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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    • Henning Sondergaard

      Oct 17, 2:44 PM

      Eric,

      I will attach my reply to you from Facebook since it answers part of your issues. But let me preface that with some comments on your questions about tests and whether they are flawed. The human mind is probably even more complex than the human body. And the instruments we have to measure it are like flint tools compared to some of the instruments we have to examine the body.

      IMHO, the tests you mention are akin to taking a simple blood test, like, say, electrolytes, and trying to ascertain someone's overall bodily health from this one test.

      I try to explain but a tiny fraction of the difficulties that cognitive neuroscience are up against in the following. But you should know that even these problems are based on the minute fraction of what we know about the connection between the tissue inside our skulls and the miraculous phenomenon, called brain function and consciousness.

      I will discuss your comment on the difference between observed/anecdotal evidence vs. so-called systematic evidence at the end of this rather long reply.

      We all know how difficult studies are in dialysis for various reasons, primarily having to do with getting a proper study population. So I will not go into that here.

      Cognition studies have hampered by some of the same problems. But on top of that also by the problem of agreeing on the definition of different concepts, like memory, attention, emotion. What do they mean? How do they express themselves?

      In memory research most researchers split it up into these categories (I say 'most researchers' because this is also contested) Sensory memory (super-short memory t care less about RCTs when it comes to dialysis.

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      • Henning Sondergaard

        Oct 17, 3:01 PM

        My reply was cut off for some reason. So here's the continuation:

        Sensory memory (super-short memory less than 1 sec) - Short-term (or Working) memory - Long-term memory. Long-term is then split up into: Explicit and Implicit (conscious and subconscious) memory. A subcategory of implicit is Procedural memory (skills and tasks) Subcategories of Explicit memory are Declarative memory (facts and events), Episodic memory (experiences), and semantic memory (abstract and concrete concepts) Then we haven't even started talking about the difference between forming, maintaining, and retrieving memories.

        This makes the subject of memory loss fairly complex.

        Another problem is how we only measure things with definite endpoints. We say IQ tops in our 20s. This is true but it doesn't mean we are most skilled then. However, there is not good instruments for measuring an individual's experience. I, for one, would rather have surgery done by a middle aged surgeon than a young one in his 20s. It is common (or should we say, anecdotal?) knowledge that an experienced surgeon is better equipped to do his job than a young one. But it might be difficult to prove it.

        Then there's the large complex of executive functions and their tie-ins with emotions. Also here do we lack instruments for measuring virtually everything. I will not go into it here since it is way too complex for me to do it justice.

        So yes. The instruments we have for measuring cognitive skills are extremely crude and blunt. The way we have done cognition research on CKD patients is laughable. So no wonder we get mixed results. We are using tools we don't know how to wield, we use tiny populations and poor research designs. How can we ever expect a reasonable result?

        Now to the subject of anecdotal vs. quantitative evidence. This is one of my pet peeves, and it really has nothing to do with CKD, dialysis, or brain function... and then again... The thing I want to say is this: medicine has for nearly a century suffered from the illusion that it's a natural science and therefore it needs to use quantitative methodology, in particular the 'golden standard,' the good old RCT. The problem that time and time again ascertains to dialysis studies is that we are not able to use this methodology for various reasons that you probably know better than I do.

        In social (and human) sciences we have used qualitative measures for almost as long. And just like with the natural science methodology those measures also have their limitations. But to completely ignore a tried and true methodology while trying to press another methodology into a set-up where we all know the results are useless that is just plain stupid, if you ask me. There's a famous qoute that I think is appropriate here: "Stupidity is doing the same thing over and over again and expecting a different result."

        Going out and asking people what they think about a certain issue is a key qualitative methodology. So if we went out and asked patients, healthcare professionals, and researchers about effects of different types of dialysis in a methodical way, I think we both have an idea of what some of the answers might be. And in my book that would be far more valid than any of the hundreds of flawed quantitative studies done in this field every year.

        Granted, once we have a large enough study population and nobody tries to fiddle with the setup or any other tricks to make up for a poor study design, I am all for quantitative measures. I totally agree with John when he says he really only trusts registry studies and couldn't care less about RCTs when it comes to dialysis.

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        • Dori

          Oct 17, 9:48 PM

          See, I'd just be tempted to go with two pithy truisms: 1). Absence of evidence is not evidence of absence. And, 2). Perhaps these studies have set the ladder up against the wrong wall.

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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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    • Henning Sondergaard

      Oct 17, 3:02 PM

      John,

      When I wrote my blog post I very much felt like I was trying to solve a jigsaw puzzle where I only had a small fraction of the pieces, most of which were from the same section of the puzzle. All of them showed parts of the sky and when I was lucky a bit of the horizon.

      I struggled with my pieces and after a while I felt I had put enough of them together to let it go and send my blog to HDC. I felt like I was moving from blog writing into dissertation territory, albeit with no substantial new knowledge and therefore a rather paltry thesis.

      Then I read your comment and suddenly I see some land. You have provided me with some of the pieces that show the landscape of my puzzle. The idea or the brain swelling and not being able to get rid of the fluid fast enough for shotgun, a.k.a. thrice weekly, dialysis to remove it properly makes complete sense. This would also be why we don't see such severe effects in people doing HHD, and in particular those of us doing nocturnal.

      Of course there is still so much more to this issue. I think brain fog might be the least of our problems. The other cognitive effects, particularly on memory and concentration, that start when we're in CKD stage 4 or 5, are IMHO independent of treatment modality. They do improve drastically with better treatment options. But I don't think they go away completely. Fortunately most of us don't observe them. But if we did some studies on our loved ones they could attest to how we never become our old selves. I know because I have talked to enough of my long-time friends and to spouses when I have done my presentation on CKD and cognition - they know and we don't. I usually say, CKD is merciful in that way. We know we forget but we simply forget how much we forget.

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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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    • Henning Sondergaard

      Oct 17, 2:01 PM

      Amanda,
      I am sure the longer you live with ESRD the more prevalent some of the symptoms are. Like I said in the blog post, I am not sure it's the dialysis as much as it's the kidney disease doing this to us. Many I have talked to over the years (particularly home patients) feel that the greatest effects on their mental faculties were before they started dialysis. And that some of it went away with increased treatment.
      As for 'the age thing,' here's my story: About 10 years ago some time before I started dialysis I told my neph I had problems with concentration and memory. He sort of laughed at me and pretty much told me it might be age related. I was in my early 40's at the time so needless to say I got pretty miffed. That incident was what started me on the journey of finding out about the effects of CKD on the brain which I have pursued on and off (mostly off) for all that time.

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