Improving the VUR Grading System

In this episode of The PedSpace, Dr. Christopher Cooper explores the inherent flaws in the reflux grading system, which has long been the accepted keystone in determining vesicoureteral reflux (VUR) management. Dr. Cooper explains the limitations of the grading system proposes possible solutions.

Dr. Cooper's research focuses on the etiology, diagnosis and treatment of fetal genitourinary anomalies and pediatric bladder dysfunction. Over the last several decades, his research studies have concentrated on the decision making process for treating children with VUR. Dr. Cooper and his colleagues have developed several computational models to predict VUR outcome in order to provide more individualized management of patients with VUR.  

Transcript

Welcome back to the PedSpace. I’m Simone Howell, Head of Medical Affairs for Palette Life Sciences, sponsor of this podcast.

The content of this podcast is solely the opinion of the guest speaker. Part of Palette Life Sciences’ commitment to bring compelling issues around Pediatric Urology is shared in today’s podcast by Dr. Chris Cooper, Vice Chair and Professor of Urology at University of Iowa, Carver College of Medicine.

Over the last several decades, Dr. Cooper’s research studies have concentrated on the treatment decision process in children with VUR: actively investigating factors which may determine spontaneous resolution, breakthrough UTIs, and when intervention is warranted. In this episode Dr. Cooper explores the reflux grading system and proposes an alternative method to this standard. And now, it is my honor to introduce someone I have known and admired for over 20 years: Dr. Christopher Cooper.

Reflux has been an interest of mine for over two decades now, and I want to talk a little bit about grading the current vesicular ureteral reflux grading system. Before we get into that I thought it'd be important to back up and ask first of all-- why do we care about reflux? And I think most of us know this, we worry about reflux because we recognize it is a risk for recurrent UTIs. It’s a risk for febrile UTIs and pyelonephritis that can ultimately enter the kidneys and we're aware that they can lead to potential long-term sequelae. So, then the question I think becomes why do we grade reflux? I think that goes back to early on after, sort of the discovery of reflux if you will, we recognize that pretty quickly not all reflux is created equal. Some reflux obviously has higher risk than others.

Ultimately, we came up with the international reflux classification for the currently used grading system. When it was published in 1985, from that we learn certain things that along the way. And we obviously recognize that there are more risk factors than just grade for developing infections or kidney problems. If you actually look back at the original classification it was more complex than just the five grades that we currently use.

We currently use grades 1 2 3 4 5, but if you look back when they first put it out each one of those had three sub-grades. If you take a look at the picture of basically those 15 different grades you see what we're really doing there is trying to draw a line basically in shades of gray. The problem with that is, it's inherently subjective. Yet whenever we put a number on something grade 2, grade 4 our mind I think does a little bit of a trick and we start thinking ‘this is really very objective’. We know what each other is talking about, and don't give me wrong we needed a grading system. The grading system I think did a really good job in helping us better understand reflux. There are huge studies that came out using the grading system-- The international reflux study, the EUA meta-analysis. It was done about 25 years ago and we learned certain things-- we learned that lower amounts of reflux were more likely to resolve. We learned that lower amounts of reflux were less associated with renal dysplasia or scars. We also learned that if you were younger you were more likely to resolve your reflux for any given grade, than if you were older. Ultimately what we thought we knew was that grades one and two were pretty low risk but higher resolution. On the other hand, in grades four and five I think were higher risk but lower resolution. And grade three was right in the middle there and it hits where the intermediate risk in variable resolution rates. And I think most people are pretty much on board with that, certainly the majority is. But, I’m not. And again, don’t get me wrong I believe that the lower amounts and degrees of reflux in general have lower risks than higher degrees of reflux.

But what has become clear is that we don't actually agree with each other on what each grade is. In fact, we often don't even agree with ourselves from one day to the next and there have been multiple studies now that demonstrate our sort of inability to objectively grade reflux and reproducible grade reflux. One of those studies was kind of neat, it came out from Metcalf and McNeely, in Canada about 8 years ago. They took a series of VCUG’s and they passed them out to pediatric urologists, they passed them out as I recall to residents and radiologists and they had them grade them. I think it was about a month later, they took the same X-rays and handed them out again, had them grade them again. And what they found at the time seemed pretty shocking and that was it was a huge difference in how people graded. And also, there is a difference in how people would grade from again one day to the next.

What was worse was that critical grade, grade 3 where things can go one way or the other that's where there was the most disagreement. Then it was pretty much a coin toss as far as the reliability are interobserver reliability. Even big studies, like the River’s study that came out-- they found the same thing. And these were obviously we'll done studies, in that study they had three radiologists reviewing all the VCUG’s from the rivers study. And they pretty much came out and found similar results to that previous study.

I think in the river study all three radiologists agreed on what degree was in a given patient only 59% of the time. So again, it just demonstrates the sort of subjectivity of the current grading system. Ultimately if you know that goal of the grading system is to find something reproducible that we can communicate with each other. If I was going to grade our grading system based on that, I'm thinking it would get maybe a C- or a D+. Now I suspect that is despite those studies that I just mentioned listeners are going to say that's overly harsh and you're a tough grader and I suspect many listeners are going to believe that they're better graders than that. 

A couple of things I'd say in response to that, and a couple things to keep in mind. First there’s some great studies in the psychology literature-- now these are really really kind of interesting studies some of you're probably aware of it others may not. But one of these studies-- actually more than one of these studies looks at how people rate themselves on various things. One of the things they ask them to rate themselves on was their driving abilities. And again, it's been reproduced multiple studies. In general, if you ask the people to rate themselves about 75% of people rate their driving ability as above average. Obviously, that can’t be, half the people should be less than average. But time and again they rate themselves not only above average but they most often give themselves a 7 out of 10. So, they’re well above average.

In fact, I reproduced this in generic form about six months ago in front of a large sort of international audience I was giving a lecture at. I asked them to close their eyes and raise their hand and rate on their driving ability. And counted back from 10 down to about 4 when at which point nobody was raising their hand anymore. And again, just taking a look at the audience-- it bored out as well. We tend to overestimate our driving ability. And I think we overestimate our ability to grade reflux despite given the previous data. And it's interesting in those psychology studies when you look at the people who are asked to rate themselves-- if you tell them ‘look this is the scale that experts use to rate you on driving ability’ people will nod and say yeah that's a good scale. But ultimately what they end up doing is believing that the scale they have developed their own mind is still valid and they still do that.

So I know when I tell you that our grading scale is not good and almost 50% of the time we don't agree with grade 3 reflux based on these studies I know a lot of the listeners are going to say well yeah but that's not me I'm good at grading reflux. To that and just a couple other points-- One, remember the VCUG study itself often differs in how it's done between institutions. And this is a problem Dominique Frimberger a work with the section of Urology in the AAP in the section of Urology and radiology and came up with a consensus guidelines types statement several years ago that was published in the journal Pediatric Urology I think back in 2016 and it basically was a call for both a standardized way of doing a VCUG and a standardized way of reporting a VCUG. Despite that they are still tremendous variability from one institution to another. 

And the final thing I have you keep in mind when you're thinking about how objective or subjective grading is on a VCUG is that the results even if the study is performed the same the results in a given individual will probably differ from day-to-day. So, keep in mind it’s variable and variable it is somewhat subjective.

 I wanted to switch gears a little bit because I have sort of come down too harshly on grading our grading system and I gave it a C- or D+ and when I think about truly the goal of grading and the ability to objectively stratify patients and the ability to communicate in a similar fashion with our colleagues to do other studies-- so that we can compare apples to apples. I really think that we need improvements in the grading system and we shouldn’t fool ourselves. Truly if I was going to grade it, I’d probably give it a D a solid D. I just want you to keep in mind that those things from now on when you're reading a VCUG is that the data we built all of our sort of paradigm for managing patients on is relatively flawed. The other thing to keep in mind is, when you’re talking to someone and they mention this is how I treat and grade 2 reflux, grade 4 reflux, whatever grade of reflux-- I think you should be thinking we don't even really know what grade that is. And there’s a good chance that if you looked at that VCUG you might not agree with the initial premise of what that person is calling grade X.

So that’s the bad news, let me switch gears.  The good news is I think we can do better-- I think we can actually do much better with information that is right there on the VCUG readily available. And I think there's a couple of more objective factors that we could use to categorize VCUG or grade VCUG if you will. One of those factors is the volume in the bladder when reflux first occurs. And I published some studies on this probably 15 to 20 years ago and have continued to publish some studies on the importance of the bladder volume at the onset of reflux.

We’ve shown that this is an independent predictive factor of resolution and is a significant factor. In fact, it's more predictive of resolution and other adverse outcomes such as urinary tract infections, than age or how you might present. And its independence of the greater reflux, in fact when you combine those two things you can really start to categorize a patient's risk much better than you could if you use grade alone. So, for example if you had a child that was 18-20 months, less than two years of age and they had what we would consider grade 3 reflux now again what is grade 3 reflux? We might disagree but for the sake of argument let's say this less than 2 year old has grade 3 reflux.

If you know that the child started refluxing when their bladder capacity was less than half of the predicted bladder capacity their chance of resolving that reflux in a couple years is only about 14%. Now that same child starts refluxing at over half their bladder capacity, same grade-- grade 3 their chance of resolving reflux is 80%. So just by adding in and combining the volume at the onset of reflux with grade you can see tremendous differences. And that's the type of information that you need, it’s the type of information parents need to help decide what would be the best treatment options. By the way, part of that statement that the AAP came out with, as far as standardizing VCUG’s actually mentions that the radiologists really should start to put in their reports the volume that they have instilled in the bladder when they first see reflux. And if they do that then I think that can help you tremendously. 

The other reason they should do that is a nice study came out of Atlanta by Mike Garcia, just a year or two ago and I worked with him on this we sent VCUG pictures to radiologists and urologists, we knew the volume that the reflux occurred and we had them tell us did reflux start occurring early or late on his child. Bottom line is they were not good at guessing when it occurred so really, I would push strongly to have your radiology techs or radiologist just a routinely noting-- when does reflux occur at what bladder volume did reflux occur. The other reason it's important is not only predicting resolution-- I published a study a little while back that shows that it's an independent producer of breakthrough urinary tract infections. So, if you’re refluxing pretty early during bladder filling, your chance of having a breakthrough infection is 1.6 times than if it starts occurring later. So, a big push for starting to pay attention to bladder volume.

The other factor that’s readily available on a VCUG is the distal urethral diameter-- I’ve been sort of pushing on this concept now for about 15 years and it's starting to get some traction. Not only here in the United States but also internationally. More recently there has been some good work, coming out of places like Turkey and China that have been using of the distal ureteral diameter to help predict outcome. So, my original idea with this was that since reflux resolution really happens now and at the bladder level where the ureter plugs in. Maybe we should be paying more attention to the distal ureter than paying so much attention to what the upper tracks and KLC’s look like as far as resolution.

Along the way as we started to realize that grading is limited by subjectivity that we already talked about I started thinking you know I suspect measuring the distal ureteral diameter on a VCUG is going to be a lot more reliable and objective than the grading system. And so, we published a study showing that to be true just a couple years ago in 2017. It makes sense obviously if you truly measure something it's going to be more objective than if you're just taking a look at something and trying to figure out which line in the shade of gray categorizes the reflux as.

And I do want to point out that we normalize that distal ureteral diameter by dividing it by the distance between the L1 and L3 vertebral body. And so, it’s actually a dysphoria real diameter ratio that we're looking at, and the reason I did that again early on when I was thinking about this concept I wanted to control for a couple of things. I wanted a control for the size of the patient and the orthopedic literature pointed out that vertebral body growth was pretty standard based on size and in children. And the other reason was to control for magnification the images themselves and we did a study along with Dr. Arlen-- could we get by with just measuring the distal ureteral diameter or did we really need to do this extra step of having the ureteral diameter ratio. And what we showed in that study was that ureteral diameter ratio was better and more predictive than the ureteral diameter alone. 

You know you can ask what have you found? What does ureteral diameter ratio actually show you that grade doesn’t? First of all, there’s a strong association between grade and ureteral diameter ratio-- you would expect that because the bigger the ureter the more likely it’s going to have a higher grade, so we found that.

But we did find that it was an independent predictive factor, independent of grade for predicting spontaneous resolution, for predicting breakthrough UTIs, for predicting patients that would go on and need operative intervention. So, we’ve developed the series of models actually where we incorporated ureteral diameter ratio with or without grade in trying to predict outcomes. And often times when we added grade into the models the predictive ability got worse. And again, I think that's probably because grade was so subjective that when you start to put it in sometimes it actually decreases your ability to predict things like resolution or breakthrough UTIs. And again, I'm excited to see that these findings are being reproduced not only here within the United States but in other countries.

 In fact, the study that was published coming out of Turkey show that UTR has a strong correlation with renal scarring as well. Similar degree we know higher grades of reflux have an association with scars and again higher bigger ureteral diameters do as well. That study out of Turkey was also interesting because it was predictive of endoscopic correction. And it was actually more predictive of success with endoscopic correction and grade was. So those are my thoughts on the grading system-- to some of the limitations and some proposals for things we could do to maybe make things better.

Clearly, I think a grading system is needed, and again not all reflux is equal-- we know this. And certainly, lower amounts of reflux and late onset of reflux during bladder filling those children do better than if you've got high volumes of reflux or early onset reflux this is clear. I think you know we should all be doing VCUG’s in a standard fashion and at the very least, again having a radiologist note the volume at the onset of reflux. And I really strongly encourage you to start paying attention to the distal ureteral diameter ratio-- stay tuned ultimately, I think we may be better off going to a grading system using objective and reliable measurements such as volume in ureteral diameter. Rather than sort of the subjective grade to confirm this and really to go to the next step what we're going to need is a larger multi-institutional and international studies. Actually, prior to Covid, I was planning on convening a new international reflux group to start working on this. That’s sort of on hold now although with the advent of Zoom meetings now I’m starting to think maybe easier to do this now in a virtual fashion than what I was planning pre-Covid. So, thanks for listening those are my thoughts grading the reflux grading system-- where we are, where we've been, and where I think we could go. Thank you.

Thanks for joining us this week on The PedSpace! We hope you enjoyed Dr. Cooper’s insight. Feel free to share with your colleagues while we deliver more pediatric urology-focused content in the coming weeks. There are some great resources for you and your patients for Deflux on www.Deflux.com .  Additionally, you can learn more about our company and our products on www. Palettelifesciences.com