The Impact of CKD on Cognition: An Inside and Outside View

This blog post was made by Henning Sondergaard on October 11th, 2018.
The Impact of CKD on Cognition: An Inside and Outside View

I am a clinical psychologist specialized in health psychology. As an undergraduate, I was very interested in neuropsychology and cognitive neuroscience. So, when it came time to choose my specialty it was a toss-up between health psychology and neuropsychological studies. I chose health psychology, because I thought there aren't many people with chronic illness in the health field, unlike fields like women's or minority studies where researchers belong to the group being researched are the norm. I think many of the problems with healthcare these days are grounded in the "outside-in" look at health issues that most professionals have - this is not a critique, just a matter of fact.

I think, rather humbly, it is time to incorporate the patient view more systematically and diligently so we can better include some of the more non-clinical issues, like how chronic illness affects quality of life. So, this blog will be an inside and an outside look at cognitive issues in CKD and dialysis. I will start from the inside by looking at anecdotal evidence (most of it gathered from my own experience and in my capacity as psychologist for the Danish Kidney Association.) After that, I will delve into some of the research that has been done on the subject.

What initially triggered my curiosity was my own experiences. A few years before I was a dialysis candidate I started experiencing a lack of focus leading to an inability to retain complex bodies of knowledge. One day I asked my nephrologist about it. He strongly implied it might be age-related. I was in my 40s at the time so I took it as an insult. Later I learned he simply didn't know about cognitive issues of kidney disease and he didn't believe in it.

Soon after that, I became involved in the Kidney Association. I volunteered to do counseling for fellow patients and their relatives. I recognized others expressing concerns about a number of cognitive issues often way more and way worse than I had experienced myself:

  • Fatigue was the big one, something I recognized personally as my disease progressed.

  • The second-most prevalent issue was poor memory skills, especially recall of events, concepts, and words.

  • Attention was another big one, people complained about not being able to concentrate like they used to.

  • A combination effect of poor memory and concentration was learning difficulties. We learn things slower than others. We don't retain what we are trying to learn. We need more repetition than others.

No wonder starting HHD is tough for some—especially when coupled with the shock of starting dialysis itself. Other things people typically complain about are executive function problems, like planning and decision making, troubleshooting, overcoming habitual responses, and resisting temptations. Finally we have complaints of a more emotional nature: fragile temperament, responding with anger, sadness, frustration, despair, or resignation.

On top of this, I would observe symptoms we normally consider mental health issues. Symptoms of depression and anxiety are very likely 'healthy' reactions to suddenly having to deal with the effects of CKD. But, they might also be triggered by an abnormal brain chemistry. As we will see, it is very hard to pull things apart and say conclusively what the underlying cause if all these things are. And we are in the very early stages of research in this field.

All these changes lead to altered behavior that in many cases is more obvious to relatives than to the person with CKD. Personally, I was very good at finding excuses for my altered state. I could accept my poor memory skills and my lack of concentration was due to my kidney disease but when it came to the behavioral stuff I had a hard time realizing it. The excuses piled up until my bubble burst, and I had to admit things were not as they were supposed to be and it was probably my CKD playing games with my brain.

Once I started dialysis, many of the emotional issues seemed to wane and finally disappear, while many of the other symptoms lessened greatly—but they never completely disappeared. I became so well that I started being curious enough to think about what triggered the poor brain function we all seem to experience, a.k.a. "Kidney Brain."

I think everyone who has undergone hemodialysis knows another symptom of kidney brain: post-dialysis brain fog. Brain fog is especially prevalent in those doing standard in-center treatments. The condition lasts anywhere from a few minutes to more than a day, and:

  • You are lethargic. Not 'normal' tiredness, but a deep-seated lack of energy.

  • You feel awful.

  • You can't think properly.

  • Your memory all but shuts down.

  • Focus and concentration only exist in the realms of cameras and orange juice.

Dialysis definitely does something to our brain and our cognition. But, in many ways it seems to be the same symptoms as before we started dialysis, only exaggerated. So how do we distinguish between the two causes? I was strongly convinced my symptoms had to do with the variations in the electrolyte solutes that are measured every time we draw labs. Sodium, potassium, phosphate, and calcium.

I thought so, because those electrolytes happen to be the most important minerals in brain and nerve function. All neurons work by relaying an electrical signal from one cell to other cells it is connected to. After the cell decides to pass a signal along, calcium plays a vital role in triggering the signal. The signal itself is created by sodium and potassium ions switching places, thereby changing the electrical charge inside the cell. And, since the signal is partly electrical in nature, the cell needs insulation, called myelin—which consists primarily of phosphorous. In short, these four electrolytes are fundamental in the most basic principle of brain function.

I came to the logical conclusion that if the blood serum levels of these ions were out of whack, they'd also trigger disturbances in brain function. There were old studies that showed how "small changes in intracellular and or extracellular solute composition can dramatically alter neuronal signaling and information processing."1 John Agar has explained over and over again how fluid and solute accumulation happens in three separate compartments in the body; inside the cells, between the cells, and in the blood.2, 3, 4, 5 To make matters even more complicated, the brain has two separate extracellular compartments: the first one is the cerebral spinal fluid (CSF) which many may know, the other one is the interstitial fluid compartment (ISF) that surrounds the neurons and the glia-cells. I honestly have no idea what the extra compartment means for fluid and solute clearance in dialysis. However, it seems very likely that it makes matters more complicated than in other parts of the body.

I was a little sad to find out that in general the literature doesn't deal with the direct effect of solutes and fluid on a neuronal level. I was also sad to find out that, despite clear anecdotal evidence, only a few studies have been done on cognitive decline in CKD.6 One review article points to three articles that found an inverse relation between eGFR and tested cognitive functioning7. But, by far, most of them focus on how dialysis affects the brain, or, rather, some of the effects of dialysis; rapid fluid removal, interdialytic hypertension, and intradialytic hypotension (high blood pressure between sessions and blood pressure drop during sessions, respectively.)

The studies do not distinguish between the effects of CKD and the effects of dialysis. To make matters even more complicated, McIntyrevi points out that the cognitive assessment tests used in these studies are made for measuring dementia in the general population. Some recent studies have utilized MRI to look at structural changes in the brain. However, only a few have8 been coupled with cognitive assessment tests.

Conclusion:

If I am to conclude something from my look into this, it might be that CKD and hemodialysis has significant impact on cognitive functioning. This, in turn, has major consequences for quality of life. We can also conclude that we have a poor understanding of the connection between cognitive impairment and CKD and/or dialysis.

Finally, it seems like longer and more frequent dialysis9 alleviates much of the cognitive impairment we see in the general dialysis population. Considering how we obtain better control of solutes, fluid, and blood pressure—both during and in between sessions—when doing long and frequent treatments, this makes absolute sense.

This ought to be another strong argument for longer and more frequent treatments. There are many road blocks to adopting a standard built on “longer and more frequent.” One of them is that patients on in-center treatments are too sick to see the difference and too sick to demand better treatments so they can feel better. They think—and to a large extent, they are told by professionals—this is how dialysis is supposed to be. It's a catch22 that can only be solved by a joint effort by those patients who know better and by the conscientious health care professionals among us.


  1. Strange, K. Regulation of solute and water balance and cell volume in the central nervous system. J Am Soc Nephrol. 1992 Jul;3(1):12-27

  2. https://www.homedialysis.org/life-at-home/articles/fluid-and-solute-removal-part-one

  3. https://www.homedialysis.org/life-at-home/articles/fluid-and-solute-removal-part-two

  4. https://homedialysis.org/news-and-research/blog/116-dialysis-a-duopoly-of-solutes-em-and-em-volume-not-a-solute-monopoly-alone

  5. https://www.homedialysis.org/news-and-research/blog/94-slaying-the-water-dragon

  6. McIntyre, C. Recurrent circulatory stress: the dark side of dialysis. Seminars in Dialysis, 2010 Sep-Oct;23(5):449-51

  7. Bugnicourt, JM, et al. Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc Nephrol, 2013 Feb;24(3):353-63

  8. Eldehni, MT, McIntyre, C. Are there Neurological Consequences of Recurrent Intradialytic Hypotension? Seminars in Dialysis, 2012

  9. https://homedialysis.org/news-and-research/blog/127-the-land-of-longer-more-frequent-dialysis

Comments

  • Eric Weinhandl

    Oct 14, 6:09 PM

    Dear Henning,

    Thank you for a wonderful blog post.

    One sentence captured my attention:

    "Finally, it seems like longer and more frequent dialysis alleviates much of the cognitive impairment we see in the general dialysis population."

    This matches my observation, but one could fairly criticize any "observation" as non-systematic, anecdotal evidence.

    Complicating matters is that systematic studies of cognition on dialysis have generally failed to support a beneficial effect of longer and more frequent dialysis.

    Why is this?

    Are the tests flawed?

    Are only a subset (minority) of patients expected to experience benefit?

    I am very curious about your opinion, particularly as it relates specifically to some of the very widely used instruments (3MS, Color Trails, et cetera).

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    • John Agar

      Oct 15, 11:02 AM

      Eric ... I may be wrong, but these studies - and there are only a few - do not, I think, test time-related function .. ie: before, at the end, then ‘x’ or ‘y’ hours following dialysis.

      Patients say that they emerge ‘in a fog’ and much like Bob Lindsay showed in his ‘recovery time’ study of more than a decade ago, it takes them a variable time to shake the brain back to clear thinking. Those that dialyse long and slowly claim - I believe correctly - that they ‘shake off their fog faster, and their fog is lighter - but the 3MS studies do NOT capture this dynamic state at all. Yet, it is this treatment-related fog period that bothers patients the most. It’s not their ‘day after’ baseline brain function that is at question, but rather, their progressive en-fogment during dialysis and the time to return to their baseline brain that matters most. It is just like McIntyres first studies of myocardial function DURING dialysis opened our understanding of the progressive change in myocardial perfusion DURING dialysis ... studies that would have missed the treatment-driven nadir if he had waited till the next day.

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  • John Agar

    Oct 13, 1:20 PM

    Excellent blog, Henning, on a shamefully neglected issue.

    As you know, imperfect though they yet be, consortia like SONG-HD are just beginning to open the door on things that matter to patients, and not just to ‘us’ ... but there is a long, long way to go.

    Most studies remain hopelessly restricted and useless un-real world RCTs, or small, short-period clinical trials of the stuff we think is important - like survival - while the things patients care about - like the quality of the remaining time - languish, their stone unturned.

    Brain function is one such stone ...still firmly face down!

    But, like the late night TV ads like to tell us ... there’s more!

    I have spent decades emphasising the largely valueless impact of urea in dialysis ... and regarding clearance, solute behaviour, and as a measure of ‘adequacy’, that remains my view.

    But not so with the brain. We have known for decades that urea crosses most cell and fluidic compartment barriers with ease ... but not so the so-called ‘blood/brain barrier’ ... a physiological interface that behaves differently from other internal transit surfaces.

    Why? ... I truly have no idea, and as I am on holiday, I plan not to delve and see if advances have been made in our understanding of this odd phenomenon. Let’s just go with the thought that urea - for whatever reason - crosses the blood/brain barrier or, importantly in reverse, the brain/blood barrier.

    Now hold that thought.

    Next ... as urea and water (among many other things) are removed by dialysis, the blood urea falls. This creates an increasing concentration difference between the blood (and other tissues) urea, and the brain urea as urea only slowly diffuses across the brain —> blood barrier ... for whatever reason that is.

    That means the brain urea concentration, relative to the blood urea concentration, progressively increases as the gap widens.

    Urea is osmotically active. It attracts water. It says to water in the blood compartment ... ‘come hither, mate, and dilute me’!

    Water, ever obliging, obeys. The brain ‘sucks in’ water, despite that water is coincidentally being removed by dialysis.

    Do you remember the concept of dialysis equilibration from the ‘early years’? This was (and remains) the underpinning physiological principle at work here.

    So ... during dialysis, the brain sucks water .. it .. just .. does! Your brain is slowly progressively swelling!

    Enter McIntyre!

    Enter the concept that, as blood volume falls, organ perfusion falls and oxygen delivery falls.

    Meanwhile, the brain cells are swelling around their micro-circulation, further reducing their perfusion and oxygenation ... a simple principle that Alexander Leaf [Emeritus Professor at Harvard] taught us (and me) in my Fellow years of the early-mid 1970’s ... he was a giant, was Alexanger.

    A perfect storm has been created in the brain, or what I would like to call ‘a double whammy’!!

    (1) Cell swelling, impaired perfusion, and reduced oxygen supply [Leaf] and (2) reduced blood volume with diminished perfusion pressure and reduced oxgenation [McIntyre] ... NB: another giant.

    .... and we are telling you it is just that you are ageing?

    Can we fix this?

    Well ... to a point, yes ... by slowing down the rates of change in both blood volume and in the rate of removal of urea ... not, mind you, the total solute removed, but the speed at which it is removed.

    I must sound like a broken record ...but longer, slower dialysis is the answer, for we can’t change human physiological constants like the blood/brain barrier ... certainly not now, and, likely, ever.

    But ... we can regulate the rate and dimension of change in the urea concentration ‘gradient’ from brain —> blood ... and should.

    Allowing TIME for slow diffusion is critical, yet we deploy dialysis by ‘blitzkreig’, rather than by ‘assimilation’.

    Using a smaller surface area dialyser for our nocturnals also seems to work well ... and we do that, pretty much routinely.

    So, Henning, there is your dialysis fog, in a nutshell.

    Have we researched this? ... No!

    Do we understand this any better than in the days when disequilibration was common? ... No!

    Am I embarrassed, and ashamed of myself and my colleagues on your behalf? ... Yes!

    Am I too old to make a difference? ... Absolutely!

    But ... I hope you will allow me to add this bit of physiology - or, better, dysphysiology - to your awesome blog.

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    • John Agar

      Oct 15, 2:48 PM

      As you know, there is no edit function at this blog ... and I erred ... in my previous entry, I meant to say, early on, that UNLIKE other transit surfaces where urea ‘zings’ ... at the brain/blood barrier, it dawdles’. Hence the effective retention by the brain as ‘other’ tissue an/or compartment urea concentrations fall

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  • Leong Seng Chen

    Oct 12, 5:41 PM

    I agree with Amanda Wilson though I am only for 4 years. We as a haemodialysis need to positively response & feedback into the system of medical professionals within Chronic Kidney Disease & or dialysis treatment or therapy. In Asia or South East Asia rather I believe & trust we are far behind the Western medical data as well as knowledge of research etc as we are more conservative. This is what how when where & why I am so interested in each session my own haemodialysis (HD) treatment or therapy with my variable blood pressure & the UF rate records or data as I frequently encounter stress & strain (cramp on legs & stomach) during the our standard 'one size for all' of 4 hours as normal treatment or therapy both in Singapore & Malaysia. However, we too have Nocturnal Dialysis available recently though it is also 3 times weekly. Tkans for the kind & timely sharing & prompt contribution articles! Keep up the excellent works please! Smile with CHEERS always~~~

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  • Amanda Wilson

    Oct 12, 9:11 AM

    Henning, great article. What a shame that these cognitive effects are so unrecognised and researched. I agree completely with what you are saying, but another component that could be added to this is time on dialysis. This goes even unrecognized and passed off ‘as getting old’ which I accept does come into play to. From my own experience I believe that it is more than age. Despite doing nocturnal dialysis, I am finding my thought processes are increasingly less sharp in all of the ways that you describe, and in quite a marked way over the time I have been on dialysis (15 years).

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