Episode 17: Building the World’s Largest Renal Genomic Registry with Dr. Frank Maddux
Nephrology has been under-represented in clinical research, even as we have witnessed rapid progress in precision medicine in other specialty areas. A new initiative to build the world’s largest renal-focused genomic registry of Fresenius Medical Care, aims to change that. Dr. Frank Maddux, Global Chief Medical Officer, joins Field Notes to explain how this groundbreaking registry will impact the future of kidney care for years to come.

Brad Puffer: Welcome, everyone to this episode of Field Notes. I'm Brad Puffer on the Medical Office Communications Team at Fresenius Medical Care in North America, and your host for this discussion today. Here, we interview the experts, researchers, physicians, and caregivers who bring experience, compassion, and insight into the work we do every day.

Nephrology has been underrepresented in clinical research even as we have witnessed rapid progress in precision medicine and other specialty areas. Frenova, the clinical research division of Fresenius Medical Care has recently embarked on a new initiative to change that. And enrolling the first participants in what is hoped will be the largest renal focused genomic registry in the world.

This new registry will contain genomic data from chronic kidney disease patients worldwide, which researchers can use to improve our understanding of what drives kidney disease and to find new treatments. Here to tell us more about this exciting new initiative and its potential to make an impact in the lives of all people with chronic kidney disease is Dr. Frank Maddux Global Chief Medical Officer for Fresenius Medical Care. Dr. Maddux, welcome to Field Notes.

Dr. Frank Maddux: Brad, it's nice to be with you today.

Brad Puffer: You've been long interested in how genomics can play a role in furthering our understanding of kidney disease. Why is that understanding so important?

Dr. Frank Maddux: I think there are two primary reasons that it's important. One is I think we've long recognized that a number of kidney diseases are, in fact, inherited in family members, and that there are genetic determinants for that. And some of those have been unlocked at this point. But more specifically, I think we've recognized that we have a classification of kidney disease problem and that we classify kidney disease through pathologic observation, visual inspection of how a kidney looks after its injured.

More and more, we're seeing that it's a combination of mechanisms of injury that actually lead to kidney failure. And so the genomics project is one that can help bring us closer to what those mechanisms and pathways of injury are, and how they ultimately lead to kidney failure.

Brad Puffer: Well, turning to the genomic registry, why is it so important for the field and for all of you to have something like this? It seems like the field has been waiting for a while to have a registry of this kind. Has anything like this been done before?

Dr. Frank Maddux: There are a number of renal related registries. But they are relatively small. They're mostly based on populations of patients that are known to have had kidney biopsies. And these biopsy related registries have given us the chance to begin to unlock the issues.

But remember, most of the scientific analysis today is being done on what's called the exome or the part of the genome that is coding for proteins. And these coding regions occupy a very small component of the overall genetic makeup. And so as we begin to see the various combinations of ways in which a kidney can get injured, it looks like it's going to be an incredibly complicated process to untangle all the relationships and the associations.

And in doing so, it's going to be important that we have large numbers of patients in these registries to be able to study. And so our opportunity is to build a highly scaled registry of people who ended up with advanced kidney disease. And in doing so, we begin to actually allow scientists to use larger populations of patients with wide ethnic diversity and a lot of different cultural background to pair with the clinical data that exists about how they've responded to therapy, how they respond to medications, and all the various treatment, and diagnostic interventions that we have. So I think these things will allow us to build a registry that lets researchers go to the next level of their analysis.

Brad Puffer: Maybe you could dive into a little bit about the practicality of how this registry itself is going to work. How is it going to get up and running?

Dr. Frank Maddux: So we've been working with a dedicated team in Frenova Renal Research, our clinical research operation that is primarily focused with external researchers. And in this, we are looking to create a way in which we consent patients.

And because we already collect blood from all of our patients for their monthly laboratory work and other studies that their physicians order, we hope to not have to create an additional acquisition of blood or a swab or any other kind of material to generate the bio sample. But collect those bio samples in a way that it allows us to then sequence that data and get the genetic fingerprint of that individual. And then pair that with this wealth of clinical data that we have so that researchers have a combination of what's called phenotypic data, which is the clinical data that we have on how people have done with their therapy from their physicians.

And number two, the genetic data of what their particular personal genetic profiles look like so that researchers can combine the understanding of both of these data sets in their analysis of what different disease states may lead to certain kinds of injury mechanisms.

Brad Puffer: Well, Dr. Maddux, when we think about the genetic markers, I think most people may think about oncology or cancer. And how genetic markers have become really important to identify what drives that cancer or mutation, and how we better treat it. There are some incredible examples in the oncology field, correct?

Dr. Frank Maddux: There are numerous examples. And many people are well aware of them just even in the public airways today. You can see people referencing the genetic makeup of certain tumors and cancers that yield the opportunity to take certain medicines that have been shown to work better. And metastatic breast cancer is a good example of that when you look at the combination of tumor markers and the makeup of particular tumors at the molecular level. There are particular treatment programs and a variety of medication profiles that work very well for certain specific subpopulations of patients. So we've seen that in oncology.

In oncology, we've also seen that there is a routine use of trying to make sure patients are well aware of clinical research trials that may be available to them because of the specific nature of the type of cancer that they have. And that doesn't exist to the same extent in nephrology today. My hope would be is that this process of generating more interest in the science and research of kidney injury may offer the opportunity for us to move closer as a field towards being able to offer clinical research protocols to patients with particular types of kidney injury mechanisms that are defined by this precision type of process.

This will take years to fully untangle. But it offers the chance for us to become somewhat more like the way oncology has developed a much more precise approach towards the care that they give to the diseases that cause cancer.

Brad Puffer: Some people may say, well, kidneys are very different than a cancer or a mutation that is driving in the body. How would you describe what you're hoping to get out of these genetic markers for kidneys? Are there already some indications that there are genetic markers that we really should be paying more attention to?

Dr. Frank Maddux: It's well known that there are a number of kidney diseases that are clearly genetic markers. So we see genetic traits and genetic markers and polycystic kidney disease. We see genetic markers and mechanisms of injury and disease states now that are more common like diabetic kidney disease. We see some that are in more rare diseases like a disorder today called focal segmental glomerular sclerosis.

These types of diseases may actually be a blend of different injuries to the kidney. And it's that ability to untangle what are the actual mechanisms of injury an individual has that leads to the scarring of the kidney or the loss of function of the kidney. So I think in the future, we will surely be looking to supplement the way that we identify the diseases, and then subsequently, identify either potential medications that would help a patient, or potential therapy cocktails of one kind or another that might define an individual's illness.

The second way that I think this will be used is to begin to look at which medicines  an individual patient will be more likely to respond to. Whether those are medicines for the treatment of primary kidney disease, or one of the comorbid diseases. And so a good example is a blood thinning medicine that is on the market today that is an antiplatelet agent. And it helps patients avoid blood clots forming or interruptions in blood flow..

But there are certain genetic traits in which that medicine will not work and certain people. Trying to understand how an individual would respond to an individual medication is one of the secondary benefits that I think would be very important in our population of patients with kidney diseases that are based on inflammatory processes in the kidney, and patients with a kidney transplant, and in those that have suffered certain infectious diseases. So I think the opportunity is quite wide in how this might be applicable ultimately in the actual care of patients.

Brad Puffer: Well, what you have really defined here is that goal of precision medicine, where we can deliver the right therapy to the right patient at any given time. And I know we're doing a lot of work across the board to be more precise in our therapies. If this is successful, do you hope this will be a turning point for the entire field?

Dr. Frank Maddux: My hope is that the whole field will  see a turning point where we develop a mechanism to have much more precise personalized care. Given that we know it's in a framework of what we know goes wrong with patients when they have kidney disease both directly in the kidney and with affiliated organ systems and other parts of their body, it's really important to begin to understand how we can identify what an individual needs that's unique to what's causing their injury. And I think that is not only on the physiology that's going on in their body, but it's also are they more prone to, for example, having severe itching as a symptom, or to having severe anxiety with the therapies that they receive. It may cross over into a number of other comorbid areas that they're facing when they're trying to live with their kidney disease.

So my hope is that this will be a substantial turning point in both the investment in the field and the opportunities for us to be much more precise in the care that we are ultimately able to give. The patients that participate in the registry, it's an enormously altruistic activity of theirs. Because many of them will already have gotten to an advanced stage of their disease. And so the direct benefit to them is probably less than it will be for many generations of other people that come behind them with either similar or other types of kidney injury that they're trying to deal with.

I think this is a long term benefit to the field, and it's a long term benefit that ultimately I think will be quite helpful for patients. But the people that sign up and consent in the registry are providing an enormous gift to the field and to researchers and companies like ours who are very interested in trying to learn how to do better what we do.

Brad Puffer: And how has it been going so far? Have you had good reception from those patients you've approached in the early stages?

Dr. Frank Maddux: So we are still in a very early stage of the pilot stage of consenting and utilizing our processes to consent patients. But in our initial clinics that we went to, we had over a 75% rate of patients interested in participating. And I don't know whether that rate will hold up as we scale this out. But our goal is to build this registry over a period of time to one that is between 100,000 and 200,000 patients across the world with wide cultural and ethnic diversity.

So it's a long term project. It is not a project that's going to happen overnight. But it is one that I think is quite compelling in trying to take the knowledge that we have about our patients and take the gift that the patients give and actually create a remarkable resource for physician scientists around the world.

Brad Puffer: This is a really exciting project. And it must be exciting for you to think about where this could go. It also must be a bit daunting given the aspirational scope of what is trying to be accomplished here.

Dr. Frank Maddux: Yes. I think any of these projects that are trying to be done at scaleand are so new in this, where even the physician scientists don't have all the techniques, areultimately going to need to develop a new understanding of how physiology can go wrong in the kidney. I think that it's going to take some number of years for us to get enough patients that we really have this registry at scale.

And then we've got to help the researchers of the world begin to understand that they can look at both the coding and the non coding regions of the genome as an example, and try to understand what's happening in that 98% of the genome that is recognized as non coding, but may certainly have an impact on how other parts of the genetic makeup actually do the work that it does. And so I think it's a big bold project over time. It could yield some fundamental insights that will really help patients in the future.

Brad Puffer: Well, we certainly hope so, Dr. Maddux. I find the field of genomics really fascinating. And I hope others listening have found this discussion interesting as well. It's been great talking with you, Dr. Maddux. Thank you for joining us.

Dr. Frank Maddux: Thank you so much and I appreciate you helping get the message of what we're doing in our medical office out through your Field Notes podcast. Thanks a lot.

Brad Puffer: And to our audience, thank you for joining us. Please know that your feedback is always welcome. If you have comments on today's episode, topics of interest to you, or speakers you would like to hear from, let us know by clicking on the feedback link featured on the Field Notes website on fmcna.com.

Don't forget, you can find Field Notes on the Apple Store, or Google Play, or right here at fmcna.com, or you can also find our annual medical report and other featured articles. We hope you'll come back and join us as we have many more topics to discuss in the weeks ahead. Until next time, I'm Brad Puffer. And you've been listening to Field Notes by Fresenius Medical Care. Take care everyone.