The global burden of chronic kidney disease (CKD) continues to rise. Patients’ increasing life expectancy, however, has caused researchers to shift their focus from urgent care to addressing long-term symptoms and complications. Neurodegeneration and cognitive impairment are among the most debilitating long-term contributors to significantly reduced quality of life for CKD patients.*

Cognitive impairment and CKD

A known association between impaired cognitive function and uremia (elevated levels of urea and other nitrogen-based waste products in the blood) dates back to the 1930s. Post-mortem studies in both humans and animals showed brain atrophy, white matter abnormalities, and degeneration of neurons. The severity of symptoms ranged from mild cognitive impairment to coma.

These developments were initially thought to be reversible with the removal of blood toxins through hemodialysis. By the late 1960s, though, uremia, cognitive impairment, and their relationship to one another were recognized as having more contributing factors and being more complex than previously realized. 

What is mild cognitive impairment?

The term mild cognitive impairment (MCI) was initially coined to describe the prodromal (preceding) form of Alzheimer’s disease. Today, it is also used to refer to the stage preceding other forms of clinical dementia and cognitive decline that go beyond the normal effects of aging.

Reduced function in MCI is noticeable but not severe. It affects several crucial cognitive domains, such as:

• Working memory 
• Problem-solving
• Impulse and emotion control

Screening for MCI in CKD

Despite the high prevalence of MCI in CKD patients (30%-63%), routine screening is not yet an official recommendation. This could be due to the lack of reliable, widely applicable intervention approaches. 

Nevertheless, nephrologists should take note of indicators, including when:

• The patient (or caregiver) reports forgetfulness concerning medications or appointments; confused or inappropriate speech, depression, or altered sleep patterns.  
• The patient is unable to answer questions without the family member/caregiver present.
• There is a history of stroke and/or unexplained falls.

When MCI transitions to clinical dementia, impairment has begun to noticeably interfere with the person’s daily living activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs include eating, bathing, dressing, and going to the bathroom, while IDALs include list-making, shopping, money management, banking, cooking, and other similar activities.

Risk factors for MCI in CKD

Determining risk factors for MCI that are specific to people with CKD can be challenging.

General MCI risk factors include:

• Older age
• Family history of MCI
• Lower education level 
• Exposure to chemical pollutants
• Lack of physical activity
• Diabetes, heart disease, or stroke
• Past brain injuries
• Male gender
• High blood pressure and cholesterol
• Smoking
• Overweight or obese

Many of these are risk factors apply to people with CKD, too, which blurs the lines between the two conditions. Thankfully, scientists have identified a few possible MCI risk factors specific to CKD, which include:

• Stage of CKD (the lower a person’s kidney function, as measured by their estimated glomerular filtration rate (eGFR), the greater their risk of MCI)
• Frequent presence of electrolyte disorders
• Duration of CKD

Other possibilities being investigated include poor nutrition/wasting, albuminuria, anemia, acidosis, sleep disturbance, and polypharmacy (concurrent use of multiple medications).

MCI and renal replacement therapy 

It has been suggested that patients with end-stage kidney disease (ESKD) are particularly at risk. Some of this risk is related to the method and adequacy of their renal replacement therapy (RRT). 

Some studies show that the risk of MCI is lower for patients on peritoneal dialysis than for those on hemodialysis, and when a central venous catheter is not used. Randomization, the gold standard for testing is not feasible for this population, though. 

Kidney transplantation has been shown to reduce MCI, which suggests that the condition at this stage may be reversible to some degree. 

Questions for further research

The problem of MCI in CKD has garnered increasing attention among nephrologists since 2013,  as evidenced by the rapidly-growing body of literature describing neurological and psychological changes in CKD patients. 

Some questions being investigated include:

• Is CKD-related MCI a separate condition or another form of MCI as manifested in the general population?
• How do cardiovascular risk factors affect MCI-CKD?
• Are there firm criteria for diagnosing MCI-CKD?
• What is the natural progression of MCI-CKD?
• Can MCI-CKD be prevented, treated, and/or reversed?
• How can we accurately assess the personal and socio-economic burdens of MCI-CKD?

Several recent innovations pave the way toward answering these questions. 

Looking ahead

According to scientists, theoretical approaches that are ripe for investigation include:

• Using measures of kidney function other than eGFR and albuminuria to explore the link between brain and kidneys
• Exploring the sympathetic-parasympathetic inflammation and imbalance that occur in CKD

New tools may also provide insight into the development and early identification of MCI in CKD. Some of these new technologies include:

• Imaging methods, such as two-photon microscopy 
• 3D neuron location tracing
• Robotic systems for drug testing and identification
• In vitro modeling using patients’ stem cells

As the problem of MCI-CKD increases, these theoretical and technological advances offer an opportunity to gain a deeper and broader understanding of the MCI-CKD dynamic, which will hopefully lead to more innovative and effective approaches and more optimal outcomes.

*Viggiano, D., Wagner, C. A., Blankestijn, P. J., Bruchfeld, A., et al. (2020, Jan.). Mild Cognitive Impairment and Kidney Disease: Clinical Aspects. Nephrology Dialysis Transplantation 35 (1): 10-17. https://academic.oup.com/ndt/article/35/1/10/5434148