Zachary Klaassen: Hello, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm joined today on UroToday by Dr. Dan Barocas, who is a urologic oncologist at Vanderbilt University Medical Center in Nashville, Tennessee. Today, we're going to be discussing Dan's take on the most recent AUA/SUFU guidelines for microhematuria. And we'll be discussing some of the background behind these guidelines, some of the key changes to the guidelines that were recently presented at AUA. So, Dan, thanks so much for joining us today.

Daniel Barocas: Sure, my pleasure. Thanks for having me.

Zachary Klaassen: So before we dig into the guidelines, just set the stage for our listeners about the burden-- and, really, the denominator-- of what microhematuria is, not only to urologists but primary care physicians and the healthcare system in general.

Daniel Barocas: Sure. So to start with, microhematuria-- hematuria is a very common issue. If you screen healthy populations, the prevalence is somewhere around 6 and a 1/2%. And it ranges widely, depending on what population you're looking at and what their risk factors are. But it's an enormous public health population.

And, in fact, hematuria is the most common reason for urology evaluation. So it is quite a big pool of people. And I would add that what we're worried about when we're evaluating these people is bladder cancer, people with microhematuria.

And the reality is, it's not that common. Only somewhere between 2% and 4% of people evaluated for microhematuria actually have bladder cancer. But you can risk stratify people to define populations in whom that risk is really, really low-- like, less than 1%-- and other populations where it's significant, 5% or higher.

And so that's the nature of the risk-stratified approach that AUA/SUFU guidelines took on in the 2020 version. And then the 2025 version, this latest version, we made some refinements to that.

Zachary Klaassen: Yeah. And it's a great article and a great document. And we'll get into it in a second. Before we do, just talk about the rigorousness of how these guidelines are put together from a quality standpoint. How many people are involved? How much time this takes-- this is a huge undertaking, isn't it?

Daniel Barocas: It is. It is a rigorous process. I think the whole process was about a year in duration, maybe a little bit less. And what was entailed was an update of the literature review, so from the close of the 2020 guideline, which was 2019 until now. And so that literature review went from December 2019 to June 2024.

And actually, we define our questions up front. The panel for review consisted of five of us plus methodologists and a staff person from AUA. We do a systematic review of the literature, looking for articles that would inform the update.

And we find, well, some of these recommendation statements that we had don't need to be updated because there's no new literature, whereas others do need to be updated or even added.

The team, the committee then works on any updates and edits, guided by that literature review, where we get not just the information but, actually, a grade of evidence using a standardized scale so that we can use that to determine the strength of the recommendation, whether it's a strong recommendation, moderate recommendation, conditional recommendation, expert opinion, or clinical principle.

And then it goes through a really extensive review process that includes all of the original panel members. And it's sent out-- I don't know how many people they sent it out to, but on the order of about a hundred people. And we collect all of those comments, and we actually have to respond to each one of them.

Then it goes through an approval process. That's the peer review. And then it goes through an approval process through the AUA Practice Guidelines Committee, the Science and Quality Council, and the AUA Board of Directors before it's sent to the Journal of Urology, where it then again undergoes review. So it is quite an extensive process.

But I think that that bolsters-- the rigor really makes it have higher value than consensus-based recommendations because it's very clearly evidence based. I would add that there are requirements for the panel members' conflicts of interest.

And so they really limit that. Although, as you know, experts in the field are often working with industry to study interventions and biomarkers and other things. So there are some conflicts of interest, but people recuse themselves from things that they're involved in.

Zachary Klaassen: Yeah, no, it's a wonderful document. And we'll link it to this video. But certainly, I encourage people to go to the AUA website, look at it in the Journal of Urology to become familiar with those statements. But what I want to dig into next is basically the risk stratification. And there's a lot to unpack here, but mostly, some of these changes in the risk stratification that you guys made. Maybe you can walk our listeners through some of those key changes based on this algorithm.

Daniel Barocas: First, Zach, I'd like to mention a few things that were preserved, some key principles that were preserved from the 2020 guideline version. First is the definition of microhematuria. We define it as greater than or equal to three red blood cells per high-powered field on a UA with microscopy. The urine dipstick test is insufficient because of the high false positive rate with that.

Secondly, we really strongly recommend a thorough evaluation looking for any benign, nonmalignant urologic or gynecologic sources of hematuria. Importantly, though, we recommend repeating the urinalysis after those are addressed.

Too often, especially in women, hematuria is attributed to UTI. Someone gets antibiotics and gets forgotten about. Really, the appropriate thing is to, if you suspect a benign cause, you prove it, get the urine culture, you treat it and then repeat the urinalysis to make sure it went away. And if it didn't, then they need a risk-based evaluation.

And the other thing, as I mentioned, was preserved, was this concept of a risk-based approach, which we'll get into in a moment. And then lastly, people who are suspected of having a nephrologic cause, a medical renal disease cause of their hematuria, that doesn't get them out of undergoing a urologic evaluation if appropriate. Because they can have concurrent bladder cancer or other urologic diagnosis.

And similarly, those who are on anticoagulation blood thinners, antiplatelet agents have the same risk of bladder cancer as people who are not on those agents in the setting of hematuria. And so they should undergo the same evaluation as if they were not on those medications. And so those are the core principles that were preserved.

In terms of changes to the risk stratification system, again, the basis for these changes are three studies that actually sought to validate the 2020 guideline risk stratification system. And those studies are Woldu et al.—and that's from 2021—Sancie from 2021 and Saxon from 2022.

Again, what they've done in each of these studies is apply the 2020 risk strata and see what the actual risk of bladder cancer was within each of those risk strata. And what they found, each one of them, is that, first of all, the risk stratification actually does separate groups into different risk categories.

And furthermore, what they found is that the low-risk people had almost a 0% chance of having bladder cancer. Almost no one in the low‑risk group, particularly in the Saxon article, where it was only women-- there were no cancers found in people who met those criteria for low risk. And so we renamed that category as low, negligible risk and actually recommend not putting them through an immediate evaluation.

Whereas before we said you could do shared decision making to decide whether to do an evaluation of the low‑risk people or repeat the UA, now we're recommending, just repeat the UA within six months, whether that's in eight weeks or three months or whatever is appropriate for your practice. And if that's positive, then we put them back through the risk stratification system, and it would bump them up into intermediate or high risk, depending on how much blood is seen in the urine.

And so that's one of the major changes to the risk stratification system. The other one that also stems from that Saxon article, which was focused on women, is the finding that women really are lower risk. Age group for age group, they're much lower risk than men. And in fact, in that study, none of the malignancies that were identified in women were found just because of age alone.

In other words, women who are over the age of 60, before, we had classified them as high risk. None of the women over 60 were found to have cancer unless they had other high‑risk features. And so we changed the age ranges for women such that women under the age of 60 would be in the low, negligible group and women 60 and over would be in intermediate risk. But women can't be categorized as high risk based on their age alone.

And so those are the two major changes to the risk stratification system.

Zachary Klaassen: No, that's great, Dan. And specifically, these are important changes that may get lost in the subtleties of such a high‑volume diagram and algorithm. But maybe just speak to, again, some of the changes in the recommendations based off of these risk categories.

Daniel Barocas: Sure. So again, in the low risk, we're not recommending immediate evaluation anymore. We're saying repeat the urinalysis within a few months to determine whether they actually do need an evaluation. One of the most important changes that we made is in the intermediate risk category. In the intermediate risk category, the standard should be to offer a cystoscopy and a renal ultrasound.

However, based on some research that has been done since the 2020 guideline, we now say that the clinician may offer a urine‑based tumor marker or cytology to help decide whether to do cystoscopy in this population. Why did we make that change? Well, there are some people who are reluctant to do cystoscopy. If they're well informed about the risks and benefits, it may be reasonable to use the urine‑based tumor markers to help make these decisions.

In 2020, though, there really were not available studies in the microhematuria population specifically to show the sensitivity and specificity and predictive value of these urine‑based tumor markers which, in large part, were validated in bladder cancer populations and follow‑up for bladder cancer.

Since then, there have been a number of studies where either they were specific to microhematuria, or the results were stratified, so the results in the microhematuria population were reported separately. And this opens up the possibility of their use in this space.

There was a very nice study led by Sol Woldu and Yair Lotan, a modeling study where they demonstrated how the result of a urine‑based tumor marker test could alter the probability of finding bladder cancer on a subsequent cystoscopy.

So, for example, if you take somebody in that intermediate risk group where the chance of finding bladder cancer is somewhere between 1% and 3% and you perform one of these urine‑based tumor markers, based on what's called the negative likelihood ratio, which is a ratio involving sensitivity and specificity, if the test is positive, it alters that probability such that they really look more like the high‑risk people. And really, we're pretty sure they should undergo an evaluation involving cystoscopy.

Whereas if it's negative, now their probability of identifying cancer is more like the people in the low‑risk category where you think, well, maybe we could forgo that cystoscopy. And so that's how we're anticipating that biomarkers will be used in this space. There was, indeed, one randomized study in this space. And so the quality of evidence has really changed and come into its own here.

So we're not saying that's the top‑line recommendation. Still, the standard would be to do cystoscopy and renal ultrasound. But this is an option for people who are reluctant to undergo cystoscopy and who are well informed. Importantly, if it is decided that we're going to forego the cystoscopy based on the result of a urine‑based tumor marker, we still recommend you get the ultrasound-- and, actually, not just renal but renal and bladder.

And we also recommend that you repeat the urinalysis about a year later, as was done in that randomized trial. And if they're still having hematuria at that point, we do recommend doing a cystoscopy.

Zachary Klaassen: Yeah. No, it's a great breakdown-- and I think especially some of those nuances that, again, may get lost in a very detailed, rigorous algorithm. So let's both put on our HSR hats because we both like to do that on a daily basis.

Daniel Barocas: Sure.

Zachary Klaassen: You and I both do. If we-- look at this guideline and it's going to be across the country now across the world. But let's take the US in particular. You mentioned the prevalence is 6 and 1/2% of microhematuria in the population-- if this is used appropriately, particularly this risk stratification and then the recommendations for workup and intervention, what's the goal here? And what may be the benefit to the patient and benefit to the physician, benefit to the healthcare system?

Daniel Barocas: I'm glad you asked, and I'm glad you asked it that way. Really, what our goal was-- so if you think back to the 2012 guideline, the old version, the recommendation was, across the board, everyone is recommended to have cystoscopy and CT urogram. That approach is designed to maximize sensitivity with no regard for cost or specificity.

And the result is, that was a very low‑yield strategy when compared to other guidelines, for example, those that are more selective about whom to evaluate or those that rely more on ultrasound than CT. The AUA guideline from 2012 was far and away the most costly and really did not increase the yield much, if at all.

By using a risk‑stratified approach, the hope is that you maintain sensitivity. You still find the cancers in those who are at higher risk. But you improve specificity, meaning you avoid doing unnecessary evaluations on those at lowest risk.

So in this current version, we are taking that low‑risk population, saying don't evaluate them. So that pulls a large number of evaluations out of the pool to begin with. But those are the lowest‑yield evaluations.

In the intermediate risk group, we're saying-- well, often they're going to get cystoscopy and ultrasound. But some will actually get a biomarker instead. That could obviate the need for cystoscopy, which has been shown to be a cost‑effective strategy. And then, finally, in the high‑risk category, we're still recommending cystoscopy and cross‑sectional imaging, preferably CT urogram. Because even though it's small, there is a risk of upper tract urothelial carcinoma in that population.

And so just to bring it home, to answer your question, the hope is that you maintain sensitivity, you still find the cancers, but you eliminate low‑yield evaluations that are costly, have side effects and false positives, and thereby reducing cost and evaluation burden for the patients.

Zachary Klaassen: That's well said. And first of all, congratulations on leading the charge on this revised update and for your time on UroToday. Any closing remarks before we wrap things up then?

Daniel Barocas: Just that we had a great team. I get to come on and talk about it, but the team really did the work. And the AUA staffers and methodologists, everyone contributed a lot-- and, like we said, very rigorous process. One other thing I'll add is that it is a rigorous process and, in some respects, rigid.

So when we set up our queries for the systematic review, that's all we get to include in our guideline statements. And, in fact, at least one new biomarker came to market with data that would have qualified it to have been in our guideline after the initiation of our query.

And so I'll just say that this is an evolving process. This is not the best this guideline will ever be. It will continue to evolve. And as we learn new things, they'll be incorporated.

Zachary Klaassen: Great conversation. Appreciate your time and your thoughtfulness discussing the guideline and really laying it out nicely for our listeners. Thanks so much for joining us.

Daniel Barocas: No, thank you for having me. It was a lot of fun.