May/June 2023

Chronic Kidney Disease and Cognitive Impairment
By Mark Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 16 No. 3 P. 10

Cognitive deficits in patients with chronic kidney disease are often overlooked.

Good kidney function is essential to ensuring health as the kidney removes wastes, toxins, and excess fluid while also helping control blood pressure, stimulating red blood cell production, maintaining bone health, and regulating essential blood chemicals. Unfortunately, more than one in seven American adults is estimated to have chronic kidney disease (CKD), which is characterized by a gradual loss of kidney function.1

It’s defined as glomerular filtration rate < 60 mL/min or the presence of albuminuria (a marker of kidney damage). Well-known consequences of CKD include common health problems such as gout, anemia, secondary hyperparathyroidism, bone disease, heart disease, and fluid buildup. Individuals with CKD are also at a substantially higher risk of developing cognitive impairment compared with the general population. And although cognitive impairment in CKD is common, it’s frequently unrecognized.2 Therefore, improving awareness about CKD and related cognitive impairment, contributing risk factors, and potential interventions is essential.

CKD Statistics
Kidney diseases are a leading cause of death in the United States.3 The cost of treating CKD in Medicare beneficiaries alone in 2019 was $87.2 billion, with treatment of those with end-stage renal disease costing an additional $37.3 billion. An estimated 37 million adults, or 15% of the US population, have CKD, and 40% of people with severely reduced kidney function (not on dialysis) are unaware they have kidney disease.3

Leading Causes of CKD
Diabetes and high blood pressure are the key causes of kidney failure, accounting for 3 out of 4 new cases.4 Diabetes is the leading contributor to the development of CKD, with approximately 1 in 3 persons with diabetes having CKD. Hypertension is the second leading cause of CKD, with an estimated 1 in 5 persons with high blood pressure having CKD.1

Diabetes
The reduced production of vasodilator nitric oxide plays a prominent role in the development of CKD in persons with diabetes. Normally, endothelial cells lining the walls of blood cells secrete nitric oxide to widen blood vessels while also keeping blood vessel lining smooth and slippery to help prevent blood clots. However, in persons with diabetes, high blood glucose levels (hyperglycemia) impair production of nitric oxide, which causes constricted blood vessels, high blood pressure, and atherosclerosis. When this occurs in the kidneys, millions of tiny filtering units called nephrons can become irreversibly damaged, which prevents the kidneys from filtering waste out of the blood, effectively leading to CKD. Hyperglycemia can also directly damage the lining of blood vessels, exposing them to persistent inflammation and oxidative stress.

The link between CKD and diabetes appears to be bidirectional, as CKD also contributes to the development of type 2 diabetes. When kidney function is impaired, there’s a buildup of urea, a natural byproduct of metabolism that’s typically removed from the body by kidneys in urine. As a result, high levels of urea can directly affect beta cells in the pancreas, preventing them from effectively making, storing, and secreting insulin into the bloodstream, leading to the development of type 2 diabetes.5

Hypertension
Regardless of the cause, uncontrolled high blood pressure can damage the network of blood vessels that supply nephrons, and over time the kidneys lose their ability to filter blood and regulate the fluid, hormones, acids, and salts in the body.

The hormone aldosterone, which is produced by the adrenal glands, also plays a role in hypertension leading to CKD. Healthy kidneys respond to aldosterone to help the body regulate blood pressure through its effects on sodium, potassium, and total fluid in the body. In kidney disease, increased aldosterone levels cause the kidneys to increase sodium and water retention. As a result, blood pressure becomes elevated, and blood vessels in the kidneys become blocked, eventually leading to kidney failure. It’s been discovered that medications that decrease the effects of aldosterone may be able to slow CKD progression.6

Cognitive Impairment in CKD
Cognitive impairment includes reduced mental alertness, intellectual impairment, decreased attention and concentration, memory deficits, and diminished motor coordination.7 Patients with CKD are at a substantially higher risk for developing cognitive impairment compared with the general population,8 and the prevalence of cognitive impairment is high among persons with CKD, ranging from 30% to 60%.9

Consequences
Cognitive impairment in CKD is associated with decreased functional capacity, reduced quality of life, increased health care resource utilization and cost, and increased mortality. Cognitive impairment can range from mild to severe and the severity of cognitive impairment appears to be associated with the severity of CKD and is independent of age, education, and other potential confounders including demographic characteristics and relevant comorbidities.10 Executive function and attention are most affected in mild CKD. Patients with mild CKD are typically still able to care for themselves and perform normal activities of daily living but may experience mild cognitive symptoms such as forgetting their keys more often, forgetting appointments, and having increased difficulty coming up with words. However, in persons with severe CKD, cognitive impairment is also more severe and involves major domains of cognition such as general cognitive abilities, executive function, and episodic memory.11 Patients with CKD-related cognitive impairments are also at risk of loss of independence and neuropsychiatric manifestations such as delirium, dementia, anxiety, depression, withdrawal from dialysis, sleep disorders, and suicidal tendency.12

Cognitive impairment in patients with CKD has a significant impact not only on the quality of life for the patient but also on that of their caregivers/family. It can limit a person’s ability to understand and comply with health care provider and caregiver instructions and prescribed treatments, including medications, and limit their ability to provide self-care. As a result, caregivers are at risk for increased burden, stress, depression, and a variety of other health complications.13

Assessment
Early identification of cognitive impairment is essential to allow for the implementation of supportive measures that may improve outcomes and reduce disease burden. However, a number of studies report that, despite its high prevalence, cognitive impairment in CKD patients is largely undetected and under treated by clinicians.

Evaluation of patients with CKD should include periodic cognitive function assessment. There are no consensus recommendations for an optimal screening test to identify cognitive impairment or dementia in persons with CKD. The choice of test will often depend on clinician familiarity and practice setting. A number of tests may be useful to assess cognition in patients with CKD, including the Mini-Mental State Examination, Montreal cognitive assessment, clock-drawing test, and others.14 For patients with CKD receiving maintenance hemodialysis, administering cognitive tests during the first hour of hemodialysis is recommended.15 The evaluation of cognition also should include history taking from the patient’s caregiver/family as they often will see signs of cognitive decline and behavioral deficits before they are apparent to clinicians.

Mechanisms Leading to Cognitive Impairment
The development of cognitive impairment in CKD is multifactorial, with proposed mechanisms including factors related to cardiovascular risk, kidney disease, and dialysis.15

Cardiovascular Risk Factors
Cardiovascular disease (CVD) and CVD risk factors such as older age, hypertension, dyslipidemia, and diabetes are prevalent in persons with CKD and likely play a significant role in cognitive impairment.15 The persistent presence of CVD risk factors places individuals at dramatically increased risk for stroke, transient attacks, and other serious vascular consequences in the brain and subsequent cognitive decline.

Kidney Disease–Related Factors
Kidney disease–related factors leading to cognitive impairment include uremic toxins, increased homocysteine levels, anemia, albuminuria, vitamin D deficiency, and inflammation.

Uremic Metabolites
Uremic metabolites (toxins) accumulate with deterioration of renal function and cause many deleterious effects such as systemic inflammation, cardiac failure, anemia, immune dysfunction, anorexia, and neurological damage. Furthermore, these uremic toxins can pass through the blood brain barrier and cause cognitive dysfunction and neurodegeneration.16

Anemia and Malnutrition
Patients with CKD often have concomitant anemia and malnutrition, which has been linked to both a greater incidence of stroke and cognitive impairment. Both anemia and malnutrition can impair oxygen delivery to the brain, affect brain metabolism, and increase the prevalence and severity of cognitive impairment.16

Homocysteine
Homocysteine is an amino acid made in the body that becomes elevated in persons with CKD. Increased homocysteine levels are detrimental to the brain, resulting in oxidative stress and subsequent neuronal damage that worsens cognitive and motor function.17

Vitamin D Deficiency
Vitamin D exerts neuroprotective and regulatory roles in the central nervous system. Vitamin D deficiency is common in persons with CKD and is associated with muscle weakness, bone loss, CVDs, oxidative stress, inflammation, immune suppression, and neurocognitive impairment.18

Dialysis-Related Factors
Hemodialysis itself is a risk factor for the development of cognitive impairment.15 The rapid fluid shifts that occur with hemodialysis can lead to wide fluctuations in blood pressure that are detrimental to cognition.19 Also, intradialytic hypotension has been linked to cerebral atrophy,20 while hemodynamic instability during hemodialysis is associated with brain injury.21

Other Factors
Other factors such as depression, sleep disorders, and medications also contribute to impaired cognitive function in CKD.

Depression
Depression is highly prevalent in patients with CKD and is known to contribute to impaired cognitive function. The prevalence of depression in CKD patients is three to four times higher compared with the general population and two to three times higher compared with other chronic diseases including diabetes, coronary artery disease, and COPD.22

Medications
Patients with CKD often have a number of comorbid conditions requiring many different medications, which can lead to polypharmacy. As the number of medications increases, so does the potential for drug-drug interactions which, along with reduced renal clearance of medications, greatly increases the risk for sedation, delirium, and cognitive impairment. Thus, avoiding medications that are highly sedating such as benzodiazepines should be a priority.

Sleep
Sleep disorders are prevalent in patients with CKD, especially in those receiving hemodialysis, which can lead to impaired daytime cognitive function and increased depression.23 In addition, poor sleep quality is common in predialysis CKD patients and is an independent factor associated with cardiovascular damage.24

Interventions
Interventions to help prevent or minimize cognitive impairment in CKD may include controlling CVD risk factors and blood pressure, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), treating depression, improving sleep hygiene, and avoiding sedating medications/polypharmacy.

Controlling CVD Risk Factors
Given CVD’s contribution to cognitive impairment in CKD, taking steps to reduce risks may be beneficial, especially in those patients with mild to moderate CKD. Control of traditional CVD risk factors, including management of dyslipidemia, hypertension, and hyperglycemia, has been shown to have beneficial effects on cognitive function in the general population, although there’s limited studies specifically evaluating the benefits on cognition in persons with CKD.15

ACE Inhibitors and ARBs
For patients with mild to moderate CKD, reducing albuminuria with either ACE inhibitors or ARBs may be associated with slower cognitive decline.15 A post hoc analysis from the ONTARGET/TRANSCEND trial found that participants with CKD who were able to either reduce or completely eliminate albuminuria had 20% to 40% lower odds of having a decrease in Mini-Mental State Examination score of three or greater compared with those who had an increase or no change in albuminuria.8,25

Other Interventions
Patients with CKD should be evaluated closely for depression due to its high prevalence, its contribution to decreased quality of life, and its role in cognitive impairment. Addressing sleep disturbances is also important, can help improve quality of life, and may be helpful in reducing cardiovascular risk by reducing blood pressure. According to research, optimizing sleep quality and duration to more than six hours a night improves blood pressure control and is associated with a significant delta change in systolic blood pressure within three months of follow-up.26 Correcting anemia and malnutrition is important and can improve cognitive impairment. Vitamin D supplementation in CKD patients may also be appropriate; it can improve endothelial function and may reduce cardio-cerebrovascular events.27 Increased physical exercise has been found to be a useful nonpharmacological strategy for preventing cognitive decline, with a randomized controlled trial consisting of 24-week exercise intervention showing significantly improved memory function in older patients with predialysis CKD.28

Final Thoughts
CKD and related cognitive impairment are significant health concerns. As the population ages, there will be a growing need to identify persons with CKD in earlier stages along with a greater need to prevent and manage cognitive dysfunction. Increasing clinician’s awareness of cognitive impairment in CKD is essential to improving its early identification. Due to the complexity of CKD, there is tremendous need for increased multidisciplinary team management—including dietitians, pharmacists, psychologist, social workers, and others—which could improve quality of life and outcomes.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Centers for Disease Control and Prevention. Chronic kidney disease in the United States, 2021. https://www.cdc.gov/kidneydisease/pdf/Chronic-Kidney-Disease-in-the-US-2021-h.pdf. Published 2021.

2. Tollitt J, Odudu A, Montaldi D, Kalra PA. Cognitive impairment in patients with moderate to severe chronic kidney disease: the Salford kidney cohort study. Clin Kidney J. 2021;14(6):1639-1648.

3. Chronic kidney disease basics. Centers for Disease Control and Prevention website. https://www.cdc.gov/kidneydisease/basics.html. Updated February 28, 2022.

4. Diabetes and chronic kidney disease. Centers for Disease Control and Prevention website. https://www.cdc.gov/diabetes/managing/diabetes-kidney-disease.html. Updated December 30, 2022.

5. Koppe L, Nyam E, Vivot K, et al. Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease. J Clin Invest. 2016;126(9):3598-3612.

6. Bakris GL, Jaisser F. Aldosterone excess and cardiorenal risk: more common than appreciated. Eur Heart J. 2022;43(38):3792-3793.

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15. Drew DA, Tighiouart H, Scott TM, et al. Cognitive performance before and during hemodialysis: a randomized cross-over trial. Nephron Clin Pract. 2013;124(3-4):151-158.

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18. Cheng Z, Lin J, Qian Q. Role of vitamin D in cognitive function in chronic kidney disease. Nutrients. 2016;8(5):291.

19. Daugirdas JT. Pathophysiology of dialysis hypotension: an update. Am J Kidney Dis. 2001;38(4 Suppl 4 ):S11-S17.

20. Mizumasa T, Hirakata H, Yoshimitsu T, et al. Dialysis-related hypotension as a cause of progressive frontal lobe atrophy in chronic hemodialysis patients: a 3-year prospective study. Nephron Clin Pract. 2004;97(1):c23-c30.

21. McIntyre CW. Recurrent circulatory stress: the dark side of dialysis. Semin Dial. 2010;23(5):449-451.

22. Simões e Silva AC, Miranda AS, Rocha NP, Teixeira AL. Neuropsychiatric disorders in chronic kidney disease. Front Pharmacol. 2019;10:932.

23. Rodriguez L, Tighiouart H, Scott T, et al. Association of sleep disturbances with cognitive impairment and depression in maintenance hemodialysis patients. J Nephrol. 2013;26(1):101-110.

24. Zhang J, Wang C, Gong W, et al. Association between sleep quality and cardiovascular damage in pre-dialysis patients with chronic kidney disease. BMC Nephrol. 2014;15:131.

25. Barzilay JI, Gao P, O’Donnell M, et al. Albuminuria and decline in cognitive function: the ONTARGET/TRANSCEND studies. Arch Intern Med. 2011;171(2):142-150.

26. Ali W, Gao G, Bakris GL. Improved sleep quality improves blood pressure control among patients with chronic kidney disease: a pilot study. Am J Nephrol. 2020;51(3):249-254.

27. Zhang Q, Zhang M, Wang H, et al. Vitamin D supplementation improves endothelial dysfunction in patients with non-dialysis chronic kidney disease. Int Urol Nephrol. 2018;50(5):923-927.

28. Otobe Y, Yamada M, Hiraki K, et al. Physical exercise improves cognitive function in older adults with stage 3-4 chronic kidney disease: a randomized controlled trial. Am J Nephrol. 2021;52(12):929-939.