Advancing Transplant Science with Daniela Ladner, MD, MPH

[00:00:00] Erin Spain: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Very few people with liver cirrhosis will ever receive a liver transplant. This is an issue that is impacting millions of Americans as the number of people with cirrhosis related to obesity and alcohol use disorder is on the rise. Today's guest, Dr. Daniela Ladner recently led an investigation into the personalities of patients with cirrhosis and she found Some interesting results that may inform healthcare providers on new ways to communicate with and help these patients. Dr. Ladner joins me with these findings. She is the founding director of the Northwestern University Transplant Outcomes Research Collaborative, or NUTORC. Welcome to the show.  

[00:01:03] Daniela Ladner: Thank you very much for having me. 

[00:01:05] Erin Spain: You're a surgeon scientist with a really interesting background. Can you share with our listeners a little bit about your path to Northwestern? 

[00:01:12] Daniela Ladner: I was born and raised in Switzerland by a Swiss dad and an Indian mom, which allowed me to have a very unusual upbringing in otherwise a very homogeneous country. I went to medical school in Switzerland and then had the opportunity to do some research. I also really wanted to be a surgeon. Michael Abecassis, who was the chief at the time. brought me here in 2008. The effort was really to create a community of outcome scientists. within just the month of me arriving here, there was a huge U01 due, and we created this collaboration and submission of this huge grant bringing together outcome surgeons, biostatisticians for risk prediction. And we got this grant, and it was this fantastic opportunity because within very short period of time, we had this very intense collaboration and it kicked off what then became the Northwestern University Transplant Outcomes Research Collaborative. And really the only thing to focus on and remember is the C in NUTORC because it's truly a collaborative. All our work here was finding people are really good at what they do and collaborate with them, primarily with scientists. Finding people with specific skills that would help answer important questions within transplant, starting to work with them and then publishing papers together, putting in grants together. You're constantly challenged in the way you look at things. You know, social scientists will see something fundamentally different than myself or an engineer or a biostatistician. And they challenge way me and my clinical colleagues look at questions, and it allows for this truly transdisciplinary collaboration, which is different from multidisciplinary in that you need both expertise to create that new knowledge. 

[00:03:09] Erin Spain: Just explain outcome science in transplantation. 

[00:03:13] Daniela Ladner: Outcome science is really pushing the best methodologies out there to answer important questions. A lot of my research focuses on liver cirrhosis. It's scarring of the liver that affects two to 5 million in the country, and only about 2 percent of those will ever get a transplant. And very little is known in terms of what can be done to improve their outcomes, but also we don't have the resources for all these millions of people to be seen by hepatologists. So having good risk prediction of which patients really need that care is really important. And to do that, we have a lot of data from electronic health records, from administrative data, but you need very sophisticated analytic expertise. So for instance, I have one grant with one of my colleagues who's a professor in engineering Jay Mehotra, and he uses his methodological skills to help answer some of these questions. In another grant, we wanna understand the economic impact of this chronic disease, which affects so many people, yet not a lot of public health awareness exists around this chronic disease. And so, Charles Mansky, who is a professor in the Weinberg School of Arts and Science, an economist, is a partner there to answer economic questions. So these are very skilled scientists who use their skills to help answer this clinical question. They wouldn't know which part of the clinical question is important, and no matter how sophisticated I might or might not be in answering economic or risk predictive questions, somebody who does nothing else, like, Dr. Mehotra or Dr. Mansky, they will be able to do this at a much higher, much more sophisticated level. Plus they can use this as a training ground to establish and to move forward some of their science.  

[00:05:16] Erin Spain: In a recent paper that you just published looked at the personality traits of some of these patients with cirrhosis. How did you decide to investigate one's personality and how that could play into who ends up getting a liver transplant? 

[00:05:31] Daniela Ladner: We have weekly scientific meetings where we invite people to talk about their science. I through one of my collaborators have heard of Dan Mroczek and because he has specific expertise in personality. I'm like, I know nothing about personality. Let's have him over. And he gave this amazing talk about how he studies personalities and how he's also collaborated to figure out how to mitigate certain personality traits to get college students to exercise more. It was like a light went off.  I was like, well, let's look at personality in patients with cirrhosis. And we looked at this and there was nothing. No one has studied that. Then I was like, well, why don't we study it? What are the traits in these patients? It turns out they're different than the general population. We found they had greater openness and were more extroverted, which can go along with traits found with alcohol use disorder, which is a major driver of cirrhosis. So what we found was conscientiousness is, for instance, one of the personality traits and we found not so surprisingly that those who are more conscientious personality- wise are more likely to be listed for transplant and are more likely to be transplanted. Well, that strikes me as unfair, right? Personality trait is something that you just have. So, if you tend to be conscientious, it kind of makes intuitive sense that it would be easier to then navigate a very complex medical system. From my perspective, it is our job to provide access to all patients, no matter what their internal and external resources are. We are talking with personality traits, we're talking about internal resources. So if we were to routinely take this into account, somebody who's less conscientious, let's say, or has less agency, if we know that we can help them to overcome that. And maybe they need more reminders. Maybe we can give them electronic reminders. But this all speaks towards how can we provide best care to everybody? And that doesn't have to translate to, oh, this is gonna be way expensive. A lot of this can be done really easily, inexpensively if we think about it and if we are aware of it.  

[00:07:57] Erin Spain:  Describe to me some of the misconceptions out there about cirrhosis. 

[00:08:02] Daniela Ladner:  The three main drivers: alcohol use disorder; NASH cirrhosis, so non-alcoholic steatohepatitis, which is really related to the obesity epidemic combined with diabetes and/or hypertension, which leads to cirrhosis. And the third is Hepatitis C. So, about seven years ago, a medication became available that has helped on the path to eradicating hepatitis C, which we will achieve. So, the incidence and prevalence of cirrhosis based on Hepatitis C is decreasing. However, unfortunately that's made up by the huge increase in obesity related cirrhosis, which has had the fastest growing trajectory over the last 15 years. And that is really scary to see because it affects younger and younger people. We have many young folks who already have fatty liver disease, which can lead to cirrhosis. The alcohol use disorder has gotten worse, has affected more people with Covid. Often there's like a gut reaction when you talk about alcohol use disorder. Oh, that's the patient's fault. And it's really a disease like every other disease like diabetes. It is a very vicious disease that has many effects, including if it's extensive, can lead to cirrhosis. I notice there's tremendous bias in the population, and also amongst caregivers towards alcohol use disorder as something people do to themselves. And I just wanna use this opportunity to iterate that I think it's really important that we look at this is a disease like everything else, which is also something that we are studying by the way, as part of NUTORC. So we have a lot of work to do as a society to help folks not get to the point where they have cirrhosis or also find medications that might slow down the progression from cirrhosis to then decompensated cirrhosis and death. 

[00:10:07] Erin Spain: It is interesting that a lot of the folks who are subjects in your studies, they do not end up in transplantation. 

[00:10:15] Daniela Ladner: Yeah, unfortunately, receiving a transplant is really not what the majority are lucky enough to receive. The barriers to receiving a liver transplant are huge, which is in large part why some of our scientific focus has been on living donor liver transplant. That is a large resource. Unfortunately, only about 5 percent of the transplants right now in liver are living donors, whereas it's more like 30 percent for kidney transplant recipients. It requires tremendous resources to have a liver transplant. It requires support, it requires insurance. Not everybody has insurance. Whereas for kidney transplant it's an entitlement to get Medicare insurance once you're on dialysis. So the transplant is paid for and it's also very cost effective to get a transplant. In liver, that's presently not the case. And so, I think it's really important to also focus on what's going on prior to receiving a transplant, there's a lot of disparity that is encountered. Dr. Simpson leads our African American transplant access program that tries to mitigate the disparity. We've published papers showing that African Americans in the greater metropolitan area are more affected by cirrhosis. They're clearly more affected by end stage kidney disease. But they're proportionally less likely to get a transplant because they're all these different barriers. So some of our science tries to figure out, what are these barriers? How can we overcome this? That's where a lot of the social science qualitative work comes in. 

[00:11:57] Erin Spain: As the founding director, describe to me the Northwestern University Transplant Outcomes Research Collaborative and what type of work is happening there, and what you want your fellow scientists to know about it, why they might wanna get involved. 

[00:12:10] Daniela Ladner: NUTORC is really part of the Comprehensive Transplant Center. It's the outcome science arm of the Comprehensive Transplant Center. And there's a lot of exciting work being done related to epidemiology, related to the study of frailty, related to opioid use, related to aging, related to racial disparity. Many of my surgeon colleagues are part of these initiatives and so are many hepatologists and nephrologists. It really involves all clinicians related to end stage organ disease as well as transplant. But then also within the Comprehensive Transplant Center, there's a lot of exciting basic science and translational science going on. Joe Levinthal leads one of the largest tolerance and only tolerance study in the world, with the largest enrollment and people of immunosuppression, which is super exciting. We have Josh Levitsky, who looks at translational, top-down proteomics science and also John Friedewald. They've been looking at early markers of rejection. We have Satish Nadig looking at nanotechnology and interventions prior and after transplant. So there's a lot of energy. One of the biggest efforts of NUTORC the CTC has been to break down silos, to not be restricted to our discipline, to not be restricted to our clinical expertise and really reach out to different schools within Northwestern different departments, different divisions. Just as many different people to get them together into a room to talk about a specific problem. And it's very exciting the kind of conversations that happen and each time you walk out from such a conversation, it creates ideas for studies to advance the field. And that's really what we are trying to do, right? We are trying to provide the best care possible to our patients on a daily basis as we take care of them in the clinical setting. But then we're trying to advance science so it can inform ultimately how we can provide better care for our patients.  

[00:14:21] Erin Spain: Thank you so much Dr. Daniela Ladner for being on the show today we appreciate it.  

[00:14:26] Daniela Ladner: Thank you very much for having me.  

[00:14:28] Erin Spain: Thanks for listening, and be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts. And rate and review us also for medical professionals. This episode of Breakthroughs is available for CME credit. Go to our website, www.feinberg.northwestern.edu and search CME.