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Dr. Gord Boyd

“Visuospatial and executive impairments in patients with acute and chronic kidney disease” - Dr. Gord Boyd

James King, MSc Candidate (TMED)

Last week’s Medical Grand Rounds welcomed Dr. Gord Boyd, an associate professor in the Department of Medicine and clinician-scientist practicing neurology and critical care medicine. Dr. Boyd presented on the connection between visuospatial and executive impairments to chronic and acute kidney disease (CKD and AKD, respectively). Afterwards, he sat down with the students of TMED801 to discuss how his research can benefit patients, the press’ representation of similar topics, and his career path.

 

Rounds initially focused on the high prevalence of cognitive impairments (CIs) in patients with CKD (1). Dr. Boyd explained that most CI tests conducted on CKD patients relied on dementia screening tools, including the Mini-Mental State Examination (MMSE), where pre-dialysis and hemodialysis (HD) patients score significantly worse than non-CKD controls (1). However, Dr. Boyd outlined a need to more accurately quantify rates of CKD-associated CI.

 

Dr. Boyd’s research group employed the Kinarm robot, a device that objectively and quantitatively assesses cognitive function, with the goal of identifying patients with CIs that may be missed by traditional examinations. The Kinarm characterized more CKD patients as having CIs (especially in areas of perceptual-motor function, executive function, and complex attention) compared to a traditional clinical measure of various aspects of cognition (2). Dr. Boyd also convincingly showed that neurological consequences of AKD exist. In a small cohort study of mostly AKD patients, the Kinarm identified 48%, 50%, and 52% of AKD patients with visuomotor, attention, and executive function deficits, respectively (3).

 

Dr. Boyd also discussed several examples of translational research that help to elucidate mechanisms underlying CKD-associated CI. Microhemorrhages were 2.0-2.5 times higher in a mouse model of CKD compared to healthy mice, and the CKD mice showed evidence of increased blood-brain barrier permeability (4). There is also evidence that white matter dysfunction and ventricular enlargement may mediate CKD-associated CIs (5). Furthermore, autopsies of CKD patients showed increased ischemic infarcts (blocked arteries that supply blood to the brain), and this was associated with both large artery atherosclerosis and arteriosclerosis, further pointing to CKD-associated CI as a cerebrovascular (blood vessel and blood flow in the brain)-mediated phenomenon (6).

 

Dr. Boyd also showed several pieces of evidence demonstrating that CKD patients on dialysis experience various worsening CI symptoms. CKD patients that transitioned to HD (from no dialysis) experienced a significant decline in executive function, but no significant change in memory or global cognition (7). HD results in changes to blood flow and function of blood vessels, including intradialytic hypotension (8). Increased HD sessions with intradialytic hypotension were associated with reduced white matter and hippocampal volume, and these patients had lower MMSE scores (8). Patients on HD also performed worse on a test of cerebrovascular function compared to those CKD patients not undergoing HD, which points to a mechanism involving recurrent HD-induced ischemia (decreased blood flow) (9). This work showed that CKD patient’s cerebral blood vessels may have trouble dilating in states of low blood pressure, which can lead to brain damage. One new development that Dr. Boyd believes could lead to improvements in patient care is the use of cooler dialysate during HD which may increase the stability of blood flow and reduce HD-induced ischemia (10). His future research will investigate cerebral oxygenation in patients undergoing HD and attempt to correlate this with long-term cognitive function and brain pathology (11).

 

In the conversation following Rounds, Dr. Boyd’s long and arduous path to becoming a clinician-scientist stood out. Specifically, Dr. Boyd emphasized his background in neurology and critical care as an asset to his career success and of great benefit to his patients. He also provided excellent insight into daily life as a clinician-scientist.

 

There are several ways that last week’s Rounds apply to the practice of translational medicine and to patient care. Dr. Boyd’s observation of a problem in the clinical setting (underdiagnosing cognitive dysfunction in CKD patients) and subsequent employment of human research to fill this gap, is an excellent example of applying principles of translational medicine that could ultimately lead to improved diagnostics and patient care. Additionally, he emphasized the importance of operationalization and providing objective measurements in the research process. The discussion of mechanisms outlined the importance of biomedical research to the practice of translational medicine, as well. Moreover, the discussion of the perils of HD demonstrated that various translational approaches exist to assessing the same issue, a perspective that can be applied to the study of other diseases.

 

On behalf of the TMED801 class, I would like to thank Dr. Boyd for his excellent presentation and discussion.

 

Works Cited

  1. Vanderlinden, J. A., Ross-White, A., Holden, R., Shamseddin, M. K., Day, A., and Boyd, J. G. (2019). Quantifying cognitive dysfunction across the spectrum of end-stage kidney disease: a systematic review and analysis. Nephrol 24: 5-16.
  2. Vanderlinden, J. A., Holden, R. M., Scott, S. H., and Boyd, J. G. (2021). Robotic technology quantifies novel  perceptual-motor impairments in patients with chronic kidney disease. J Nephrol 34: 1243-1256.
  3. Vanderlinden, J. A., Semrau, J. S., Silver, S. A., Holden, R. M., Scott, S. H., and Boyd, J. G. (2021). Acute kidney injury is associated with subtle but quantifiable neurocognitive impairments. Nephrol Dial Transplant: 1-13.
  4. Lau, W. L., Nunes, A. C. F., Vasilevko, V., Floriolli, D., Lertpanit, L., Savoj, J., Bangash, M., Yao, Z., Shah, K., Naqvi, S., Paganini-Hill, A., Vaziri, N. D., Cribbs, D. H., and Fisher, M. (2020). Chronic kidney disease increases cerebral microbleeds in mouse and man. Trans Str Res 11: 122-134.
  5. Vemuri, P., Davey, C., Johansen, K. L., Zuk, S. M., Reid, R. I., Thostenson, K. B., Reddy, A. L., Jack, C. R., Knopman, D. S., and Murray, A. M. (2021). Chronic kidney disease associated with worsening white matter disease and ventricular enlargement.  J Alzheimers Dis: Pre-press.
  6. Vinters, H. V., Magaki, S. D., Williams, C. K. (2021). Neuropathological findings in chronic kidney disease (CKD). J Str Cerebrovas Dis 30(9): 105657.
  7. Tamura, M. K., Vittinghoff, E., Hsu, C. Y., Tam, K., Seliger, S. L., Sozio, S., Fischer, M., Chen, J., Lustigova, E., Strauss, L., Deo, R., Go, A. S., and Yaffe, K. (2017). Loss of executive function after dialysis initiation in adults with chronic kidney disease. Kidney Internat 91: 948-953.
  8. Cedêno, S., Desco, M., Aleman, Y., Macías, N., Fernández-Pena, A., Vega, A., Abad, S., and López-Gómez, J. M. (2021). Intradialytic hypotension and relationship with cognitive function and brain morphometry. Clin Kidn Jour 14: 1156-1164.
  9. Slessarev, M., Mahmoud, O., Albakr, R., Dorie, J., Tamasi, T., McIntyre, C. W. (2021). Hemodialysis patients have impaired cerebrovascular reactivity to CO2 compared to chronic kidney disease patients and healthy controls: a pilot study. Clin Res 6(7): 1868-1877.
  10. Eldehni, M. T., Odudu, A., and McIntyre, C. W. (2015). Randomized clinical trial of dialysate cooling and effects on brain white matter. J Am Soc Nephrol 26: 957-965.
  11. Jawa, N. A., Holden, R. M., Silver, S. A., Scott, S. H., Day, A. G., Norman, P. A., Kwan, B. Y. M., Maslove, D. M., Muscedere, J. Boyd, J. G. (2021). Identifying neurocognitive outcomes and cerebral oxygenation in criticall ill adults on acute kidney replacement therapy in the intensive care unit: the INCOGNITO-AKI study protocol. BMJ Open 11: e049250.

Comments

Name
Sophia Linton

Mon, 09/20/2021 - 12:14

Well done James.

Something we discussed in the post-round discussion was the impact of cognitive impairments in CKD on mental health.

Has anyone found any studies looking at mental health (anxiety, depression etc.,) in CKD patients?

Thanks,

Sophia

Name
Sophia Linton

Hi Sophia,
Thank you for the question.
There have been a number of studies looking at mental health in CKD patients. I found this narrative review by Shirazian and colleagues (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720531/) to be particularly helpful as a starting point when looking at this topic. I really liked how this review looked at differences between CKD patients, and those on dialysis, as I found the effects of dialysis to be of particular interest during the discussion!
Best,
James

Name
James King

Name
Kiera Liblik

Mon, 09/20/2021 - 13:27

Dear James,

Thank you for an interesting discussion post on Dr. Boyd's presentation last week. Additionally, the sources you provided give excellent background to a complex topic! Our discussions on neurological and quality of life implications of dialysis were an important reminder that many medical interventions, while helpful, can have negative implications for patients. Furthermore, the mention of post-intensive care syndrome (PICS) underscored the crucial role of physicians in supporting the mental health of their patients following traumatic health events.

Although psychiatrists are specially trained to support mental health, I wonder if there is value in increasing the degree of psychiatric training for all medical specialties? I can imagine scenarios in every patient population in which psychiatric training may help with patient care, follow-up, and even difficult conversations with their family members. Do you think that this type of training could help in the context of this dialysis population or overall in medicine? Or do you think the increased resources/time needed for such training does not justify its existence when trained counsellors and psychiatrists specialize in this area?

Once again, excellent job!
Kiera

Name
Kiera Liblik

Hi Kiera,
Thank you for your comment. I completely agree that the discussion of mental health is an important one, and surely physician training in this area would be helpful in dealing with patients experiencing mental health crises, regardless of the physician's primary specialty. I found one study that suggested what I believe would be a feasible strategy for getting physicians further mental health training. The study found that weekly training for 6 weeks, had a significant impact on mental health knowledge, attitudes, and self-efficacy scores in the short-term, and that this was sustained 18 months after training (Spagnolo et al., 2020). Furthermore, the primary care physicians that were trained reported lower referral rates to mental health specialists 18 months after training, compared to before undergoing training. Hopefully, further mental health training can lead to better patient outcomes! Ultimately, it is of course important to have specialists in every field for more complex cases, however, I think physicians generally have an important role in recognizing and helping to treat mental health issues with their patients. Please let me know if you have found any interesting studies regarding mental health training for physicians.
Best,
James
https://pubmed.ncbi.nlm.nih.gov/31794027/

Name
James King

Dear James,
Thank you for linking that study! It's excellent to see that literature to support better mental health training in physicians is emerging. That study was conducted in Tunisia - I wonder what results the same study in Canada would produce. Perhaps an opportunity for a future TMED student!

Kiera

Name
Kiera Liblik

Hi Kiera,

You’ve raised some interesting points. Considering the biopsychosocial model, there exists an interplay between genetics, mental health and behaviour, and one's sociocultural context in health and disease. I see merit in all specialties having some psychiatric training, such that physicians are able to recognize when a case requires specialized mental health care at which point they may refer patients to a trained counsellor or psychiatrist. Perhaps a tiered, multidisciplinary system of care, as is often the case, may be more supportive for both patients and healthcare professionals. Nurses are also crucial in this scheme, as they are liaisons between patients and their families and other healthcare professionals. In the context of the ICU, critical care nurses play a pivotal role in providing specialized care and in supporting post-ICU follow-up services for patients.

Great questions, and thanks for your insights!

Lubnaa

Name
Lubnaa Hossenbaccus

Thank you, Kiera, for bringing up an interesting solution! I think having more mental health training for physicians would yield many benefits not only in the ICU, but in other fields as well. I think it would be most efficient to implement psychiatric training specific for major health events during medical school so that the skills learned could be employed throughout learner's clerkships, residencies, and beyond.

The speaker's unique role inspired another possible way to address mental health after critical care. Perhaps a psychiatrist could be cross-appointed between critical care and psychiatry, similar to how Dr. Boyd specialized in critical care neurology. This would allow for highly niche research and care to take place in an environment where we know mental health is one of the most foremost concerns after a patient's physical health is stabilized.

Lastly, I think it is important to remember the role of nurses, counselors, and social workers in this situation, as you mentioned in your post! These professionals could be highly competent in psychiatry and psychology as well as critical care, so maybe appointing someone with a background in one of those fields to work specifically with patients leaving the ICU would be an efficient and helpful innovation. This role might already exist, but from what Dr. Boyd mentioned about the rates of regret for being saved, I feel that it is still an area that could be improved upon.

Excellent work!
Georgia

Name
Georgia Kersche

Name
Lubnaa Hossenbaccus

Mon, 09/20/2021 - 14:56

Hi James,

I enjoyed reading your summary of Dr. Boyd’s talk. You did a wonderful job highlighting the key points that were discussed.

Something that really stood out to me, that you pointed out in your summary, was the effectiveness of the Kinarm at evaluating cognitive function compared to conventional assessment methods. It appears to be a more precise, yet non-invasive method. While I understand that the Kinarm is still in its research phase, it already appears to have interesting clinical potential, which leads me to wonder what it takes for a technique to become standard of care. I am also curious if the Kinarm may allow for more targeted management of cognitive impairments, as it can distinguish between visuomotor, attention, and executive function deficits in patients with AKD, as you mentioned.

In what ways do you think technology has the potential to impact the field of medicine?

Look forward to hearing your thoughts,

Lubnaa

Name
Lubnaa Hossenbaccus

Hi Lubnaa,
Thank you so much for your thoughtful comment. I certainly think that technology has the potential to completely revolutionize the practice of medicine, however, I believe there will always be a role for humans. One area of technological innovation in the medical field that already is having an impact is artificial intelligence. I found this paper interesting (https://pubmed.ncbi.nlm.nih.gov/28182259/), it looks at how algorithms have been employed to search large medical databases. I definitely think this is an area that as artificial intelligence develops, its usefulness will increase. I could imagine physicians implementing artificial intelligence when it comes to complex medical case diagnoses and treatments, and the ability to more efficiently search medical databases would be very useful. Do you think there are any potential drawbacks to the increased implementation of technology in the field of medicine?
Best,
James

Name
James King

Hi James,

Thanks for your thoughts - I agree that AI has potential in medicine. As much as technology is useful, when it fails it can be problematic, which could perhaps be one of the drawbacks of its increased use. There are also ethical and socioeconomic considerations in the implementation of technological tools, such as accessibility of such resources, which may perpetuate pre-existing inequities.

Lubnaa

Name
Lubnaa Hossenbaccus

Name
Nolan Breault

Mon, 09/20/2021 - 15:59

Hi James,

Nice job on completing the first student-led discussion! Something I noticed & that you voiced during the session was a difficulty for our group to stay on-track with questions which pertained to mainstream media's representation of the topic. I think this difficulty was very much for good reason.

Traditional explorations into the world of health science by mainstream media are most commonly for the diseases we're all familiar with - cancer, cardiovascular disease, depression, Alzheimer's, etc. Less often, there may be a segment on something more specialized or cutting edge, such as when gene therapy & CRISPR were making headlines a few years ago. But it's rare to see full pieces dedicated to the interplay between disease states, especially when an illness outside of the average person's realm of understanding, like chronic kidney disease/acute kidney injury, is involved. Browsing the "News" results from a Google search, the most recent piece with both CKD & cognitive decline in the headline that wasn't explicitly from a scientific journal (though still intended for a medically-savvy audience) is from early May of this year (1). Kidney disease is exceptionally common, with a meta analysis for the estimated prevalence in the global population being 11-13% (2). Despite this, little information on the cognitive impacts of the disease reaches the lay population, potentially leaving early symptoms of such decline unnoticed by a patient's family members/close friends.

What I'm wondering is how you think the findings of Dr. Boyd's & other labs could be best brought into the realm of public knowledge, and how the medical community in general can make complex, yet important information like we learned in Grand Rounds more accessible to the lay learner (via radio interviews such that the work is delivered conversationally? working more closely with public health units to disseminate findings?).

Looking forward to your thoughts,

Nolan

Referenced works
(1) https://www.healio.com/news/neurology/20210505/dementia-risk-increases-…
(2) Hill, N., Fatoba, S., Oke, J., Hirst, J., O'Callaghan, C., Lasserson, D., and Hobbs, F. (2016) Global Prevalence of Chronic Kidney Disease - A Systematic Review and Meta Analysis. PLoS One 11(7): e0158765.

Name
Nolan Breault

Hi Nolan,
Thank you for taking the time to contribute to the discussion. I think you make a very astute observation regarding the limited awareness and promotion of certain scientific issues. Admittedly, in a world where the news is dominated by the newest information surrounding COVID-19, it can be difficult to get the public to focus on other health/medicine/research-related news. Nonetheless, increased public awareness of medical research could lead to better funding in the future, and greater compassion towards important issues. In my personal experience, I have raised awareness for organ and tissue donation through a student run club. I think that getting involved at the local level really is a great way that anyone can bring awareness to important medical information and causes without requiring a large platform. An especially useful way of promoting life-long interest in science, in my opinion, is doing presentations in schools. Additionally, I wonder what impact social media services have in capturing the public's attention on science topics. Furthermore, podcasts can be a fantastic way of getting information out to the public, however, there may be some level of bias towards individual personal interests when it comes to selecting what to listen to. Do you think that the answer lies in concise and exciting scientific explanations that could be seen on TV for example, or long-form deep-dive looks at science, such as podcasts?
Best,
James

Name
James King

Hi Nolan and James,

Thank you, James, for leading a really interesting and enjoyable discussion last week!

When searching for chronic kidney disease and dementia in the news, I also found very few news articles that investigated the intersection of these two diseases. I came across a similar article as you did, Nolan, which gave a fantastic summary of a new study out of Sweden looking at the association between kidney function and risk of dementia (1). However, this article was also written with quite a lot of medical and research terminology, likely making it inaccessible to the general public.

As for your question about how to better translate medical research into interesting, accessible content for the public, I think that news articles are still a fundamental part of how adults consume media, especially for age groups who may not be on social media as much. In addition, a news article, or podcast, can provide more information and therefore a bit more nuance than what’s possible in a social media post. However, in my experience, sometimes news articles can misinterpret or misrepresent scientific findings. For example, the headline “Are smartphones making us STUPID?” is inaccurate considering the study the article examined was a preliminary, correlational study (2). Therefore, I don’t think relying on news writers alone is enough when scientists aim to share their findings with the public, as it’s important to be accurate to avoid mistrust and misinformation about science. Perhaps when publishing their research, scientists may want to write their own short summary of the research, targeted towards the general public. This could be released in a university press release or newsletter.

I also agree with James’s opinion that a love for science can often be developed while kids are in school – my favorite classes in middle school was science class, especially when we watched Bill Nye explain the content. I wonder if a similar series of videos could be made but focused on new research and explaining it to the level of middle or high schoolers?

News articles
1.https://www.technologynetworks.com/neuroscience/news/dementia-linked-to…
2.https://www.vox.com/science-and-health/2019/6/11/18652225/hype-science-…

Name
Samantha Ables

Hey James,

Thanks for the response! I think that even with "simple" concepts, increasing the scientific literacy of the public is a very multifaceted process and ties in with some big-ticket issues in media consumption.

Science is meant to be the closest approximation to objectivity that humans can achieve (still very iterative!), but throughout the pipeline of benchwork to publication to dissemination, there's plenty of opportunity for subjectivity and bias to enter. Depending on who, say, analyzes a set of data, reads/interprets a paper, or produces a TV special for a piece of work, different features may be emphasized or the story may change ever so slightly. This is inherent & not necessarily a bad thing, as it opens the door to critique and peer review, thus creating new questions and further refining our collective understanding of a concept.

For better or worse, misinformation has taken a central position in the public eye when it comes to science or otherwise, and with it, distrust. Even from reputable sources, there comes the challenge of delivering information in a friendly and digestible manner. I think you're right in pointing out the effectiveness of introducing scientific inquiry to children, whether it be in school or through TV programming. Some of the most impactful influences I've personally had in developing my interest in a scientific education came from shows on Discovery Channel like Mythbusters and Daily Planet. I think good deliveries of science are made through identifying something relatable to the average person and using that to show the impact of what you're discussing (ex. A podcast or TV episode about metabolism might start with describing/showing a soccer game and honing in on "the burn" from running before talking about lactic acid and where it comes from).

What Dr. Boyd said about communication is something I value a lot. Depending on how one speaks, the same message can come across wildly different, and so I ultimately think to improve scientific understanding, scientists/educators need to come across as confident, but also gentle and enthusiastic. Making science palatable to people in a variety of forms (children's books, podcasts, etc.) can really spark a self-sustaining curiosity. The key is getting the ball rolling for as many people as possible.

Cheers,

Nolan

Name
Nolan Breault

Name
Kyla

Mon, 09/20/2021 - 17:50

Hi James,

I wanted to start off by saying great job facilitating this discussion. You did a wonderful job and that allowed us all to dive into the cool research that Dr. Boyd and is team is doing.

I find the topic of cognitive impairments with chronic kidney disease fascinating. When thinking about kidney disease your mind doesn’t jump towards cognitive impairments, in fact, it almost seems the two wouldn’t have a connection at all. My hypothesis at the start of this lecture was leaning towards a secondary co-infection which may cause the neurological complication. However, as we continued, I began to think more along the lines of epigenetics and the potential for DNA methylation causing oxidative stress. I have found an interesting paper that reviewed the potential interaction between CKD and gene expression leading to cognitive impairments, but this still remains unknown [1]. It’s just so fascinating how two, seemingly different disorders, are linked by some unknown interaction. I’m curious what was your original hypothesis? And did it differ as Dr. Boyd continued his talk?

Thanks again James,
And thank you Dr. Boyd for the amazing talk!

Kyla

Reference:
[1] Ingrosso D, Perna AF. DNA Methylation Dysfunction in Chronic Kidney Disease. Genes. 2020; 11(7):811. https://doi.org/10.3390/genes11070811

Name
Kyla

Kyla, 

Thanks for sharing. 

I was also wondering the same thing. What comes first, the chicken or the egg? My hypothesis was similar to yours, and several of our classmates, in that there must be a biochemical pathway at play. 

As we learned, cerebrovascular disease is likely the predominant pathology underlying these associations. However, impaired clearance of uremic metabolites, depression, sleep disturbance, anemia, and polypharmacy may also contribute.

Can anyone speak to translatability of these findings? Will cognitive impairments in CKD make it to the clinic?

Name
Sophia

Hi Kyla and Sophia,

Great question. I was also surprised to learn how CKD impacts the brain, as well. When I heard Dr. Boyd’s training was in neurology, I asked myself, “why is he doing kidney research?.” At the start of the lecture, my hypothesis from the background readings involved biochemical pathways where metabolic and hemodynamic changes impact other organs such as the heart and brain (1). Factors such as perfusion and/or changes in the blood-brain barrier permeability increased albumin or other compounds, and the kidney may have a protective effect in preserving cognitive function (2). Following the lecture, I do not think there is a firm answer, and it is likely a multitude of factors between CKD and cognitive factors, as Sophia mentioned.

From the literature, I think there is a growing awareness that CKD patients are at a higher risk of developing cognitive impairments and mental illness, namely, depression (which also have a 30% overlap Dr. Boyd mentioned). Controlling for cardiovascular disease (CVD) risk factors may have some benefits like it does for the general population, pharmacotherapy to target biochemical pathways involved in the disease pathophysiology such ACE inhibitors, screening for cognitive impairments using screening tools may help prevent and identify patients with CKD and cognitive impairment. Treatment strategies inlude avoiding sedating medications and polypharmacy, improving sleep hygiene, strengthening family and social support, treating depression, and encouraging mental stimulation and exercise (3). Many of these rely heavily on patient behaviours for improvement, which may be challenging in real-world settings.

Michna M, Kovarova L, Valerianova A, Malikova H, Weichet J, Malik J. Review of the structural and functional brain changes associated with chronic kidney disease. Physiological Research. 2020 Dec 1;69(6).
Viggiano D, Wagner CA, Martino G, Nedergaard M, Zoccali C, Unwin R, Capasso G. Mechanisms of cognitive dysfunction in CKD. Nature Reviews Nephrology. 2020 Aug;16(8):452-69.
Drew DA, Weiner DE, Sarnak MJ. Cognitive impairment in CKD: pathophysiology, management, and prevention. American Journal of Kidney Diseases. 2019 Dec 1;74(6):782-90.

Name
Alyssa Burrows

Hi Kyla,
Thank you for this thoughtful comment.
My original hypothesis (without reading the pre-MGR review papers we were assigned) was that kidney dysfunction would result in an increase in a particular metabolite (that was normally filtered and excreted in healthy individuals) that could cross the blood-brain barrier and damage the brain (please excuse my lack of mechanistic detail). Throughout the talk, I found Dr. Boyd's explanation of cerebrovascular changes resulting in neurological damage to be quite convincing. I'm sure like many complex conditions, there are a multitude of factors at work in the pathogenesis of cognitive impairments in CKD patients. I'm curious, to what degree do you believe a researcher's (or physician's) background biases their hypotheses? For example, my background in neuroscience may increase my propensity to look for neurological explanations to phenomena.
Best,
James

Name
James King

Name
Emmanuel Fagbola

Tue, 09/21/2021 - 00:14

Hey James,

Thank you for your exceptional summary concerning Dr. Boyd's presentation at last week's Medical Grand Rounds.

The link between chronic and acute kidney disease-associated cognitive impairment is interesting as there appear to be endless risk factors and potential culprits in the association between the two. These factors seem to span topics from patient biochemistry to the effects of traumatic experiences on the brain.

Furthermore, every individual is quite different: one's propensity to develop CDK-associated CI very much depends on another level of diverse factors that make each one of us unique. Thus, the concept of precision medicine also seems to apply.

In a field like this, where many risk factors contribute to CDK-associated CI, how important do you think review articles are? Do review articles become just as important as primary literature in ensuring that researchers work efficiently to advancing knowledge in the field using the work of others in the past? I would love to hear anyone's thoughts on this.

Once again, this was indeed a well-written synopsis of the talk's key points!

Emmanuel

Name
Emmanuel Fagbola

Hi Emmanuel,
Thank you for taking the time to contribute to the discussion. I think this is an important issue that you bring up. Regarding the importance of review papers in rapidly advancing areas of research such as CKD-associated cognitive impairments, I think they are vital to the development of new research hypotheses. A properly functioning review paper synthesizes all (or the most important) knowledge in a current research area, and importantly identifies gaps in the current knowledge. This allows researchers to conduct work to fill those gaps, as well as forming new hypotheses based on existing data. However, as was mentioned in our TMED802 class, there is also a problem with unnecessary reviews. Thus a delicate balance exists between access to information and wasting one's time reading or writing unnecessary review papers that do not contribute anything new to the conversation.
Additionally, to touch on your second question, I think primary literature is vital and more important than review papers. I think this because review papers do not exist without primary literature, however, primary literature would exist without review papers. That being said, I am not trying to say that reviews are unimportant, and I take your question to deserve greater nuance than how I have answered it.
I'm curious if you thought of any other important reasons for review papers in the kind of research area discussed in the blog post?
Best,
James

Name
James King

Hi Emmanuel,

This is a really interesting question you’ve asked and I’d love to hear what you and others think!

When reading the review articles last week, I had the same thought: that it looks like there are a million risk factors and potential mechanisms for the association between dementia and chronic and acute kidney disease. I think that review articles are incredibly important for a topic where there are a variety of associations and possible mechanisms, so that researchers investigating one avenue don’t lose sight of the other factors involved in the disease. This brings me to a point Dr. Archer made in TMED 800 this morning, about the blind men and the elephant - that in the research for pulmonary arterial hypertension, different research groups each viewed the disease as having a different basis, for example vasoconstriction, which led to the creation of drugs that don’t target the underlying cause of the disease and therefore aren’t curative. Review articles can be a potential solution to this problem. By bringing together all of the possible mechanisms and associations related to the disease, a review article may help a researcher integrate findings and mechanisms they hadn’t previously considered into their research.

Samantha

Name
Samantha Ables

Name
Bethany Wilken

Tue, 09/21/2021 - 12:07

Hi James,

Thank you so much for leading an engaging discussion with Dr. Boyd and for posting an excellent critical report on the topic of visuospatial and executive impairments due to kidney disease. I really enjoyed the Grand Rounds topic and I think we can all agree that Dr. Boyd gave an outstanding presentation. We were very lucky to have the opportunity to have a more intimate discussion about his research and career afterwards. The passion he has for both his work as a physician and his research endeavours is reflected in all interactions and is particularly inspiring. One of the things that really stuck with me from his presentation is how he mentioned seeing his patients after their time in the ICU and how many of them were not doing well mentally, to the point where some wish he had not saved them. I can’t imagine how hard that would be for a physician to hear and I applaud Dr. Boyd for his positive morale. Fellow classmates have discussed the mental health implications of ICU stays and possible solutions so I will not dwell on this topic.

I would like to start a conversation instead focusing on the first pillar of our discussion, how this topic can benefit patients. We currently know there is a huge hurdle to diagnosing these cognitive impairments in patients with kidney disease. The traditional MMSE is not a reliable tool in recognizing visuospatial and executive impairments. I do believe the Kinarm robot can have a substantial impact on precisely identifying cognitive impairments but its implementation into clinical settings could be challenging due to costs and other factors. Say Kinarm robots are commonly used in the clinical setting to diagnosis kidney disease patients with cognitive impairments, this then raises the question what can we do to help these patients? Stopping dialysis is not reasonable, so do we focus efforts on changing principles of dialysis that are linked to mechanisms of cognitive decline or do we focus on developing drugs or other interventions that treat visuospatial and executive impairments after they have developed? Dr. Boyd mentioned the improvements that have resulted from using cool dialysate which supports my opinion that it would be best to try and intervene before the problem (cognitive impairments) begins. However, maybe in researching drugs and other interventions for visuospatial and executive impairments we could develop something that is applicable to other neurological disease. Does anyone have thoughts on this?

Thanks again to James and Dr. Boyd!

Best,
Bethany

Name
Bethany Wilken

Name
Cassie Brand

Wed, 09/22/2021 - 09:42

In reply to by Bethany Wilken (not verified)

Hi Bethany,

These are some very interesting points you made. I too was intrigued by the KINARM and think that its use in clinical settings could be extremely beneficial. However, as it is only being used for research right now, I unfortunately think this might take a lot to bring it into clinic due to associated costs and training. Perhaps "proving" that earlier and more accurate diagnosis of the type and degree of cognitive impairment, facilitated by the KINARM, improves treatment and patient outcome would help with start the transition from using the MMSE to the KINARM.
Regarding your point about possibly changing our focus to developing new drugs specifically for visuospatial and executive impairments, I think this brings us back to the "chicken or egg" paradox as discussed earlier in the blog. Is the cognitive impairment a result of CKD or vice versa? Perhaps really focusing on the underlaying mechanisms which connect the two could help lead to the development of a therapy. instead of researhing drugs that could potentially apply to other neurological diseases, I think it also might be worthwhile to look at current therapeutics for visuospatial and executive impairments and conduct studies on their use for CDK associated cognitive impairments. Due to their already marketed status, this would save on trial costs and speed up the process of using these therapeutics, provided that the research is successful.

Thanks!
Cassie

Name
Cassie Brand

Hi Cassie,
Thank you for your interest in my post. I agree that investigating the underlying mechanisms could help the development of therapies and may prove to hold insights into cognitive impairments with other chronic illness, perhaps a common denominator linked to mental health. I also like your suggestion of applying current therapeutics to overcome costs and the extended duration of clinical trials. Did you have any ideas on how dialysis treatments could be improved to lessen cognitive impairments or do you think knowledge of the underlying mechanism is required first before altering dialysis?

Best,
Bethany

Name
Bethany Wilken

Name
Trinity Vey

Tue, 09/21/2021 - 12:12

Hi James,

I first want to commend you on a very well-facilitated discussion and an excellent blog post! The level of detail you included in the blog prompted me to think further about many of the things we discussed with Dr. Boyd. I would also like to thank Dr. Boyd specifically for a very interesting grand rounds and for taking the time to engage with us in the discussion! Something from Dr. Boyd’s talk and James’ post that has caught my attention was the concept of employing a cooler dialysate during hemodialysis. It is absolutely fascinating that a slight change to dialysate conditions, 0.5°C below body temperature, has been associated with protection against hemodialysis-associated brain injury (1).

This innovative finding, (an excellent example of translational research) prompted me to wonder if perhaps small changes to the actual composition of dialysate could lead to improved outcomes as well? While researching dialysate, I learned that it typically includes sodium, calcium, magnesium, and bicarbonate concentrations, however, the “optimal dialysate” seems to remain up for debate (2). Furthermore, appropriate glucose concentrations are a large consideration for patients with diabetic comorbidities, and even water quality can be taken into account (2).

A common recurrence in our TMED courses is the idea of personalized medicine. While it seems that physicians do alter dialysate ion concentrations within a given range, I wonder if using a dialysate that is even more “personalized” in terms of both composition and temperature (based on a patient’s baseline physiology and additional comorbidities) could lead to further protection, specifically against cognitive outcomes? Perhaps a small group of individuals would benefit further from even cooler dialysate than what has been tested so far. We also discussed neurotoxins potentially implicated in CKD-associated cognitive impairment – perhaps it may be possible to further alter dialysate composition in a way to directly protect against these? I wonder if this is feasible given the time, resources, and cost that might be required.

Thank you again for your insightful blog post, I have enjoyed reading everyone’s comments thus far!

Trinity

1. Eldehni, Mohamed T et al. “Randomized clinical trial of dialysate cooling and effects on brain white matter.” Journal of the American Society of Nephrology : JASN vol. 26,4 (2015): 957-65. doi:10.1681/ASN.2013101086

2. Locatelli, Francesco et al. “Optimizing haemodialysate composition.” Clinical kidney journal vol. 8,5 (2015): 580-9. doi:10.1093/ckj/sfv057

Name
Trinity Vey

Name
James King

Wed, 09/22/2021 - 20:35

In reply to by Trinity Vey (not verified)

Hi Trinity,
Thank you for this comment. I think this is an excellent insight regarding the potential for personalized medicine. Furthermore, I think there is great potential for taking translational approaches to personalized medicine. For example, today I attended Dr. Mulder's DBMS seminar presentation which discussed the role of computational and molecular biology for inflammatory bowel disease (IBD) research. He was able to employ a "bench-to-bedside-to-bench-to-bedside" approach to diagnose and treat a rare monogenetic case of IBD (https://www.nature.com/articles/s41588-021-00803-4). I think this is really a fantastic example of translational medicine at work. I'd encourage everyone to give it a read!
Best,
James

Name
James King

Name
Alyssa Burrows

Tue, 09/21/2021 - 12:57

Great post James,

I think a great example of translational medicine that I gathered from the lecture is the shift towards a change in the dialysate temperature, which has been found to have better outcomes. As you are aware, many patients with CKD need hemodialysis (HD) to filter and remove excess water and compounds from the blood. Dizziness, weakness, nausea and fatigue are adverse side effects frequently encountered by patients undergoing HD. The standard of care for dialysate temperature is 37 C, which the body temperature increases throughout the course of therapy. Decreasing the dialysate temperature may potentially help with hemostability, incidences of intradialytic hypotension (IDH), and adverse side effects (1, 2). No studies have identified long-term outcomes such as death or heart disorders. Although much more research is needed on this to determine outcomes more, concretely. Cooler dialysate temperature is potentially beneficial to diabetic patients (3-study on n=32, ESRD caused by diabetes, dialysis fluid 36 degrees C).

This leads me to ask, how much evidence is needed to make changes to the standard of care? And eventually, could aspects of personalized medicine come into play here where a patient’s stage of disease, age, sex, genetic profile etc. Could these factors determine what the optimal temperature for their HD dialysate therapy is?

I am looking forward to hearing your thoughts!

-Alyssa

1) Tsujimoto Y, Tsujimoto H, Nakata Y, Kataoka Y, Kimachi M, Shimizu S, Ikenoue T, Fukuma S, Yamamoto Y, Fukuhara S. Dialysate temperature reduction for intradialytic hypotension for people with chronic kidney disease requiring haemodialysis. Cochrane Database of Systematic Reviews. 2019(7).

2) Roumelioti ME, Unruh ML. Lower dialysate temperature in hemodialysis: is it a cool idea?.

3) Sarbaz H, Kiyani F, Keikhaei A, Bouya S. The Effect of Reduced Dialysate Temperature on Dialysis Adequacy of Diabetic Patients (A Clinical Trial Study). Medical-Surgical Nursing Journal. 2019 Feb 28;8(1).

Name
Alyssa Burrows

Thanks for the great discussion, James, and thank you to Dr. Boyd for sharing your fascinating research with us. I was also quite intrigued by the idea of a cooler dialysate, and what other opportunities there are to modify hemodialysis so that it can be optimally functional and minimally harmful to each patient. Considering all of the factors that Dr. Boyd mentioned in his lecture, along with other factors that are known to be involved in both kidney health and brain health, there's a huge range of research opportunities to dive into personalizing treatments. For example, oxidative stress and the renin-angiotensin system are factors involved in the risk of cognitive challenges in CKD patients (1), yet the relationship between the condition, these risk factors and the standard treatment is unclear. As we begin to understand how the hemodialysis treatment is involved in each of these key factors that lead to cognitive impairments, we can begin to tailor treatments more specifically.

Tsuruya K, Yoshida H. Brain Atrophy and Cognitive Impairment in Chronic Kidney Disease. Contrib Nephrol. 2018;196:27-36. doi: 10.1159/000485694. Epub 2018 Jul 24. PMID: 30041201.

Name
Katie Lindale

Name
Pierce Colpman

Wed, 09/22/2021 - 10:35

Hi James, firstly I wanted to start this off by saying you did a really good job with your role as facilitator. I thought that you really allowed Dr. Boyd the floor while also keeping everyone on track and within the key topics brought up during the presentation, great job!

One thing I wondered when listening to Dr. Boyd speak about how the Kinarm robot can identify disease such as AKD, is what implications robotics and AI will have in medicine in terms of replacing jobs in the hospital. It first came to my attention when Dr. Boyd mentioned that electronic diagnostic tools (in this case specifically the Kinarm robot) have greater sensitivity in their assessment than what a neurologist can determine. Furthermore, at the park yesterday Dilakshan mentioned he had done previous work with children with pontine tumors and that a major roadblock to therapy is that these tumors could not be resected because the surgery was too precise. He told me he is now working with AI and robotics to try and pioneer a new more precise method of resecting tumors which may prove to be better than traditional surgery. If these advancements turn out to benefit patients in a greater way than traditional therapy than I am sure we can agree they are undoubtedly good. In fact, a 2017 study by MIT displayed that an artificial intelligence system which they have developed was better than radiologists at reading mammograms for high-risk cancer lesions (1). In addition, Gulshan and his colleagues published a paper in JAMA which details the use of machine learning to examine the retinal images of diabetics. They reported that the results of using AI to identify diabetic retinopathy were extremely positive having increased consistency, specificity, sensitivity, and instantaneous reporting of results (2). These advancements are groundbreaking and open up avenues for further machine learning and AI in medicine. However, I wonder what the implications of this are in the long term with respect to replacing doctors and members of the medical community. Do you think that in the future diagnoses will be done only by machines, why or why not? And additionally, do you think this is a good thing or do you think that there are more problems and complications which come with it. Again, thanks for a great session and a good summary, I am interested to see what your guy’s thoughts are on this.

Conner-Simons, A. (2017, October 16). Using artificial intelligence to improve early breast cancer detection. MIT News | Massachusetts Institute of Technology. Retrieved September 22, 2021, from https://news.mit.edu/2017/artificial-intelligence-early-breast-cancer-d….

Gulshan, V., Peng, L., Coram, M., Stumpe, M. C., Wu, D., Narayanaswamy, A., Venugopalan, S., Widner, K., Madams, T., Cuadros, J., Kim, R., Raman, R., Nelson, P. C., Mega, J. L., & Webster, D. R. (2016). Development and validation of a deep learning algorithm for detection of diabetic retinopathy in retinal fundus photographs. JAMA, 316(22), 2402. https://doi.org/10.1001/jama.2016.17216

Name
Pierce Colpman

Hi Pierce,
Thank you for your comment, I really appreciate your deep-dive into the role of technology in the future of medicine. In my opinion, I could imagine the future of medicine to be a lot like chess. In 1996, IBM's Deep Blue supercomputer shocked the world and defeated then world champion Garry Kasparov in a game of classical chess, the first time a computer had defeated a world champion! However, over 20 years later, chess has evolved, and high level players have integrated computers into their preparation to improve their own game. Kasparov has maintained that humans and computers together, can defeat the best computers. For example, humans can simplify the search for the chess algorithms by eliminating obvious poor moves, allowing the algorithm to work more efficiently. If you've followed my anecdote thus far, I'd like to suggest that doctors and computers can work together in diagnostics in the future. I foresee a future where doctors play a role of limiting the search parameters for computers, such that the two can more efficiently and accurately diagnose and aid patients than either on their own. On the other hand, I could also imagine a future where AI succeeds human capacity to such a degree that working together would actually worsen patient care (and I think this may affect some fields more than others). At the end of the day, patient care is most important! I'd love to hear anyone else's thoughts on this topic.
Best,
James

Name
James King

Name
Dilakshan Srikanthan

Thu, 09/23/2021 - 11:13

Hi James,
Thank you so much for initiating the discussion on Dr. Boyd’s presentation and a wonderful summary.
One of the things I found interesting during our discussion is the ethical implications of cognitive impairments primarily executive functioning in CKD. In a situation like this, I think it may be important to think about medical decision-making capacity as currently the patient is deemed to have capacity to accept a proposed treatment or to refuse treatment or to select among treatment alternatives. However with the presence of cognitive impairments, it is important to interrogate whether the patients’ decision-making capacity is compromised. Previously, studies have found that patients with mild cognitive impairments demonstrate impairments in medical decision-making capacity relative to healthy controls (Okonkwo et al., 2007). The study went on to describe that on the three most stringent and clinically relevant consent standards of appreciation, reasoning, and understanding, patients with mild cognitive impairment performed significantly below age-, education-, gender-, and racially matched normal control participants.
I think it would be important to clearly identify whether medical decision-making capacity is compromised in CKD patients with cognitive impairments, as it has important clinical, legal and ethical implications for patients, their families and healthcare providers.

Name
Dilakshan Srikanthan

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