Corinn Cross, MD (Host): Welcome to PedsCast, a podcast brought to you by Children's of Alabama in Birmingham. I'm your host, Dr. Cori Cross. Thanks for joining us. Thanks to medical advances, people with cystic fibrosis are living longer, but cystic fibrosis is not just a disease of the lungs. And as patient's live longer, there can be other complications that arise, one of them being an increasing incidence of kidney disease among patient's with CF.

Dr. Tom Harris, a Pulmonologist at Children's of Alabama and the University of Alabama at Birmingham is a physician scientist who is working tirelessly to improve early detection through his research on emerging biomarkers. We are lucky to have him here with us today to discuss his research and how biomarkers of CF and early diagnosis of kidney disease can change the course of this disease.

Dr. Harris, thank you for joining us.

Tom Harris, MD: It is my pleasure.

Host: So why is kidney disease such a crucial concern for people with cystic fibrosis?

Tom Harris, MD: Yeah, so in the past we've thought a lot about lung disease, but as the new therapies have come on board, a life expectancy has increased and lung disease, has stabilized. So we're starting to look outside the lung of other place, other organs where CFTR is expressed. And interestingly, there's more CFTR, which is the protein that causes cystic fibrosis in the kidneys than the lungs.

Host: So what type of kidney dysfunction do these patient's experience as they age?

Tom Harris, MD: Well, we see both types. So there's a, what's called acute kidney injury. So like if patients are admitted to the hospital and given medicines or sick, we see that kidney function is impaired in that context. But also, very importantly, we see an increased amount of what's called chronic kidney disease.

And that results in kidney failure over time. So as people live longer, the chronic kidney disease becomes more important and the acute kidney injury and how that impacts chronic kidney dysfunction, becomes more important.

Host: So this isn't necessarily all patients experience this, right? So it's important to figure out which patients are going to and have early detection?

Tom Harris, MD: Yeah, so in the general population, chronic kidney disease affects about one in seven people. So it's quite high, but often it's not detected until it's too late, until there's things we can't do about it. And we know that the prevalence of both acute kidney injury and chronic kidney disease is increased in patient's with CF.

It's just in the past we hadn't really thought about it. We were focused so much on the lungs and lung outcomes, we thought, hey, the kidney is something that doesn't matter as much. But now as people are living longer, a chronic kidney disease and acute kidney injury become more important. And we want to prevent acute kidney injury so that we can preserve kidney function moving forward.

Host: Right, because you want the extended life that they have to be a really great life.

Tom Harris, MD: Right. It's all about health outcomes and quality of life, correct.

Host: So in August you published a study that was related to diagnosis and early biomarkers for kidney disease. It looked at some emerging approaches for diagnosing this disease. Can you explain what those are?

Tom Harris, MD: Yeah, so in the past, again, the measurements of kidney dysfunction were really crude. They're basically a blood measurement. It is how we clear protein and again, by the time those measurements are elevated, a lot of dysfunction has occurred. So we want to like look in the urine itself to see, basically it's more subtle measures of kidney injury.

Host: So what is a biomarker?

Tom Harris, MD: A measure of health. So a lot of times for lung function, I'll have somebody blow in a machine that's a biomarker how well my lungs are working. That's a measurement occur where we as a lung doctors are very familiar with that. The urine from the kidneys is in some ways almost like a, we call it like a liquid biopsy, where with every urinary output, you can actually measure how well that kidney is functioning. But the issue there is the sensitivity. So traditionally we waited till too much disease develops, but, and now we want to say, we know that an increased prevalence of disease will happen and we want to act sooner.

Host: So does that mean you're checking the urine both sooner, but are you checking it for things that you didn't check for before? So as a pediatrician, you know, we're really looking at like, we do our little urine dipsticks, we do protein creatinine ratios. What is it that you are looking for that's different than that, and how early are you starting?

Tom Harris, MD: Yeah, that's exactly right. So in the past you waited till like there was protein in the urine or, some electrolytes weren't being kind of filtered out. We needed to detect kind of sooner. So, there's one that's called KIM, kidney injury marker, KIM, KIM 1. So we look at the urinary levels of KIM1.

There's other ones like INGAL and, and all sorts of measures of basically, cellular health, but again, basically those can be leaked out into the urine, but not like protein, which is very end-stage or lots of damage has occurred. We want to know what's happening upfront. In addition to detecting which patient's might have some evidence of disease, we also want to use those biomarkers to help us understand what are the pathways of disease. So, is it more fibrotic? Is it more inflammatory? There's some work on exosomes, which are basically cells release those packages of information, for cell-cell interaction. Some of that's inflammatory.

So the first steps are really to say, okay, what type of pathways might be altered in cystic fibrosis? And then we move from there.

Host: And are you doing this on patients like right out of the gate, so you have a baseline or are you waiting a certain number of years?

Tom Harris, MD: Well, there's always this process of how you're doing it. So right now we're trying to establish which are the biomarkers that are important, and specifically again, how these biomarkers might relate to the progression of chronic kidney disease over time. So this particular study is a three year study where we're going to enroll a series of patients and then follow them over a period of time, both in the outpatient setting as well as in the inpatient setting.

Host: Now this work is a collaboration between UAB and other institutions. How has that helped?

Tom Harris, MD: Yeah. Oh, absolutely. It is very thrilling. It's helped on a couple of different levels. So this grant specifically is through the Cystic Fibrosis Foundation, and there's a unique mechanism called a multi PI mechanism and so, it really engenders us to work in teams, but very importantly, it's like, we're teams, but each center has unique responsibilities for that. So I'm a pediatric pulmonologist, so I have great experience with the lungs and maybe like the lung-kidney axis. And then I'm working with a nephrologist at UVA and she has, she has a lot of experience with how the lungs are developed.

And then there's an a rheumatologist or immunologist up at Dartmouth, and she has a lot of interest in the inflammatory picture in CF and how CF lung inflammation may affect the kidney.

Host: It's amazing how you work, just like across the country. Yeah, it's really, it's really is wonderful. So what role do you see as these studies play out? This is really what we call like precision medicine. How do you see precision medicine really changing early detection for these patients and changing how we sort of plan what we're going to do and the future for them?

Tom Harris, MD: So everything's about making sure that the right patients receive the right therapies. And so cystic fibrosis have been the, at the forefront of this because we know this specific CFTR mutation for every patient. And we know that, that individual's CFTR mutation may cause different ways for CFTR not to work. And then we're extending that from the lungs into the kidneys.

So there may be certain mutations that have more or less CFTR impact. We also are looking at new mechanisms. In the past we've looked at, how a loss of CFTR caused some of your airway secretion to be more thick and tenacious and focused on chloride. Now we're looking in the kidneys that are a little bit more about kind of acid-base metabolism and how basically bicarbonate may affect those pictures. So it's allowing us to kind of think about new horizons and new organs with new mechanistic pathways.

Host: And when you look at the future for cystic fibrosis, tell me a little bit about the strategies you think that are going to be applied to patients with CF.

Tom Harris, MD: Yeah. So, so the future's bright and because, patients are living longer than they've ever lived and really Cystic Fibrosis has primarily been thought about a pediatric lung disease before. Now it's very much an adult lung disease, or an adult disease. And we as pediatricians now have to think about the future.

And so we're trying to really focus our transition from disease to health. So how can children who are born with cystic fibrosis have long, healthy lives?

Host: I remember as a resident, being in the hospital and, uh, working in the cystic fibrosis clinic there, and we had a patient that they had known since she was a little girl and she was insisting on coming back there even though she was well into her twenties because she was pregnant and she didn't trust anybody else to take care of her.

And she was the first pregnant patient they had ever had with cystic fibrosis because that just didn't usually happen. So, it really is amazing how medicine helps us progress, but as doctors, then we have to catch up.

Tom Harris, MD: Right. That's right. And we have to ask, ask new questions you're absolutely right. Fertility rates in CF have tremendously expanded. And so we're thinking about basically how to take care of CF mothers and then also their children at the same time. It's a fascinating time.

Host: It really is amazing. In summary, can you give us a 30 second take-home message for our listeners?

Tom Harris, MD: Yes. So healthcare is expanding in the context of CF, cystic fibrosis. We're at the front edge of medicine, whether it be the current therapies which have a tremendously lengthened the life expectancy. We're looking at gene therapy in that context. And then we're taking a disease that really we had thought about, perhaps a little more limited with the, like the lungs.

And now we're thinking about throughout the whole body. And then we as physicians are starting to think instead about disease, we're thinking about health and how can we partner with families in the pediatric context, or patients that are older, to basically achieve their life goals.

Host: That's amazing. Thank you, Dr. Harris for joining us today and for all the work you're doing in this field.

Tom Harris, MD: That's my pleasure. Thank you.

Host: For more information or to refer patient's to Children's of Alabama, visit childrensal.org and search cystic fibrosis. That concludes this episode of Children's of Alabama PedsCast.

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