Chronic kidney disease (CKD) is widely understood to be associated with cognitive impairment, yet the problem remains under-addressed. To explore the biological mechanisms, social determinants, and clinical blind spots that shape cognitive decline in CKD, we spoke with Sumair Akhtar, MD, MHCDS, chief clinical officer at Strive Health.
A board-certified internist and primary care physician with more than a decade of experience caring for patients with complex conditions and building scalable care delivery models, Dr. Akhtar offers a clinician’s perspective on why cognitive decline in CKD is multifactorial, difficult to detect, and essential to confront head-on. He also discusses a recent study in the American Journal of Physiology examining sex-specific differences in kidney-heart-brain pathways and their association with cognitive outcomes, highlighting both emerging signals and important limitations in this evolving area of research.
This transcript has been edited for clarity.
Several studies have linked CKD to cognition, but what are some specific ways CKD contributes to cognitive decline?
There’s no one answer. With chronic kidney disease and end-stage renal disease, there’s multiple pathways by which cognitive function is affected in patients who have these conditions. I think the first thing is just the nature of most chronic kidney disease being associated with vascular dysfunction. Your blood vessels don’t work as well as they should, for a variety of reasons. And so, you get long-term damage to the brain because the blood vessels themselves are damaged—[the vessels] to the brain.
The second thing is, when your kidneys aren’t working well. They are the filtering organ in our bodies. If you’re not filtering out all the toxins, those toxins build up and those toxins—a lot of them actually do have an impact on the brain. You get sort of uremic toxins, as we call them, that end up causing long-term damage to the brain.
The third thing is patients who have kidney disease, and usually the other conditions associated with them, have long-term inflammatory processes that are active. And just the fact that you’ve got this increased chronic inflammation. And oxidative stress affects cellular function, really everywhere in the body, but certainly the brain is affected as well.
Finally, … both the causes of chronic kidney disease and the associated conditions—patients usually have other conditions like high blood pressure. In a population that I manage, almost every single [patient]—around 97% of them—have high blood pressure; two-thirds of them have diabetes. When you look at this population, the confounding factors between kidney disease, diabetes, high blood pressure, for example, are all going to impact blood vessels and brain function as well. It’s multifactorial, which is part of the reason it’s not an easy thing to treat.
Which patients are most at risk and how might socioeconomic factors affect their risk?
[The] first thing I would say, from a medical perspective, [is] the worse your kidney disease stage and the longer you’ve had it overall—it’s just more time to have built up these processes. The more of these chronic conditions you have at the same time, you generally have a higher risk of morbidity and mortality. Part of that is cognitive decline. If you are a patient with kidney disease, congestive heart failure, diabetes, high blood pressure—there’s quite a few patients in that complex category that have all of the above—the more [chronic conditions] you have, the more stress you have in your body and your brain.
Then you mentioned something very, very important, which is [that] it isn’t just medical conditions, but it’s also the behavioral health and … unmet social needs that a lot of these patients have that contribute. It is no secret that advanced kidney disease disproportionately affects more marginalized and underserved populations. That is a combination—populations of Black Americans, Hispanic Americans; it affects them predominantly. Often, those patients are also located in marginalized neighborhoods where [there is] less access to [the] highest quality healthcare, primary care, nutritious food. They often live in food deserts; they have issues getting around because of transportation issues.
You can imagine that the complexity just goes up by another factor when you’re dealing with these additional issues. So that piece of it, those unmet social needs and difficult environments that these patients live in, very much contribute to increased risk as well—in addition to the medical complexity that I already mentioned.
The recent study in the American Journal of Physiology examined sex-based differences in the kidney-heart-brain relationship. What can clinicians learn from the study?
I think the study was designed to look at specific biomarkers that are involved in pathways that implicate cardiovascular disease–mediated damage and [damage to] brain tissue in patients who have CKD as well. The idea is that these proteins that they looked at are circulating more in the body when your kidneys aren’t functioning as well. I think what they essentially found was that there seemed to be a signal that cardiovascular disease is a significant contributor to chronic kidney disease.
Chronic kidney disease mediated a cognitive decline in men—the idea being that increased oxidative stress and dysregulation, in the process, that lead to fibrosis and scarring in the brain [also] lead to increased neurologic dysfunction and cognitive dysfunction. It seems that there is a correlation—that this seems to be more of an issue in men than in women—where essentially what they did was they measured the circulation of these proteins and also performed Mini Mental [State Examinations (MMSEs)]. MMSEs are a common way of screening patients for evidence of cognitive dysfunction. It’s a well-tested and commonly utilized screening test that’s done in primary care offices; specialists, anyone can really do them. So, they essentially found that there seemed to be more of a signal towards this dysregulated process being associated with men. However, what was also interesting was that there was more activity—as far as this pTau [phosphorylated tau] protein and Aβ42/40 protein that they looked at—there seemed to be more of a correlation exclusively in women, and their Mini Mental [State] Examinations.
I think the ultimate takeaway here is that there is a potential for increased contribution of cardiovascular disease in CKD-mediated cognitive dysfunction in men. But I do think it’s very important to call out the input limitations to the study. It’s a very small study. We’re really talking about just a few dozen patients. The second thing is: it’s a cross-sectional study. It’s basically just looking at these parameters at a point in time. It’s not following it over any period of time. It’s also not comparing the performance in these patients to any kind of matched controls.
I think what we have is here is a potential signal that these proteins, and the oxidative stress that’s implied by the increased circulation of these proteins, is potentially contributing to more CKD-mediated cognitive dysfunction in men relative to women. But it’s definitely not definitive proof. You are going to need a larger study that’s powered appropriately in order to truly understand how much contribution there is from these proteins circulating—and before we even get to talking about the potential for a therapeutic intervention that could target those proteins.
What are the biggest gaps in care that make cognitive decline difficult to identify or address in patients with CKD?
I think the biggest issue that we face is clearly that we’re not screening enough for the evidence of cognitive decline. I think too often some element of this quote, unquote brain fog that we often describe for patients who are on dialysis—or even just changes in cognition that we notice in patients as they get older with kidney disease—is just chalked up to, “Oh, well, yeah, well, they have kidney disease. They have all these conditions. You should expect that some level of cognitive decline is occurring, right?”
We’re not really taking the time to ask very pointed questions from caregivers and patients as to how much of a burden cognitive issues could be playing into the management of their health. So, screening is an issue. Then the second thing is … the conversations. If you do find elements [that are] evidence of cognitive dysfunction, there needs to be a conversation that follows, into potential pathways for treatment and coping that patients and their caregivers need to understand. That conversation takes time.
Because of the way our healthcare system is set up, there often isn’t the time set aside to be able to have those in-depth conversations to really understand: How are the cognitive changes affecting your health? What specific areas do you need help with? How should you understand coping mechanisms for those? I think screening and taking the time to really dig into the details of what it really means for that patient in their individual condition is really important.
I think the other issue is—the truth is—for patients with advanced cognitive decline in CKD and ESRD [end-stage renal disease] in particular, we don’t have great treatments. We have a whole bunch of treatments that have been trialed that include specific therapeutic interventions that target some of these proteins that we talked about previously, over-the-counter supplements, exercise regimens to help you have better linkage between mind and body control. But honestly, beyond eventual transplantation of a patient as a candidate for it and the use of certain dialysis-related techniques, you can change the way you provide dialysis to reduce the amount of fluid shifts that you have during dialysis. You can try to get more patients on home modalities that can potentially be easier on the body and the brain. But besides those, we just don’t have a lot of great interventions. That can be frustrating for patients that are looking for something that really is a true treatment.
But I will say that you can go a long way by screening early, identifying individual opportunities for patients for developing coping skills and alternative ways of how they live their lives that will still have a lot of impact, even in the absence of having definitive treatment, which is an area of research for us.
Cognitive decline is scary for patients. It is scary for their families. As a result, it becomes somewhat of a taboo subject where you don’t want to necessarily face the truth of what’s causing it and understanding that. Just cognitive decline is one thing, but for patients who are heading towards dementia, that is a very scary thought. Losing yourself, losing your personality, losing your ability to remember things, your family, etcetera. Highlighting the topic is important. Highlighting the need for better screening is important. Hopefully, that continues to spur action in terms of trying to identify therapies to hopefully manage this condition better in the future.
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