Nephrology Research at Children’s Health

Air Date: 3/2/22
Duration: 10 Minutes
Nephrology Research at Children’s Health
Experts from the Nephrology team at Children’s Health discuss the research that helps them examine novel treatments to improve outcomes of acute kidney injury.
Transcription:

Prakash Chandran (Host): This is Pediatric Insights, Advances, and Innovations with Children's Health, where we explore the latest in pediatric care and research. Today, we will hear about the important research conducted by experts in the Nephrology Department at Children's Health. The team has received funding, which enables them to conduct cutting edge research to achieve better outcomes for pediatric nephrology patients facing kidney disease, bone disease, and hypertension.

We'll learn about each physician's focus area in the field. With us today are Dr. Jyothsna Gattineni, Division Director of Pediatric Nephrology at UT Southwestern and Children's Health and Associate Professor at UT Southwestern. Next, we have Dr. Keri Drake, Assistant Professor at UT Southwestern and Pediatric Nephrologist at Children's Health.

And finally we have Dr. Matthias Wolf, Associate Professor at UT Southwestern, Associate Vice Chief of Research in the Division of Pediatric Nephrology and a Pediatric Nephrologist at Children's Health. name is Prakash Chandran. And Dr. Gattineni, Dr. Wolf, Dr. Drake, thank you all so much for being here today. I truly appreciate it.

Dr. Gattineni, I'd love to start with you. Could you start off by discussing extramural funding in pediatric nephrology?

Jyothsna Gattineni, MD (Guest): Sure. Thank you Prakash for talking to us today. It is a pleasure and I would like to start off by reminding everybody that physician scientists are in fact, an endangered species. As a physician scientist, we actually encounter rare patients on the floor in the hospital with rare diseases. And then we have the ability to take that back to the bench and bring it to our lab and study the question at hand. To directly quote a New England Journal Paper that was published a couple of years ago, physician scientists have been the driving force in medical research and they account for almost 37% of Nobel Prize winners.

The sad news is, that in the last four decades or so, the physician scientist numbers have been decreasing. They were 4.7% of the overall physician force in the 1980s to now approximately 1.5%. This is not a promising or encouraging statistic. And it has been well recognized nationally and efforts are ongoing to recruit and retain physician scientists.

Bringing it back to our home environment, out of nine Pediatric Nephrologists, four of us are currently physician scientists. This is actually quite rare considering what the number of pediatric nephrologists are in the country. And we are actually very proud of our accomplishments. The other colleagues of ours are also actively involved in some form of research activity.

And in fact, all their efforts are dedicated to improving the way we deliver care to our children with kidney disease. And I also want to point out that in general, percentage of pediatric nephrologists physician scientists are considerably less than the adult nephrology physician scientist.

Matthias Wolf, MD (Guest): Yeah, I would like to add that obtaining extramural funding in nephrology is quite challenging and there are not that many agencies on the federal level, on a state level that you can apply for funding. Typically your application needs to be among the top 10 to 15% level to get funded. And that is often quite cumbersome or challenging and can take a few years sometimes to improve the proposal. Compared to other subspecialties, especially, oncology, we don't have any statewide funding really compared to CIPRIT, which provides excellent funding for our colleagues in oncology.

Keri Drake, MD (Guest): And then I just want to add along those lines, that from my personal experience, you know, I have been a recipient of internal grants, both through Children's and through UT Southwestern that have really helped me bridge the gap in order to obtain then extramural funding in order to support my research and you know, this internal support is really instrumental, especially in researchers throughout their early career or who are bridging in between grants in order to keep our research going to really then obtain the extramural funding, and highlight the work that we're doing in pediatric nephrology.

Dr. Gattineni: I would like to add that within our little small group of pediatric nephrologists, we have two NIH, RO1 funded grants, one department of defense funded grant. A couple of my colleagues are co-investigators on O'Brien Kidney Research Center Grant, and also the training grant for nephrologists.

Prakash Chandran (Host): Yeah. Thank you all so much for sharing the current state of affairs for physician scientists, primarily those that focus on pediatric nephrology. I was wondering if each one of you could describe your areas of research and key findings. Dr. Wolf, we'll start with you.

Dr. Wolf: So, I am working on a disease that was many years ago considered to be quite rare. It's called autosomal dominant tubular interstitial kidney disease. And it turns out that it's now the third, most common genetic cause for renal failure in later stages of life. The disease though manifests actually in childhood and our idea is that if we can identify these patients early enough, we could intervene and hopefully make kidney function better so that these patients don't end up on dialysis later in life.

To achieve this, we have developed a cell culture model that we can use in a screen to identify medicine or other compounds that can then hopefully be modified into a medicine later. The goal is to release a mutant protein that gets stuck within the kidney cells and eventually suffocate the kidney cells so that they eventually die.

So, our hope would be if we can identify these patients early enough and can apply the track to release the protein out of the cells, to extend lifespan off these kidneys and hopefully avoid dialysis and the need for kidney transplant later in life.

Host: Yeah, that's absolutely fascinating. Dr. Drake, why don't you go ahead and describe your area of research and key findings.

Dr. Drake: Thanks. So, my specific area of research is focused on trying to better understand the biology of a rare pediatric kidney cancer called a Wilms tumor. As someone with a background in studying mechanisms that regulate normal kidney development, wilms tumor is particularly fascinating. It arises from renal precursor cells in the fetal kidney, and then the tumors actually maintain characteristics of these cells that are normally only present during development. So, the Wilms tumor is the most common kidney cancer in children. And while the overall survival rates for patients are relatively good, current treatments include surgery, chemotherapy, and radiation; all of which have long-term adverse effects. And there's still a subset of patients with much worse survival outcomes.

So, there's a need to develop new, more targeted treatments. A significant proportion of Wilms tumors have mutations in genes that are known to play important roles in kidney development. Then we are able to take this to the mouse model, to try to better understand the biology of Wilms tumor and much surprisingly still remains to be understood about how these different genetic mutations and disruptions in development drive tumorgenesis.

So, my lab uses genetically engineered mouse models to look at how known Wilms tumor genes affect normal kidney development with the overall goal of better understanding how these precursor cells give rise to this rare kidney cancer.

Host: And Dr. Gattineni, what about you? I'd love to understand a little bit more about your area of research and key findings.

Dr. Gattineni: Sure. Our laboratory's research focus over the years has changed some. And currently we are focusing on studying the effects of a hormone called fibroblast growth factor 23 or FGF 23 on the heart, in the presence and the absence of kidney disease. So, what is FGF 23? So, it is a hormone that is synthesized by the bone. It physiologically acts on the kidney to cause phosphate urea, and also decreases the levels of 1,25 vitamin D. We all know that the levels of FGF 23 are elevated up to almost a thousand fold in patients on dialysis. No other hormone is elevated to that level in any disease that we know of.

And obviously when this was discovered, there have been many association studies that have demonstrated that higher the FGR 23 levels, higher the mortality in these patients with kidney disease. And the most common cause of mortality in patients on dialysis or with kidney disease is cardiovascular disease. Rather sadly I would say that despite advancement in diagnostics and therapeutics, the mortality rates haven't recently decreased.

And there's a controversy, importantly, regarding the direct effects of elevated FGF 23 levels in the causing of cardiovascular disease in patients with kidney disease. To address this question, because it's a critical, important question that affects patient outcomes. We have designed a unique mouse model where we have elevated FGF 23 levels. And we plan to study systematically and answer the question, whether FGF 23 is a friend, a foe, or a biomarker in kidney disease.

Host: All of these areas of research are truly fascinating. And I'd love to understand a little bit more about how it actually affects the patient care. So, Dr. Drake, you talked about you know, that rare childhood cancer that starts in the kidneys. I think you mentioned that it was Wilms tumor. Could you discuss with us how it impacts patient care?

Dr. Drake: So, my work right now is largely focused on making progress in the lab and at the bench. And it's still many steps away from being translated into patient care. But as I mentioned earlier, because this is such a rare cancer and many patients still have relatively good outcomes, preclinical studies like this are going to be critical in trying to identify novel pathways that may be specifically related to development that then can be translated into different treatments for patients.

Host: So Dr. Gattineni. What about you? You know, you mentioned FGF 23 and you started to talk about this, but could you expand on how your research actually affects the patient care?

Dr. Gattineni: Sure. I think it's important, like I mentioned to understand the role of FGF 23 in cardiovascular disease because not only the role of FGF 23, but once we understand the pathophysiology of increased cardiovascular mortality in kidney disease, then we can go to the next step. So, what we're hopeful is that our studies will help identify the role of FGF 23 and then these results will then have the potential from taking science from the bench to the bedside, because if we say, okay, FGF 23 is causative for cardiovascular disease, so the next step will be to understand the mechanistic pathways, which can then be taken to literally to the bedside for children, because we already have an FGF 23 antibody that is being used in other conditions.

I don't think that is what we're going to find, but if we also find that if FGF 23 is not causative, then the work should then be focused on what are the other idiopathogenetic factors that can actually be modified in patients with kidney disease so that we can then improve their long-term outcome for these children.

Host: And what about you Dr. Wolf? I understand broadly the goal is to, you know, extend the lifespan of the kidney, potentially removing the need for a transplant later on down the line. But is there anything else to discuss around the research that you're doing and how it impacts patient care?

Dr. Wolf: So in the long run, we want to develop this hopefully medicine that helps us to release the build up of this mutant protein in the kidney cells. But for this approach, we have just recently screened at UT Southwestern 350,000 compound library that we have screened 350,000 different medical chemical structures in regard of the effect to release more of this mutant protein and we will then go from there and hopefully develop a compound and a drug out of this. But this was still possibly take several years to develop and then to test in the mouse models and then eventually in some human trials. Something that is perhaps realistic in the short run is a screen that we have performed on over 2000 FDA approved medicines. And among those, we have found one drug that is already used in the nephrology field that looked quite promising and may not be as efficient as the newly designed drug, but may perhaps offer a interim solution. And we are testing that out currently in mouse models.

Host: Now, just before we close here today, Dr. Gattineni, is there anything else that you'd like to share about the work that the nephrology team is doing at Children's Health?

Dr. Gattineni: Sure happy to. I want to ensure that folks know that our colleagues participate in multicenter clinical trials, recruiting patients with different diagnoses, like nephrotic syndrome, chronic kidney disease, kidney stones, patients on dialysis and transplant patients. And this eventually will help us understand the pathophysiology of many of these disease processes, which will then eventually pave the way for newer therapeutic agents.

And eventually it'll improve for children or adults with kidney disease. An another thing that I want to mention is that we are in the process of developing disease specific programs, like Cardiorenal Program and Center for Rare Diseases and Therapeutics and expand our Stone Center to the next level where we could actively recruit patients for multicenter national trials.

Host: Dr. Wolf, is there anything you'd like to add to that?

Dr. Wolf: Besides our research interests and invest the time in research, we also are quite a busy center for clinical cases. We see a lot of patients in our clinic and on our floor. We have a high number of dialysis patients, so we quite busy in regards to clinical service, not just on our research side.

Host: And what about you, Dr. Drake?

Dr. Drake: I would just like to add that, you know, we each have our own individual labs or clinical areas of interest, but in order for us to be successful as a division, both in how we care for patients, as well as our academic interests and really trying to not only move research forward, but move care for our kidney patients forward as well; it really takes a team approach, you know, from people in the lab, to our clinical team and support staff, as well as, you know, the support from the institution in the hospital too, you know, we really all work together and come together as a division in order to make these things happen.

Host: So, I just had one more question before we close and Dr. Gattineni, I guess I'll direct it at you. You know, as a physician, I imagine that you encounter rare diseases that then stimulate an idea in which a physician scientist can study the pathophysiology of the disease. So, is this something that you can talk about or expand on a little bit?

Dr. Gattineni: Sure. You know, I think we all encounter patients with unique presentations, I would say. And then we have a discussion. In fact, we meet every Friday to discuss all the patients that are admitted to the hospital and then among us, we have a lot of discussion. And what has happened is that we would send off additional studies, including genetic studies and when they come back and you can review our publications, that many of us have actually published case reports on what we have learned from these unique cases.

And, you know, this is how we, then the next step would be to form a registry of patients with a unique disease, and then take it back to the lab to study the mechanism behind that disease.

Host: All right. Well, Dr. Gattineni, Dr. Drake and Dr. Wolf, thank you so much for your time. I truly appreciate it.

Dr. Gattineni: Thank you for having us.

Host: That was Dr. Jyothsna Gattineni, Division Director of Pediatric Nephrology at UT Southwestern and Children's Health and Associate Professor at UT Southwestern, Dr. Keri Drake, Assistant Professor at UT Southwestern and Pediatric Nephrologist at Children's Health. And finally Dr. Matthias Wolf, Associate Professor at UT Southwestern, Associate Vice Chief of Research in the Division of Pediatric Nephrology and a Pediatric Nephrologist at Children's Health.

Thank you for listening to this episode of Pediatric Insights. You can head to children's.com/nephrology for more information. My name is Prakash Chandran. Thanks again for listening and we'll talk next time.