Crack the Case: Proteinuria

July 1, 2022

Dr. Alex Kula, pediatric nephrologist at Lurie Children’s Hospital in Chicago, provides kidney pearls in this week’s episode as we riff on confounding urine dipstick results. Join us as we navigate incidental proteinuria, hematuria and its origins, post-strep glomerulonephritis, and guidance on when to approach your friendly neighborhood nephrologist. Dr. Bryan Fate and Dr. Kula also wax nostalgic about their old cover band in Seattle, “Doctor Doctor”, which critics agree was pretty ok.


Dr. Angela Kade Goepferd: This is Talking Pediatrics, a clinical podcast by Children’s Minnesota, home to the Kid Experts where the complex is our every day. Each week we bring you intriguing stories and relevant pediatric health care information as we partner with you in the care of your patients. Our guests, data, ideas and practical tips will surprise, challenge and perhaps change how you care for kids.

Welcome to Talking Pediatrics. I’m your host, Dr. Angela Kade Goepferd. On this episode of Crack the Case with Dr. Bryan Fate, we delve deeper into kidney disease, what we can expect in the outpatient setting when patients present with proteinuria or hematuria, and how to build our differential going forward.

Speaker 2: (singing)

Dr. Bryan Fate: Welcome to Crack the Case, where we usually dive into real cases seen at our Minneapolis Continuity Clinic. As usual, we will incorporate music written by myself, and today my guest, at the end of every episode to highlight teaching points and hopefully engage the emotive side of your brain.

I’m Dr. Brian Fate, a primary care pediatrician at Children’s Minneapolis, and with me today is Dr. Alex Kula. Dr. Kula is a pediatric nephrologist at Lurie Children’s Hospital of Chicago, and assistant professor of pediatrics at Northwestern Feinberg School of Medicine. Dr. Kula and I both trained at Seattle Children’s Hospital where we forged what Pitchfork called the greatest cover band of all time, and Rolling Stone called transformational dad rock, the band Doctor, Doctor. Alex and I also worked together to co-write original songs for resident teaching, which took the billboard top 40 by storm.

Dr. Kula, as an icebreaker, I had the opportunity to hear you speak at grand rounds in Seattle just about how much music impacted you as a patient when you were growing up. If you would want to share more about that.

Dr. Alex Kula: Sure. When I was 19, I actually received a liver transplant. I had primary sclerosing cholangitis that was pretty rapidly progressing. So, through that whole process, which was a big process, I think music was a big part of it, a really important coping mechanism. Sometimes when I think back on it, it’s almost like music was a constant companion or a friend. It’s always there for whatever mood you had, a good mood, optimistic mood, bad mood, a hopeless mood. There’s always some sort of way that you could find that manifested through music.

So, it was something that, on a practical level, helped pass the time, but I think it also helped me process a lot of what was going on and really, in some ways, made the whole experience more meaningful. I’ve always been really connected to music. You see its power, and it’s something I’ll never let go of.

Dr. Bryan Fate: Our goal today is to bring out some topics that you’ve encountered as a nephrologist that you feel like general pediatricians out there might confuse, or perhaps that you get a lot of calls about that they might be able to do more work up themselves, so trying to empower more generalists out there.

So, let’s go to our first case. We have a 15-year-old who just got his sports physical done. They had a screening urine, which came back for 1+ protein. The generalist was not as sure what to do with that, so they sent him to your office. Proteinuria is something that we encounter frequently, and the differential is vast. Just based on that case, Alex, I’ll let you start talking about what things you think about there.

Dr. Alex Kula: We understand when we see people who have proteinuria and are sent to us, because the differential is so wide and there are a lot of very scary things on the differential. So, we’ll never be mad if the right step is for us to think through it. I’ll preface everything I say, that pediatricians in the community should always feel comfortable giving their local nephrologist a call if they have that resource, because a lot of times we’re happy to work with you and talk through the case with you.

So, this is a very common situation, where you have this incidental proteinuria. Right there, I think is a key factor, where there’s not someone who’s coming in for a sick visit, they’re coming in for a sports physical or who knows what, and then you have this incidental finding. That, right away helps you triage it in your brain. So, when you have this 1+ proteinuria, the key thing is, so there’s this wide differential, and how do we feel more comfortable that it’s not one of the scarier things, so nephrotic syndrome or more involved kidney disease. One of the first aspects is that they’re otherwise healthy. Right there, if someone has proteinuria but is otherwise healthy, has a normal exam, then that tells you have a little time to figure it out and figure out the next best step.

When you have that situation, often the best thing to do is have them come back a month or come back two months later, and repeat the urine sample to see is it actually persistent. Then this will be a recurring theme, is the things to look out for is, one it’s more worrisome, and when you don’t want to have them come back in two months is one, if they’re hypertensive, because that’s the sign of kidney disease. Two, if they have any edema, because again, that’s a kidney disease finding or a sign of something more concerning. Then if they have other systemic symptoms, so those are the three things. It doesn’t sound like they’re present for this individual, so this is someone who say, hey, let’s come back in two months and see if it’s still there.

You’ll see that proteinuria is very common, and it’s something where if you had a cold, if you exercised that morning, if you, I don’t know, eat too hard, you’ll have a little bit of a protein in your urine. So, sometimes it’s nice just to repeat it, because you’ll see, two months later, hey, there’s no protein, and that tells you, this is something we don’t need to be worrying about or something that we can just follow up in a very slow pace.

Then the second situation is, well, let’s say two months later the come back, they still have 1+ or even 2+ proteinuria. Again, to help you triage it in your brain you need to ask those questions. Is there edema? Are they hypertensive? Are there any other systemic symptoms? I guess when I say systemic for proteinuria, you also want to see if there’s any evidence of diabetes. So, if someone was obese or had diabetes or had glucose in the urine, that would be another situation that might not make it urgent, but just speed up wanting to come and see us. So you have someone, let’s just for the sake of this, say they again have 1+ proteinuria, everything else is negative. He’s doing great. Then I think in that situation, it’s appropriate to send a referral for a nephrology to be in the next few months.

Then what we need to do is figure out why does this person have persistent proteinuria? The most common cause in someone who’s otherwise healthy is going to be orthostatic proteinuria, and so that’s something that five to 15% of really adolescents you’ll see out in the wild in the general population have. The problem is we don’t actually know how common it is, because these are otherwise healthy people, and so we’re not really checking their pee very often. But this is a finding that’s typified by proteinuria that’s only present after standing up, and that’s where the orthostatic comes from. So, when you send them to us, one of the first things that we’ll get, is make sure that we have a first morning urine sample, because if it’s orthostatic, that would be negative, and so when we say first morning urine.

Dr. Bryan Fate: So, you can’t get out of bed, right? You have to like-

Dr. Alex Kula: Yeah, like literally

Dr. Bryan Fate: Lying down.

Dr. Alex Kula: I want to rolling out of bed, and walking straight to the bathroom, and peeing in the cup, because even just a few minutes of walking around can sometimes manifest it, and then you’ll not really be sure what’s going on.

Dr. Bryan Fate: I know in residency, when we worked together during your fellowship, we talked about the 24-hour kind of urine protein collection versus I think if you look at some guidelines right now, there’s a total protein to creatinine ratio. How do you use those, and are those tools that can be used by generalists too?

Dr. Alex Kula: So, I would say you should avoid getting 24-hour urine collections. There’s something that rarely provide more information than a spot urine. They’re a giant pain for patients to collect, and often we know, actually they’re not super accurate, because no one really wants to carry around a milk jug and pee in it all day when you’re [inaudible]. So, it’s something that I’ve used maybe one time in the last five years. It doesn’t provide much more information, so often if you’re really good at timing it or making sure you have that first morning example, you can infer from there. I would say, hold off on the 24-hour urine collection, and let us order that if it’s one of those weird situations.

Dr. Bryan Fate: Then how about the total protein to creatinine ratio?

Dr. Alex Kula: The urine protein to creatinine ratio could be another tool if you want to get a better sense of how much is there actually, and that sometimes is helpful in other conditions, and we’re trying to figure out is this a proteinuria that we need to worry about? Above 0.2 would be abnormal. I did air quotes under a table, but a lot of times we think when there’s not a lot of protein, sometimes the precision that test helps. So, I don’t think it’s wrong, but if you feel like you have a sense of it with the urine dipstick, you don’t need to confirm it with that test.

Dr. Bryan Fate: Any other proteinuria thoughts?

Dr. Alex Kula: Another key factor can be age, so if you have a younger person with proteinuria, and by younger, I mean like under eight, your likelihood of that being nephrotic syndrome goes up a little bit. So, that can be another clue to when they should come see us. Then I think what’s important is if someone has any of those concerning symptoms, so they have hypertension, edema, or some other systemic illness, I think it’s worth trying to have them either giving us a call or trying to have them come in sooner rather than later, because those are conditions that sometimes can be a little bit more rapid in their onset or they’re side effects. So, if those are present, it usually means, hey, we need to figure out a plan today. If they’re sick, they need to go to the ED. If there’s a lot of swelling, they’re very hypertensive, they need to go to the ED. But sometimes it’s just, this is when I should give a call to my local nephrologist.

Dr. Bryan Fate: Excellent. Well, we’ve talked about aggressive urinary streams, peeing in a carton for 24 hours, and we will transition to blood in the pee. So, our second case is a three-year old who had a fever without a whole lot of other symptoms, ended up having +2 protein, +2 blood, white blood cells, positive nitrates, leukoesterase, so treated with Cephalexin for UTI, and feels better, but comes back a week later, and another urine is collected that still is +1 blood, and the referring doc is concerned that there’s still blood. There was protein. Am I missing something else? Is this not just a UTI? What would you say to that person?

Dr. Alex Kula: It’s good to always have your antennas up. So, even these situations where it ends up being something benign or incidental or non-pathologic, these findings always warrant just a little bit more thought. So, I think that’s always really important. As a nephrologist, when you’re sent someone who has blood in the urine, the first thing we’re trying to figure out is this blood coming from the kidney? Then after we kind of have that, yes, no, the second part is, well, if not, where is it coming from? Because if it’s coming from the kidney, that means there’s some intrinsic renal disease. The most likely thing would be a glomerulonephritis or inflammation of the kidney, and that’s something that might require attention a little quicker. So, the most common cause of hematuria for someone in this situation actually is urinary tract infection, and that’s true for young children across the board.

If you have someone who has a urinary tract infection, they have blood and protein in their urine, I think it’s good to repeat it at some point. Sometimes we also have kidney disease that disguises itself as a urinary tract infection, so people think they have urinary tract infections that ends up being a kidney problem. So, it’s always good to keep an eye on them and have them come back for testing. Although the only thing I would suggest differently is to wait at least three weeks, because hematuria and a little proteinuria is sometimes can persist for a few weeks.

So, if everything else is fine, we don’t have any of those three concerning findings, then I think it’s okay to have them come back in a few weeks, because you have a classic story for urinary tract infection, especially if they respond to antibiotics, and we know that’s the most likely cause, and thinking will, how do we approach this if we’re worried about glomerulonephritis? If the concerning symptoms are there, that’s again, a situation where you should give us a call or have them seen within the next day or so, or even sooner, if they’re really sick.

Dr. Bryan Fate: Hypertension, edema, headaches, are obviously symptomatic.

Dr. Alex Kula: Yeah. Like other [crosstalk 00:14:01].

Dr. Bryan Fate: Like joint swelling. What else would be on your list?

Dr. Alex Kula: So, the swelling, the hypertension, and then when I say systemic, a lot of times we kind of think, is there rheumatologic condition? So, joint pain, rashes. If someone says I’ve been fatigued for the last three weeks, something where there’s symptoms and no other easy explanation, that would be, I think the best way to describe a systemic. It’s really hard, because a lot of the things that cause systemic symptoms are so vague and variable, and so it’s hard to say, oh look for these three findings. When you think systemic, you’re just thinking, if this person seems sick and there’s not some really easy explanation for it, is when we need to think a little harder about it.

Dr. Bryan Fate: You mentioned kind of pinpointing the source of bleeding. So, we talked about upper, in the tubules or glomerular apparatus versus lower tract, like the bladder or GU region.

Dr. Alex Kula: If someone has painless hematuria or asymptomatic. So, I guess for hematuria, that’s the additional finding where if everything else is fine, but they have brown urine or they have red urine, that’s not normal, especially if it doesn’t hurt at all. That’s a situation where you need to work it up more, and so you can’t always rely on the color, because I’ve seen even sometimes people like green [inaudible 00:15:21]. I don’t know why that is, but for some reason I’ve seen people who had a little bit of blood in their urine and it looked green.

Dr. Bryan Fate: Interesting. Then I was going to ask you about the value of microscopy too in identifying where it’s coming from. I know that was always hammered home to me is that you want to see if there’s dysmorphic RBCs and cast? Is that something that-

Dr. Alex Kula: Oh yeah.

Dr. Bryan Fate: That’s a tool in your toolkit you usually use, Alex?

Dr. Alex Kula: Absolutely, and it’s an important one for differentiating, and one of the key components that can be helpful in knowing if it’s kind of a glomerular source of blood or a lower urinary tract, is how the blood cells look. So, if the glomerulus is a filter, if it’s inflamed and blood cells are leaking through, they still have to kind of squeeze their way through, and that causes them to be dysmorphic. So, when you see dysmorphic red blood cells, you know it’s coming from that filter and you, it’s more suggestive of glomerular. Same if you see red cell casts, because that means the red cells are in the tubules and forming these casts. Then if you see just kind of all normal looking red cells, it’s more suggestive of a lower cause. So, microscopy is a really useful tool, and I feel like in nephrology, we have a lot of these like 60-year old tools that we still use, and they still work really well.

Dr. Bryan Fate: Then let’s say that girl came back, we’ll say four weeks later.

Dr. Alex Kula: Yeah.

Dr. Bryan Fate: …and still had some protein and still had some blood, no more fevers, no edema, blood pressure was normal. I know there’s a lot of different tools for further workup, and you can differentiate between microscopic and macroscopic for the hematuria, and those have different workups unto themselves. But what else would you be thinking about when she came back?

Dr. Alex Kula: Yeah. If it’s persistent, that’s a little weirder. So, again, that’s a point where I think it’s worth coming to see us, and figuring out how much of the workup could happen in a week or two when they see us first with the PCP. Sometimes depends on how the patient’s doing. If there’s anything concerning, then we might want to start the workup, even with just like a basic lab workup to see what the kidney function is. Possibly, they might even need to go a more urgent route to be seen in the next day or so, but let’s say if everything’s fine, but she still has these abnormal urine findings, then we would probably see her, and then the first thing we need to figure out again is it upper or lower bleed and for most kids, the most common sources that lower urinary source.

So, the differential for this is wide again, but it’s something we’d have to work through. So, a lot of times that would involve like renal ultrasound to have imaging. I’d also say for kind of general providers is that you shouldn’t ever have to order any tests more advanced than a renal ultrasound if you have nephrology care in your region, because that is the most useful test. A lot of times the more advanced tests provide you limited information or provide you information that you have to interpret in the context of the patient. So, the value is more variable. So, a lot of times, if you want to get renal ultrasound, I think that’s okay. Sometimes people think about a VCUG or some of the other urologic scans, and a lot of times those can wait till they see us.

Let’s say what we’re trying to think about a lower urinary source could be a kidney stone. There’s a classic. It could be that the bladder’s still irritated from that infection. A really common cause of hematuria is what you’d often see as a terminal hematuria, which they pee, there’s no blood, and at the very end, there’s a little bit of blood. Often that’s associated with dysfunctional urination, which is then closely linked to constipation. A common thought and diagnosis we all see is post-strep glomerulonephritis, which really doesn’t always have to be related to strep. It could be another infection. But a question we get sometimes is, what do we need to be looking out for, and what’s the workup that happens with the PCP versus USP. I think there’s a few quick guidances that I could give. The first is, so if someone comes in and you think they have post-strep, the usual story, if they had an infection three or four weeks ago, or sometimes a sibling had strep, or sometimes they tell you they had strep.

Although if the word strep isn’t mentioned, still really have to think about it. Now they’re coming in, because they’ve had brown urine, there’s blood and protein on the urinalysis. Then the most common symptoms you see outwardly is edema. So, the important thing to remember, if someone comes in, you think they have post strep, the kind of really two concerning things is one their blood pressure and two their kidney function. So, seizures was a common way that kids would present with post- strep, and they still do very rarely now due to hypertension. So, if someone has post-strep, let’s say that this is you discuss with your nephrologist, we think this is what this kid has, that’s something that needs to be monitored. If they’re not coming into the hospital, monitored daily in your office or every other day, depending on how sick they are, because we just want to make sure that they’re not getting too hypertensive.

Then as far as lab workups goes, we should always check someone’s kidney function, make sure that’s not too off the mark. Then the most useful test by far are the compliments. C3, and C4 can tell you so much. The classic post-strep is a super low C3 with a normal C4. So, if someone comes in, they said, oh, they had a cold a month ago. They have hematuria, proteinuria, a little edema, a little hypertension. They have a low C3 and a normal C4, and it’s a five-year old, I would say it’s a 98% chance. A lot of people order ASOs, which is the anti-streptolysin, and that’s a test that I don’t find is something that you necessarily have to order or that’s really going to make or break the diagnosis. A lot of people who are healthy, they’ll have a high ASO, because they had strep or some sort of an infection, and it’s gone up. So, if you have everything else rock solid, especially those compliments, even if it’s a low ASO, we’re still going to kind of move forward with the presumptive diagnosis of post-strep.

Dr. Bryan Fate: What window of time would you expect the blood pressure to be high, and to be kind of at risk for those complications?

Dr. Alex Kula: It’s variable. But a lot of times you see like a five to seven day natural history of where it could be worse, and then starting to get better. I don’t have a sense if there’s an exact number, as much of the trend of how the patient is doing. So, I think if someone comes in, this is someone who has hematuria, proteinuria, and then they have the concerning findings of hypertension and edema, so that’s someone right away, you should talk to your local nephrologist or they should possibly have to go to the ED if those are higher. But those situations where nephrology should be involved pretty early, that way we can all work together to figure out a monitoring plan.

Sometimes we say, this kid sounds a little sicker. We should bring them into the Eds, but sometimes we can manage it outpatient and these patients do fine. The key thing is that we’re all connected, and then really there’s daily follow up, especially for someone who seems more on the borderline of coming into the hospital, because sometimes things can get worse in a day or two in a bad way. So, it’s important to have that monitoring in place.

Dr. Bryan Fate: Excellent. So, we’ve talked about protein in our urine, the transient versus not, when to be more worried, when to get more of a workup, as well as blood, where it’s coming from, some of the tools we can use to find out where it’s coming from, some of those classic presentations of blood and protein, and indications for when we need to do a little bit more workup and call our nephrologist. So ,Alex, if you had a couple take home messages for the audience, what would they be?

Dr. Alex Kula: I think if you have someone who has proteinuria or microscopic hematuria, the three things you have to assess is do they have edema? Do they have hypertension or do they have any other systemic symptoms? If all of those seem normal, this is otherwise seems like a healthy kid, and it was incidentally found, those are situations where I think repeating it is the best course of action. Then if any of those are abnormal, then that’s when you should give us a call or try to have them see us sooner or possibly go in through the ED. Is this something where we can save the patient a visit, because we just repeated the urine and maybe a first morning urine? Number two, if it’s gross hematuria, whether it’s brown, pink, red, light green-

Dr. Bryan Fate: Green.

Dr. Alex Kula: …that’s a situation. If it’s painless, we should have a workup sooner, or you should get in contact with us sooner, because that could be signs sometimes of glomerular disease. Then number three, if you think someone has post-strep, get the kidney function, a C3, a C4, and then you can get an ASO if you’d like, although I don’t think it’s the most important. Then just get in contact with us, and of that, the hypertension and decreased kidney function are the two more worrisome short- term complications.

Dr. Bryan Fate: Excellent. Well, thank you so much Dr. Kula for all of your insight, and for all the work that you do for kids in Chicago and kids in the Midwest, and all the calls that you take from far away. As promised, an original musical number to help solidify our key concepts and hopefully tug at your heartstrings. (singing)

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