimming in a bunch of false positives. Because there’s a lot of things that can actually cause that to be positive, which are not reflective of a chronic, glomerular damage process, right? So even just vigorous exercise can cause albuminuria or being upright can cause albuminuria. That’s an entity known as orthostatic proteinuria.Fevers and a variety of other processes can cause some temporary spillage of albumin into the urine. And so for that reason, I don’t check in everybody. I think about the patient. Right. I think about whether they have risk factors for CKD. I certainly check it in all patients with diabetes, which is guideline based. I check it in all patients with known CKD and and more frequently if I know that they already have albuminuria, I will trend that more frequently, like say three, four times a year to make sure that I’m, my interventions are actually working. I should, let you know that the way that we measure this, right, a spot urine album in creatinine ratio. You and I spent the whole first half of this episode talking about why creatinine kind of sucks for some patients. Right. And it sucks for the same reason in this test that it does in the serum test. If you think about it, a patient with increased skeletal muscle mass for example, will have more creatinine in their urine, then someone with less. And because that’s in the denominator that affects the ratio. And so it’s important to to think about this ratio with a critical mind, in the same way you think about a patient’s estimated GFR. And if you don’t trust it, you should just measure a 24 hour urine albumin. That will be the most accurate way of figuring out how much proteinuria are patients having per day. 

Dr. Cary Blum: And so albuminuria matters because of the relationship between the albumin and the urine and cardiovascular risk. It also tells us about how aggressive we need to be about both targeted renal therapies like renal angiotensin inhibition, SGLT2 inhibitors, finerenone, but it also tells us how aggressive we need to be about modifying the risk factors. What glucose target do we need to have? what blood pressure target? And so it’s important for, a number of, different reasons. I actually learned something recently, which kind of shocked me when I was creating a talk for the residents, which is that RAAS inhibition only has an additional independent kidney protective benefit in patients with proteinuria.Right. Other than that, it just has the benefit of blood pressure lowering, like any other blood pressure medication. So, in a patient with very elevated levels of albumin in the urine, I’m really, really pushing those ACEis and ARBs. And even if that patient has hyperkalemia, I might still push the ACEis in ARBs and, and put them on a potassium binder. Whereas, you know, if I had a patient, even if they were relatively late staged CKD, but they had no albumin in their urine and things seemed to be relatively stable. If they had hyperkalemia, I would avoid an ACE and an ARB. And I would just lower their blood pressure using other agents. So albumin arguably has a more influence on management than GFR. Yet, it’s something that we measure much less than we should, right. This, the new staging system from KDIGO, I believe came out in 2018, if I’m not mistaken or even before that, and it’s just not really been picked up. Like, I don’t really talk, hear people talking about the A stage very much. Do you Greg, or?

Dr. Greg Katz: You know, I see it in notes written by nephrologists, but it’s not something that’s made its way fully into everyone’s practice. And that’s the way that, that these things happen. Sometimes clinical inertia really, really powerful, and it takes a lot of really passionate people talking about issues that matter over and over again, to drill into the heads of those of us who are sometimes slow on the uptake of new ways of doing things that we need to do it better. And so I think kind of along those lines, you’ve persuaded me that I’m not doing a good enough job at evaluating my patient’s renal function. 

Dr. Greg Katz: What I’ll take away from the things that you’ve taught me today are, number one, quality of measurement of somebody’s glomerular filtration really matters. And creatinine has flaws and cystatin C for the carefully selected patient may be a better way of evaluating their quantitative filtration through the kidney. The second thing is that quality of filtration really matters, too. And the amount of protein, particularly albumin that someone has in their urine is really a marker of endothelial function, renal risk, and cardiovascular risk in a lot of ways too. And the fact that we haven’t done a great job of disseminating the importance of both a G stage and an A stage for chronic kidney disease is flaw in the way that many of us do things that we need to get better at. And so I’m gonna take away that I need to measure a G stage and an A stage in all of my patients. I am very appreciative of the idea of having a more precise, quantitative estimate with the GFR and a qualitative estimate using the albuminuria. And so thinking about not just how much, but also how well the kidney is filtering. 

Dr. Cary Blum: Yeah, that was a great summary, Greg, you know, I couldn’t have said it better and I agree, we started with a topic that wasn’t so sexy, but I think now by the end, we’re both convinced that it’s important. So we can now go take better care of our patients.

Dr. Greg Katz: And that’s is a wrap for today. If you found this episode helpful, please share with your team and colleagues and give us a rating on Apple podcasts or whatever podcast app you use. It really does help people find us! 

Dr. Cary Blum: Thank you to Yichi Zhang for the audio editing. Thank you to Ariella Coler-Reilly for the accompanying graphic. And as always, we love hearing feedback! So email us at hello@coreimpodcast.com.

Dr. Greg Katz: Opinions expressed are our own and do not represent the opinions of any affiliated institutions. Listening to this podcast does not constitute the formation of a Doctor-patient relationship, and nothing that you heard should be construed as personalized medical advice.