Episode Transcript:

Dr. Maddux: People with kidney disease often present with cognitive dysfunction ranging from mild impairment to dementia, often affecting memory language skills, attention span and other functions as well as depression. Today's guest, Dr. Mark Unruh, professor, and chair of the Department of Internal Medicine at the University of New Mexico, discusses cognitive impairment in patients with chronic kidney disease and his research to find targeted interventions to address these challenges.

Welcome, Mark.

Dr. Mark Unruh: Well, thanks for having me.

Dr. Maddux: Mark, let's talk for a moment about how do you diagnose cognitive impairment in our patients with CKD?

Dr. Mark Unruh: That's a really important question, particularly given the prevalence of cognitive impairment and dementia in our population. I worked at a health system where they were very focused on a quick turnaround on consults. So, as a nephrologist, about one in ten consults was actually directed to a neurologist.

However, I'm not a neurologist. So as a nephrologist, what can I do to kind of make sure I have patients on a path, whether it's that they're either suffering for cognitive impairment, dementia or not. I like to think of it as sort of a routine clinical process where you do a history, you talk to the patient about and hopefully an informant, whether it's a family member or a caregiver, about what's going on.

What is the evidence of cognitive decline? Are there new behavioral issues? Are there issues with kind of function in everyday life? Then, you can turn to the physical exam. Think about if there's any overt evidence of cerebrovascular disease, stroke, obesity, which could suggest obstructive sleep apnea. Any evidence of Parkinson So, after doing those two as a nephrologist, I'm very excited to turn to labs.

I love ordering labs and looking at labs. In this case, however, the labs, the battery is rather modest. The focus is just on kind of ruling out treatable things, looking to see if there's a B12 deficiency, anemia, hypothyroidism, and subpopulations. You could consider sending a screening for syphilis or HIV. I think an important thing to consider in our population is to make sure that you've screened for depression and anxiety.

After that, refer for more extensive neuroscience neuropsychological assessment and imaging. In most cases, you're able to really have a handle on not only like how impaired the person is, but what the underlying causes.

Dr. Maddux: We know that mild to moderate cognitive impairment is associated with chronic kidney disease and advances as people develop end-stage kidney disease. Can you just talk about what the relationship is to cognitive function and CKD?

Dr. Mark Unruh: We're talking about cognitive impairment for a reason. For me, it's really great to sit down with you and take some time to talk about cognitive impairment. For many of us, as our parents, family members, and we age ourselves, it becomes very much a concern.

My interest in cognitive impairment is it's personal on that level. The public health impact of cognitive impairment is striking. The cognitive impairment, the burden of it, and the population we serve is stunning. Personally, I care for patients who are on dialysis largely with end-stage renal disease. I just have many stories of kind of the impact of cognitive impairment on their care, their outcomes, their families.

I became aware of it early on when there was a patient I was caring for who was alert and oriented at times three, but couldn't really name any of the folks caring for her, including a reputable world class nephrologist. Right. So, it's something we see and something I was aware of early on. Then there's an opportunity to continue to kind of mess up in care of folks with cognitive impairment.

I recently had a patient who's an amazing human being with cognitive impairment, who I care for on dialysis, and I called a family meeting to have that patient come in and the family come in just to make sure that they were adequately resourced. The family is really smart. They do reading, and they thought the intent of the meeting was to stop dialysis in this person because of his cognitive impairment and dementia.

That was not at all the case. This misunderstanding caused a lot of anxiety with that patient and family. For me, like the burden of cognitive impairment and the kind of relationship that we see with chronic kidney disease makes this an area of primary importance for our health system that we set up and as well as the care we provide. Experience suggests that it's really common.

The data would suggest that there is an overwhelming prevalence among patients we care for. There's a relationship between chronic kidney disease and cognitive impairment. That relationship is maybe two-fold higher for chronic kidney disease with advanced chronic kidney disease, and it can go as high as ten-fold higher among patients who are on dialysis.

Like the early studies that sparked a lot of the interest and the burden of dementia and end-stage renal disease performed by Murray et al. And later, follow up by Mark Sarnak at Tufts demonstrated that a minority of patients that we care for in the dialysis unit actually have normal cognitive function, maybe 13 to 30% tested normal, whereas the bulk of the others had either mild cognitive impairment or dementia.

Dr. Maddux: Speak for a moment about the not only the relationship of the correlation between increasing prevalence of cognitive impairment and declining GFR, but also what happens when somebody starts dialysis.

Dr. Mark Unruh: So those are tough questions, the relationship between CKD and cognitive impairment is complex. It's likely that there is a relationship between the kidney function and cognitive impairment. There also seems to be relationship to the severity of proteinuria and cognitive impairment, and that actually may be prime.

In addition, there may be intermediary factors such as inflammation, more of a causal link to cognitive impairment. The patients that we see have shared risk factors for cognitive impairment. What happens to cognitive performance with transitions in care has been relatively understudied.

The kind of transition that's probably the best studied is that of kidney transplantation. The results there are more mixed. So, with kidney transplantation, what we've observed is that the bulk of the literature suggests there may be a protective aspect of transplantation with cognitive performance. It's definitely the right thing to do for our patients.

It improves their global health. In this study that we did, we found that when you compared folks who were listed, who then went on and got transplanted to those that were listed and then did not get transplanted, the cognitive performance was relatively the same over 18 months. Even that is a little bit of a mixed bag.

I think your question is really important in that you can imagine the patients we’re caring for with aspects of cognitive impairment across a range of domains then are put into a very complex health environment and supported by a large team. That's kind of the area where we can really put a lot of focus and really improve outcomes of our patients moving forward.

Dr. Maddux: Talk for a minute about some of the tools to actually measure higher motor function and are there any special tools that are more valid for the patient population with advanced kidney disease than others? Or are these the traditional methods of assessing cognitive function?

Dr. Mark Unruh: We have largely used the traditional tools of assessing cognitive function. When you think about the tools, there are brief tools that are intermediate that we're probably familiar with and then longer tools and whole batteries of tests. Clinically, what we've taken advantage of is an intermediate tool, particularly among those folks that are going for transplantation, to screen them and see if they need additional support.

The tools that we've most widely used are the MOCA, which is the Montreal Cognitive Assessment Tool. The MOCA is a tool that takes about 10 to 15 minutes, assesses multiple domains and gives you an overall score and a risk for having cognitive impairment or dementia. It's widely used in residence. So, the MOCA is a tool that we've taken advantage of clinically.

The mini mental status is one that I grew up using and is also pretty similar, generates a similar score. I'm comfortable with using that. It has the current drawback in that there's a charge associated with every, you know, the form using the form. Most people have migrated to the more open source cognitive screens and those seem to be effective. You raise the issue are these tools useful in our population? And I'd like to speak to some of the limitations of these tools. They're designed for general use. They're set up for a group of patients or human beings who are 65 to 80, primarily English speaking, have 12 to 14 years of education.

The extent to which that represents the population you care for, you can go ahead and use them. In addition, it's pretty common to use these forms, whether they're part of a quality improvement project or screening in environments that can be disruptive. I'm thinking of the dialysis unit.

You can imagine giving someone a form in, a dialysis unit and asking them to have a high level of performance on it can be really challenging because all the things that are going on in that environment related to the patient and maybe related to others. Not only like do we have the tools, but is the right place to administer the tools and do we have the right tool for the population?

Dr. Maddux: The population we treat, obviously, is a population that's quite diverse and clearly includes a variety of communities that have been disadvantaged in one way or the other, not the least of which is education. We have so many of our measurements and tools don't work at the level of whatever the local cultural environment is. So, I'm sure this is one of the areas that we probably need to improve upon.

Dr. Mark Unruh: You're right. One can mitigate that to a certain extent. If you choose a tool that, for example, is written for primarily Spanish speakers or written or has adjustments for a level of education. There's probably no perfect instrument for the diverse group.

Dr. Maddux: Talk to us about how we as physicians can be more sensitive to understanding that somebody is developing cognitive decline and how we might look for that. what are some of the clues that we should be on the lookout for?

Dr. Mark Unruh: That is a terrific question. And it's one that we can you know, as evidenced by the prevalence of cognitive impairment and dementia. We are privileged to have a team to depend on, and it may be a tech, it may be a nurse, or maybe a social worker, or a dietitian that notice that the patient is sort of slipping.

Common things that are reported are issues around adherence, either to the dialysis treatments or to medications or to diet, evidence that they're struggling in the home environment. Hearing from family members that that there are behavioral changes. Any of those things are things that we see a fair amount of.

Dr. Maddux: So many of our patients suffer from anxiety and depression that isn't necessarily directly associated to cognitive impairment. But what's the relationship between these two things?

Dr. Mark Unruh: I would say that it's likely a bi-directional relationship. That anxiety and depression and particular depression in our population can lead to issues around memory and perhaps contribute directly to an acceleration of cognitive impairment. There's a fair amount of pathways you have to invoke to do that. But you can imagine depression leading to inflammation, leading to neurocognitive changes.

And then on the flip side, folks who are having challenges due to cognitive impairment are more likely to have issues around anxiety and depression. You bring up a terrific point in that when we have people who are struggling, people that were concerned about having anxiety of having cognitive impairment, that we should also screen for anxiety and depression.

Dr. Maddux: Are there any biomarkers? We know that some of our patients that have difficulty with cognitive decline have shown evidence of increased amyloid beta subunits, 40 and 42. Are there are there any effective biomarkers out there for this?

Dr. Mark Unruh: There's a couple of things to think about with that question. It's like, well, what if there is a biomarker? What's the use of the biomarker in a way? So, is it that you're using a biomarker as an indirect screen? In the case of the population that we care for, the prevalence is so high it's easier just to go out and screen everyone rather than rely on a biomarker.

On the other hand, I think biomarkers can be really terrific tools to understand mechanisms in our patients. There have not been a lot of studies looking at specific biomarkers and wide ranging prevalence is in the different CKD populations. Neuroimaging can be thought of as a type of biomarker. To summarize a number of investigators, what we've seen on neuro imaging suggests maybe more of a vascular component than maybe you'd see in the general population. There is increased evidence of cerebrovascular disease compared to what you'd see in a general population with cognitive decline.

Dr. Maddux: We know some of our patients have episodes of hypoxia during their treatment. We know other patients have vascular issues, as you've just discussed. Talk about the potential mechanisms and what some of the things are that the research has begun to uncover that could potentially impact somebody's brain function.

Dr. Mark Unruh: When we're thinking about potential mechanisms, we can think about potential mechanisms in the general population. then think about the extent to which that may be accelerated in the ESRD population. For example, neuroinflammation is a potential mechanism of increasing cognitive impairment in the general population, either directly or indirectly.

There is a peri-vascular system that acts glial lymphatics. It's sort of like the kidney of the brain. That system is driven or largely related to astral glial cells that are peri vascular and what it does is it clears the brain of metabolites like soluble proteins and other metabolites.

Inflammation can impact that. Depression, hypertension can change that metabolism. So, one can imagine that if that happens in the general population, in our patients where inflammation is very real and highly prevalent, that could be a possible mechanism of the higher risk of cognitive impairment. There is evidence of dips and cerebral vascular blood flow and perfusion.

Those dips may be related to hypotension. There is some evidence that using a cooler dialysate, might be a mechanism to prevent that. That's been shown in a small study of around 70 patients that there appeared to be preserved white matter over the course of a year on cooler dialysate versus the warm dialysate.

I'm waiting for the larger cool, dialysate studies to come out to see what its impact is on overall outcomes. There are a number of things that are contemporary policies that offer me hope as well, like having guidance for ultrafiltration rate. One might imagine that that could be neuroprotective, pushing people or encouraging people to consider home dialysis and particular PD may be neuroprotective, although there isn't direct evidence of that currently.

Transplantation again, might be a way to put someone in an environment to be neuroprotective. And all those things are where our field is going.

Dr. Maddux: Thinking about potential actions we might take as physicians. I've been intrigued by some of the Alzheimer's research that has not only shown that there are these monoclonal antibody drugs that are removing some substances. And I know besides Biogen's drug aducanumab, there are some others in the pipeline that's been a very controversial drug.

But I've been super intrigued by the sink hypothesis that was tested in the Anbar trial. The Anbar trial used therapeutic plasma exchange as a way to remove amyloid beta and tao proteins. And the assumption was that it would reduce the burden of these substances on the on the central nervous system. I'm curious whether you think any of those kind of absorptive or other means of removal of certain specific proteins might actually help our patients in some way.

Dr. Mark Unruh: That particular trial, I was intrigued by for the general population and how it's actually a multi-component intervention where you're removing these proteins, but also you're adding back protein. The mechanism of action of that particular intervention in that particular trial, I think remains to be seen.

It also would be great to have it replicated with a larger number of patients. I think that study had around 300 patients. So, seeing it in a larger, probably more diverse patient population would be rather promising, particularly given the moderate to large effect size that it had over the course of a year. It really actually is a great way to think about the opportunities we have for our populations.

Where I get mired a little bit, is there are so many potential proteins that we could target in our population because in addition to the proteins that you described in the general population, there is very much the possibility that uremic toxins are contributing to the high rate of cognitive impairment we observe. Are we going to target neuropeptide Y or particular protein bound molecules.

I would really like to see more study and more follow up is hemodiafiltration. That is pretty widely used in Europe. There is a potential rationale that with increased middle molecule clearance, you may see some neuroprotective effects. To date, there's only descriptive studies suggesting no particular benefit. I do appreciate that way of thinking about the problem for our patients.

Dr. Maddux: I look at the levers we have and the kind of treatments we do and we don't use all of them, so we use diffusion and convection a little bit. In the US, it's convection because we have such high interdialytic weight gains. And so, we're sieving a lot of fluid, but we also don't really use gas exchange or adsorption in any way.

It just struck me that this is one of those problems that may require that we actually think of our treatment quite differently than what we do today to try to figure out what needs to be in the system versus what needs to be removed from the system.

Dr. Mark Unruh: That's a terrific point. As a typical nephrologist, I thought about it like less frequent dialysis, more frequent dialysis with the study of more frequent dialysis. The FHN trial demonstrated no substantial changes or impact on cognitive performance. But you're right, thinking about it and being more flexible in our approach and maybe a bit more innovative might be helpful.

Dr. Maddux: It's an interesting area that I think we're just beginning to socialized certainly within our organization we spent more than a few years now and I think have a few years more to go and trying to get our arms around. What do we need to do for cardio protection, and prior to the pandemic, this being sort of one of the largest co-morbid areas for people with kidney disease.

But right behind that, I think, is cognitive dysfunction, of which we're just beginning to learn the scope of the problem and have very little that we can actively do today to try to protect people. I'm hoping that this this conversation that we're having will begin to stimulate more interest and discussions our peers that this is an area that we really need to target over the next 5 to 10 years.

Dr. Mark Unruh: I guess from my perspective, given the prevalence of cognitive impairment and dementia in our population, the future is now, and we should try to act. There really is a paucity of medications currently available that will have benefit on our population. But we do have many levers that we can pull to improve the care that patients and families receive.

For example, normalization of advance care planning discussions, given the likely progression over time of cognitive impairment in our population Just having these discussions more early and often, I think, is an area where we can really protect our patients and make sure that we're providing care that's consistent with their wishes and values.

In addition, our organizations can really do a great job of providing more integrative care, case management. One can imagine a scenario where we do more screening for those folks with cognitive impairment and dementia, setting up more wraparound care and just providing more frequent check ins, more review of medications and getting those patients and families more resources is something that we can do now.

It's always good to warn them that you have that plan for them, as I've illustrated with my patient. But I think that's something that we can do right now. I think looking at the general population, there are the common things like working to improve social networks, working to encourage exercise, managing the vascular risk profile as much as we can on dialysis. Those are likely to not hurt our patients and may be a benefit. I think that it's something where we should act, act now.

Dr. Maddux: I think the barriers between CKD care, end-stage kidney disease care, transplant care are beginning to come down a bit, which I think will be good in thinking through a more holistic view of what patients need. And certainly around this area, their functional abilities to live a life with this difficult disease in the face of either cardiac decline or cognitive decline, seems to be one of the opportunities that value-based care will bring to us. Where we're not looking at individual treatments for individual parts of this, but we're looking at the whole individual and the whole patient, and I'm quite hopeful that's the direction this will take.

Dr. Mark Unruh: I would agree with you that I think that we're uniquely poised to provide better care through this value-based care approach to our patients and support the transitions and support them as they need kind of more resources at home. And in order to stay at home and perhaps integrating palliative care and hospice earlier, if that's consistent with the values of the patient and their family.

Dr. Maddux: Last topic before we wrap up is I've had a great interest in looking at not just phenotypic clinical data, but also genetic data on patients. And I think there's a growing body of evidence that understanding genetic variation among the people that we take care of will ultimately help us do a better job at figuring out what to take care of and how to approach that. Do you think there are genetic components to the, the cognitive impairment that we see in patients with advanced kidney disease?

Dr. Mark Unruh: Yes and. Genetics is where the field is now in cognitive impairment. It reminds me of where we are in adult kidney medicine and that we're learning more and more. We're identifying genes that may play a role and trying to figure out how that can be used to provide better care.

There currently isn't really a recommendation for genetic screening for a single gene in the general population or in the ESRD population. One can imagine a role going forward where you would use screening, genetic screening and come up with risk profiles. And, how can genetics impact the likelihood of progression in our patients?

Well, you could imagine that there might be a genetic component to cerebral blood flow. There might be a genetic contribution to sort of the intactness of the blood brain barrier. So, it would make sense that in our population there may be an interaction with the genetics, host genetic. It's something to watch, and I've watched with excitement what's happening in the adult kidney world as well around genetics.

Dr. Maddux: I'm here today with Dr. Mark Unruh. He's professor and chairman of the Department of Internal Medicine at the University of New Mexico. We've been talking about cognitive impairment and cognitive dysfunction, in our patients with kidney disease. Mark, thank you very much for being with us.

Dr. Mark Unruh: Thank you, Frank, for having me.