Nephrology Hypertension

Chronic Kidney Disease: Cognitive Dysfunction in Chronic Kidney Disease

Does this patient have cognitive dysfunction in chronic kidney disease?

Cognitive impairment increases in prevalence with chronic kidney disease (CKD) severity, potentially affecting up to 60% of CKD patients. There may also be specific domains of cognition that are impaired for patients with CKD, such as executive cognitive function. Similar to the general population, a dementia diagnosis is more common among the elderly, women, and non-white patients with end-stage renal disease (ESRD), and less common among patients receiving peritoneal dialysis and transplant recipients, possibly reflecting patient selection and ascertainment bias.

Screening and diagnosis

Cognitive impairment is defined as a new deficit in more than one of the domains of cognitive functioning, which include disturbances in memory, executive functioning, orientation, reasoning, attention, language and cognitive skills necessary for planning and sequencing tasks.Cognitive impairment in the domains of memory, attention, and executive function is common among patients with CKD and dialysis. Studies reveal that working memory and executive function, two key domains of cognitive ability, are potentially important factors in medication compliance.

Mild cognitive impairment (MCI) is the term given to patients who are not normal because of deficits in more than one cognitive domain (usually recent memory) but who appear to function independently in daily functioning. Cognitive impairment without dementia is also associated with increased risk for disability, increased health care costs, and progression to dementia.

Dementia is characterized by a decline from a previous higher level of cognitive functioning along with a behavioral disturbance that interferes with daily function and independence. Alzheimer’s disease is the most common form of dementia in the general population, whereas vascular dementia, either alone or in combination with Alzheimer’s disease, is the second most common form of dementia in the United States.

Vascular cognitive impairment or mixed vascular cognitive impairment with Alzheimer’s disease appears to be much more common in dialysis patients than in people with Alzheimer’s disease alone, although further work is needed to establish this point, such as studies of larger populations and use of current brain imaging techniques . Diagnostic criteria for dementia published in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM IV) can be applied reliably and have been used widely in research.

Several studies have suggested that timing of cognitive testing relative to dialysis treatment may influence the results of testing. In a recent study, patients underwent cognitive testing at multiple time points before and after a single dialysis session. In these patients, global cognitive function varied markedly, with the greatest impairments being noted during the dialysis session, particularly with regard to memory, executive functioning and verbal fluency.

These results suggested that clinical review of dialysis patients and the communication of important information, such as obtaining informed consent or discussion of treatment changes, should be undertaken outside dialysis sessions. From a practical standpoint, the noise and activity of a dialysis unit may further complicate communication with an impaired patient.

Neuropsychological testing, when considered in conjunction with a detailed history and physical examination including a comprehensive assessment of the patient’s symptoms and concerns, and their social functioning can confirm the diagnosis of dementia and provide clues to the underlying etiology, as different causes of dementia may feature deficits in one cognitive domain more prominently and is also valuable before therapy to document the severity of dementia and follow the response to treatment.

The second step in the diagnostic process comprises the exclusion of potentially reversible conditions such as acute confusion or delirium, normal pressure hydrocephalus, depression and the confirmation of the dementia via detailed neurocognitive assessment and, if available, a computed tomography (CT) scan.

What tests to perform?

General screening tests

Given the high prevalence of impairment among patients with CKD and the implications of a diagnosis on decision-making and compliance, screening for cognitive impairment needs to start in the early CKD stage for the reference of baseline functioning. Several screening tests are available with a range of administration times and diagnostic accuracy. Scores on screening instruments are influenced by age, gender, educational level, and language such as English fluency.

The Mini-Mental State Exam (MMSE) has become the most frequently used and studied method for assessing cognitive status in the general population. It assesses orientation, attention, immediate and short-term recall, language, and the ability to follow simple verbal and written commands. The maximum score is 30 and a score less than 24 is consistent with cognitive impairment. Normative scores for age and educational level have been published.

The MMSE lacks sufficient sensitivity for mild cognitive impairment and assessment of executive function, which is a prominent feature of cognitive impairment among patients with ESRD. Another drawback is may be availability since it is under copyright. Newer instruments such as the Modified MMSE (3MS), the clock drawing test (CDT), and Montreal Cognitive Assessment (MoCA) have been developed, which have improved sensitivity, address executive functioning, and decrease educational bias.

The 3MS is a test of global cognitive function with components for orientation, attention, language, and memory. The 3MS has a maximum score of 100 (scores range from 0 to 100), and is considered to be more sensitive for mild cognitive impairment than the MMSE. A 3MS <80 was reported to have a sensitivity of 91% and specificity of 97% for detecting dementia in the general population.

The CDT has been used widely in recent years as a cognitive screening instrument and a significant amount of literature relates to its psychometric properties and clinical utility.The CDT taps into a wide range of intellectual and perceptual skills including executive functions, visuospatial ability, visual memory, comprehension, motor programming, and concentration. It takes less than a few minutes to conduct and score and has achieved excellent acceptability by patients.

From a clinical perspective, the CDT provides an easy to use visual record of cognitive function that has a good accessibility for busy clinicians. Another benefit is that the CDT is less likely affected by education and language than other tools such as MMSE which rely more heavily on language. The CDT provides a significant advance in the early detection of dementia (the mean sensitivity of 85% and specificity of 85% among published studies) and in monitoring cognitive change.

The Montreal Cognitive Assessment (MoCA) evaluates multiple domains of cognitive functioning that are affected in dementia such as short-term memory, visuospaitial ability, executive function, attention, concentration, working memory, language, orientation. The test is available at www.mocatest.org and is a one-page 30-point test that takes 10 minutes to adrninister.

A cut off score of 26 ( ≤ 25 indicating impairment) showed excellent sensitivity of 90% and 100 % in detecting MCI and dementia respectively (compared to the relatively poor performance of MMSE of 18 and 78%). In terms of specificity the MoCA correctly detected 87% of normal controls (compared to 100% for MMSE).24 Thus, the MoCA is a excellent screening tool for detecting MCI in patients performing in the normal range on the MMSE. While use of the MoCA as a screening tool has increased, there is no data available on its validity in the CKD population.

Specific cognitive tests

Comprehensive testing allows for analysis of specific impairments in cognitive function as opposed to an approach of screening for generalized cognitive impairment. It usually consists of an array of tests to determine intelligence, orientation, mental status, attention and vigilance, verbal skills, memory. These evaluations, typically lasting several hours, assess a range of cognitive domains more thoroughly than do screening instruments. These tests are summarized in the table shown in Figure 1.

Medical and neurological assessment

The patient’s medical history for risk factors of cognitive impairment such as stroke, cardiovascular disease should be reviewed and the examiner should look for focal neurological deficits suggestive of previous stroke and signs of Parkinsonism (for example, tremor, bradykinesia, or rigidity). Dialysis patients are treated with multiple medications and are therefore more susceptible to side effects (opioids, benzodiazepines, antihistamines, antipsychotics, and anticholinergics), and interactions between medications. Therefore, careful attention to medications, their dosing, potential interactions and side effects should be implemented, and all nonessential medications removed.

It is important to try to exclude delirium before establishing a diagnosis of dementia, as these conditions are reversible, although, in practice, this may be difficult. Common causes of delirium include electrolyte disturbances, medication side effects, and infections. Laboratory testing for B12 deficiency and hypothyroidism is recommended for all patients with suspected dementia. In ESRD patients, inadequate dialysis, severe anemia, and aluminum toxicity should also be ruled out.

Depression is the most common psychological problem encountered in patients with CKD and it remains significantly under-diagnosed and under-treated. Depression could influence the results of cognitive testing and should be screened before diagnosing cognitive impairment. In a recent study, hemodialysis (HD) patients with depressive symptoms performed significantly worse on tests assessing processing speed, attention, and executive function, after adjusting for age, sex, education, and other comorbid conditions.

Depressive symptoms are also highly prevalent among patients with mild cognitive impairment or dementia and are associated with an increased risk of developing mild cognitive impairment. However, the evidence for antidepressant treatment of people with depression and dementia, although suggestive, does not confirm efficacy.

Sleep disturbances are frequent in patients with advanced CKD. Patients with symptoms of sleep disorders should be referred for confirmatory testing and treated, if indicated, because it causes excessive daytime sleepiness which has been linked to the impaired quality of life and possibly cognitive dysfunction in this patient population.

Caregivers often notice cognitive deficits before they are apparent to clinicians, and their observations is useful for helping to establish the course of impairment and for differentiating delirium from dementia. Caregivers should be encouraged to accompany patients to their treatments, if possible, as this may alleviate the patient’s anxiety and reduce the need for pharmacological therapy.

How should patients with cognitive dysfunction in chronic kidney disease be managed?

Intervention for risk factors

The vascular beds of the brain and kidney have similar anatomic and hemodynamic features; these observations have led to the speculation that cognitive impairment and CKD (including microalbuminuria) are reflections of vascular injury in different end organs. Moreover, most CKD patients have high rates of hypertension, diabetes, markedly elevated levels of inflammatory markers and homocysteine, vascular endothelial dysfunction, cardiovascular events including stroke, and carotid atherosclerosis, all of which contribute to vascular cognitive impairment and neurodegenerative diseases such as Alzheimer’s disease. There are modfiable risk factors for congnitive impairment (see table illustrated in Figure 2).

Potential measures to reduce cognitive impairment in patients with CKD could include treatment of cardiovascular risk factors, although there are unfortunately no clinical trials of patients with CKD that have evaluated treatment of cardiovascular risk factors to prevent cerebrovascular disease or cognitive impairment. Several renal function and dialysis-associated factors such as retention of uremic solutes, hemodynamic instability during dialysis, and anemia have been suggested for modifiable factors.

Treatment of cardiovascular risk factors

Blood pressure control. There is a trial suggesting a protective effect of hypertension treatment on cognition. In that study, hypertension treatment reduced the risk of dementia by 55%. In a meta-analysis of antihypertensive trials, the combined risk ratio of dementia favored treatment. In a systematic review of hypertension trials, there is no convincing evidence from the trials confirming that blood pressure lowering prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior CVD. However, in many hypertension treatment studies, the incidence of fatal and nonfatal stroke was significantly reduced, and that is very important because a history of stroke doubles the risk of dementia in both the non-CKD and HD patients.

In dialysis patients, it is also important to avoid intradialytic hypotension because acute hemodynamic changes and large fluid shifts during dialysis could increase the risk of cognitive impairment through cerebral edema and decreased intra-cerebral blood pressure, blood velocity and cerebral perfusion. In a case-series of stroke among patients undergoing maintenance HD, the patients were found to have a high prevalence of events in the vertebrobasilar system compared to patients without kidney disease evaluated in the local stroke unit. The number of hypotensive episodes during dialysis also correlates with the degree of frontal cerebral atrophy, a sequelae of recurrent strokes.

Lipid and glucose control. Some observational studies have shown that statin therapy is associated with a decreased risk for cognitive impairment and dementia. However, more a recent large randomized controlled trial (RCT) suggested that statins given in late life to individuals at risk of vascular disease have no effect in preventing dementia. There is also no convincing evidence relating type or intensity of diabetic treatment to the prevention or management of cognitive impairment in Type II diabetes, even though epidemiological evidence shows a relationship between cognitive impairment and Type II diabetes.

The ongoing ACCORD-MIND trial is designed to assess the effects of long term glycemic control on cognition. Benefits and risks of tight glucose level control need to be assessed on an individual basis because of increased risks for hypoglycemia in CKD population.

Homocysteine-Hyperhomocysteinemia (HCY) is a marker for B-vitamin deficiency (folate, vitamin B12, vitamin B6) and has been linked with the risk of arterial disease, dementia and Alzheimer's disease. The small number of studies provide no consistent evidence either way that folic acid, with or without vitamin B12, has a beneficial effect on cognitive function of unselected healthy or cognitively impaired older people. The positive effect of oral folic acid on cognitive domains was found in participants with HCY and low vitamin B12 status after three years of follow-up. However, homocysteine lowering with B- vitamin supplementation has failed to show benefit for reducing the risk of cognitive decline in the CKD population.

Anti-oxidative therapy. Two RCTs showed that either 800 IU/day of vitamin E67 or 600 mg orally twice daily of N-acetylcysteine improved cardiovascular outcomes in dialysis patients. Ginkgo biloba extract can be used as symptomatic treatment for cerebral insufficiency that occurs during normal aging or which may be due to degenerative dementia, vascular dementia or mixed forms, and for neurosensory disturbances. There are no trials evaluating the effect of antioxidants on cognitive impairment in patients with CKD population.

Exercise therapy. Many studies have shown an inverse relation between physical activity and the risk of developing cognitive decline in the elderly population. The results of a recent meta-analysis showed that physical exercise is able to reduce the incidence of neurodegenerative diseases; in particular, dementia and Alzheimer’s disease. The cumulative meta-analysis to evaluate the role of physical activity on cognitive decline showed that subjects who performed a high level of physical activity were significantly protected against cognitive decline during the follow-up. Furthermore, even low-to-moderate level exercise also showed a significant protection against cognitive impairment.

Even though there is no study about effect of physical therapy on cognitive impairment in the CKD population, this is reliable therapy for patients with CKD due to the low risk of harm and many beneficial effects on muscle strength, work output, cardiac fitness, depressive symptoms and quality of life. In spite of beneficial effects of exercise in patients with CKD, there are currently no specific exercise guidelines for this population. The exercise protocols currently available have often been developed for research studies and are therefore unsuitable for many chronically sick CKD patients with significant co-morbid conditions that need to be monitored.

In view of local variations in treatment regimes, and variation in co-morbidities, exercise prescriptions for dialysis patients need to be tailored individually. Johansen suggested that the recommendations for older adults (65 years and above) and adults aged 50–64 years with clinically significant chronic conditions and/or functional limitations, published in 2007 by the American College of Sports Medicine and the American Heart Association, can be applied to patients with advanced CKD.

Management of renal function and dialysis-associated factors

Anemia treatment.. Anemia has also been identified as a risk factor for cognitive impairment in CKD, and correction of anemia with recombinant erythropoietin treatment has been shown to improve measures of cognition, such as neuropsychological and neurophysiological tests, in the several studies. However, pretreatment hematocrit level was generally lower than current practice and post-treatment hematocrit was consistent with current clinical practice guidelines.

In a small study of 20 HD patients, normalization of hematocrit from 31.6% to 42.9% with erythropoietin resulted in a significant improvement in the neurophysiological tests. These results, however, need to be interpreted with caution because in the recent large RCTs of anemia in patients with CKD, normalization of hematocrit was associated with an increased risk for stroke, and increased risk for the composite outcome of death, myocardial infarction, hospitalization for congestive heart failure and no incremental improvement in quality of life.

Effect of frequent dialysis therapy. A small uncontrolled study showed that 12 patients who transitioned to daily nocturnal dialysis achieved improved cognitive outcomes in attention, psychomotor efficiency and processing speed, and working memory after 6 months. Although the mechanism by which daily dialysis can improve cognitive function remains unknown, it is suggested that improved toxin clearance and anemia, better control of blood pressure and parathyroid hormone, and less acute hemodynamic changes may be beneficial for the cerebral circulation and cognitive function. Recent randomized clinical trials may give a more clear answer respecting the efficacy of frequent dialysis.

Effects of renal transplantation. There are a few studies which cognitive function could improve following renal transplantation. In a recent short-term observational study, improvements in cognition in relation to baseline values were demonstrated 6 months after transplantation. Prominent changes were evident with regard to memory, with minor improvements also noted in the domains of concentration and psychomotor function.

Other groups have demonstrated improvements in both neuropsychological tests, such as the mini-mental state examination, and neurophysiological markers of cognitive function, as measured using evoked potential latencies and EEG rhythms. However, in other study, significant residual impairment exists in transplant recipients compared with CKD patients.

Pharmacologic therapy. Five medications, Donepezil, Galantamine, Rivastigmine, and Tacrine (cholinesterase inhibitors) and Memantine (N-methyl D-aspartate receptor antagonists) are now approved by the US Food and Drug Administration (FDA) for treatment of Alzheimer’s disease (AD). They offer primarily symptomatic benefits, providing temporary cognitive improvement and deferred decline, but with little or no evidence of slowing disease progression. Galantamine, Rivastigmine, Donepezil and Memantine therapy for vascular or mixed dementia shows modest clinical benefits that are similar to those found for their treatment of AD, although these do not have FDA approval for this indication.

The pharmacokinetics of medications used to treat CKD patients require special consideration of the route of elimination, whether or not the medication is dialyzable and the protein binding of the medicine. Moreover, there is no published data on safety or efficacy of agents for dementia in CKD patients; thus, therapy decisions should be carefully individualized. Rivastigmine and Tacrine are mostly metabolized by liver, and very limited data suggest that no dose modification is probably required in these drugs. Galantamine is not recommended for ESRD patients and Memantine needs dose adjustment for advanced CKD and ESRD patients.

Cognitive stimulation therapy (CST). CST is an intervention for people with mild to moderate dementia, designed following extensive evaluation of the available research and is an evidence-based treatment. The CST program aims to create an environment where people have fun, learn and where they strengthen their abilities and relationships among the group members, thus maintaining their social and cognitive skills at their optimum ability.

A pilot study of long-term maintenance CST, offering 16 weekly sessions of maintenance following the initial CST program, showed a significant improvement in is in progress. Given the high risks of pharmacologic therapy in CKD patients, CST may be helpful for these populations and need to be considered for further study.

What happens to patients with cognitive dysfunction in chronic kidney disease?

Cognitive impairment in CKD not only increases the risk of mortality but also has major implications for informed consent in relation to dialysis initiation and maintenance, and ultimately transplantation. In an integrated prognostic model of 6-month survival for patients with HD, dementia was significantly associated with early mortality. Moreover, cognitive impairment may decrease an individual's quality of life, increase resource utilization, increase in medical cost, and result in suboptimal medical care because of difficulty following caregiver’s recommendations.

However, several studies have shown that cognitive impairment in CKD patients is largely undetected and under treated by clinicians. Therefore, identifying cognitive impairment may lead to the institution of supportive care measures that improve outcomes and reduce disease burden.

Cognitive impairment can alter functioning in numerous areas of life including work, school, family, social relationships, leisure activities, or maintenance of health and hygiene. The physician should evaluate the patient’s activity in each of these domains and determine the presence, type, severity, and chronicity of any dysfunction.

Informal caregivers can also experience stress from the added responsibilities of managing the patients’ medical treatments, dietary requirements, clinic appointments and psychosocial issues. Caregiver burden is associated with poor outcomes for caregivers such as depression, illness, and decreased quality of life and poor outcomes for dementia patients such as poor quality of life and early nursing home placement.

Families experiencing caregiver burden may present in any healthcare setting and thus practitioners need information on assessment and interventions. Caregivers seeking nursing home placement had significantly higher burden scores, more family dysfunction, and decreased social support compared with caregivers who did not seek nursing home placement.

How to utilize team care?

Neurologist consultation should be considered when the diagnosis and etiology of cognitive impairment is in doubt. The neurologist may also assess in developing an appropriate plan of care. In addition, referral for neuropsychological testing may help to define the specific neurocognitive deficits. Many of the patients with CKD will be co-managed with primary care physicians who will help to set goals of care and long-term planning. Lastly, a psychiatric referral would be reasonable when there is a question of whether the patient has underlying depression or depression refractory to treatment.

Nurses play a key role in the recognition and multi-disciplinary managent of cognitive impairment in patients with chronic health conditions. Nurses may also play a supportive role for caregivers and provide resourses to family members.

Given the polypharmacy of patients with chronic kidney disease, pharmacists may play an important role in the multidisciplinary care of the CKD patient with cognitive impairment.

Multi-component interventions targeting the caregiver have demonstrated improvements in caregiver burden and outcomes such as coping skills, depression, and delayed institutionalization for patients. Interventions that can be offered begin with tailored information about dementia, getting multiple family members involved, assisting the family to identify rewards from care giving, in-home environmental assessments, and education on safety issues such as door locks and identification bracelets. In summary, a multi-disciplinary approach involving primary care, geriatrics, nursing, and social work is useful for addressing the complexity of medical and social issues in these patients.

Are there clinical practice guidelines to inform decision making?

NA

Other considerations

NA

What is the evidence?

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