System Disorders in Chronic Kidney Disease: Neurocognitive Dysfunction, Depression, and Sleep Disorder

Domains

Tests

Global cognition

Mini-Mental State Exam (MMSE)

The Modified Mini-Mental State (3MS)

Montreal Cognitive Assessment (MoCA)

The Kidney Disease Quality of Life (KDQOL) cognitive function subscale (KDOQL-SF)

Mini-cog

Memory

Wechsler Memory Scale-Third Edition (WMS-III)

Auditory Verbal Learning Test (AVLT)

Delayed Story Recall Test

Attention

Trail Making Test

Paced Auditory Serial Addition Test (PASAT)

Digit Span tests from the Wechsler Adult Intelligence Scale-III (WAIS III)

Executive function

Tower of London Test (TLT)

The Picture Arrangement sub-test of the Wechsler Adult Intelligence Scales (WAIS-R)

Wisconsin Card Sorting Test (WCST)

Verbal skill

Boston Naming Test

Sentence Repetition

For global cognition, the two most widely used and studied tests are the Mini-Mental State Exam (MMSE) and the Montreal Cognitive Assessment (MoCA). Both tests have a maximum score of 30 and can be administered in 10 min. MMSE has some limitations in its application to the CKD population. First, it is most useful for diagnosing dementia and less sensitive for mild cognitive impairment, which the major form of cognitive deficit found in CKD patients. Second, there is a lack of evaluation of executive function in the MMSE, and executive deficit is a prominent feature of cognitive impairment from vascular causes that is common among CKD patients.

The MoCA overcomes the above limitations and therefore may be more suitable for screening cognitive impairment in the context of CKD. However, one should bear in mind that these screening tests are generally influenced by education level and language fluency. Hence, it is very important to consider these factors when interpreting the scores. Specific cut-off values are needed for varying education levels as well as for application in different language areas.

The Kidney Disease Quality of Life (KDQOL) cognitive function subscale is specifically designed for the CKD population and has the advantage of being self-reported. However, despite its validation against the Modified Mini-Mental State (3MS), its value has been questioned due to its low sensitivity.

It is natural to perform these tests when there is a clinical need to do so (e.g., when a patient’s family member complains about the patient’s symptoms). However, no general recommendations or guidelines exist regarding the frequency of performing the tests in CKD patients. In light of the high prevalence of cognitive impairment in CKD patients, we recommend performing a screening test (e.g., MoCA) at least once every 2 years in patients with an eGFR ≤ 60 mL/min/1.73 m² who are not on dialysis and annually in ESRD patients on dialysis. If the test results indicate the existence of cognitive impairment, referral to a neurologist is recommended for more thorough neuropsychological evaluation and management.

13.2.6 Management

The general management strategy for dementia in patients with CKD should follow the same criteria used for the treatment of Alzheimer’s disease and should involve consultation from a specialist in neurology. Cholinesterase inhibitors and N-methyl d-aspartate receptor antagonists could be beneficial in slowing cognitive functional decline, but their effect on long-term outcome is uncertain. Additionally, there are limited data on the use of these drugs in CKD patients. For a detailed description of their use in the CKD population, please refer to the review by Kurella et al. [19].

The management of mild cognitive impairment in CKD is an area of uncertainty. Although vascular injury is considered to be the most important contributor to cognitive impairment in CKD, it is unknown whether cardiovascular risk factor modification will prevent cognitive impairment/dementia. Even in the general population, there is conflicting evidence regarding the role of antihypertensive therapy in cognitive decline.

Erythropoietin has been suggested to exhibit a protective effect on cognitive function [20, 21]. However, such evidence has generally come from observational studies and needs to be confirmed in randomized clinical trials.

Transplantation has been shown to be consistently beneficial for cognitive function in various studies, whereas increasing the frequency and intensity of hemodialysis is not [22–24].

13.3 Depression

13.3.1 Prevalence

Depression is not uncommon in the CKD population. However, the exact estimate of its prevalence in patients with CKD is unknown and varies widely in the existing literature. Palmer et al. performed a systematic review of previous observational studies and found that the prevalence of interview-based depression in the dialysis population was 22.8% [25]. For patients with non-dialysis-dependent CKD, a study by Tsai et al. demonstrated that self-reported depressive symptoms are found in 37% patients [26]. It should be noted that self-report scales may overestimate the presence of depression [25].

13.3.2 Impact on Quality of Life and Outcome

The high burden of depressive symptoms in CKD can lead to significant impairment of a patient’s quality of life. In a multicenter cross-sectional study involving 194 dialysis patients, depressive symptoms were strongly associated with the Kidney Disease Quality of Life Short-Form, a measure of health-related quality of life [27]. The link between depression and impaired quality of life among patients with renal dysfunction has also been confirmed in several other studies [28, 29].

There is a lack of significant evidence of an association between depression and mortality in CKD patients in previous studies. For example, in the study by Kimmel et al., the authors found that depression (as assessed by the Beck Depression Inventory) was not a predictor of mortality in 295 dialysis patients [30]. Similar results were also noted by Devins et al. [31]. However, these studies are limited by their relatively small sample size. In the Dialysis Outcomes and Practice Patterns Study (DOPPS), self-reported depression was associated with an increased risk of mortality and hospitalization in over 5000 patients on hemodialysis [32].

13.3.3 Risk Factors

Various factors could contribute to depressive symptoms in the context of CKD. The possible pathophysiological factors include chronic inflammation, oxidative stress, and activation of the hypothalamus-pituitary-adrenal (HPA) axis. Psychological factors could also play a critical role in inducing depression in the CKD population. The anxiety induced by suffering from a chronic disease, lifestyle disruption caused by hemodialysis or peritoneal dialysis, disease-related financial challenges, and impatience of being on a transplantation waiting list are considered to be contributing factors of depression in CKD [33].

13.3.4 Diagnosis

Major depressive episodes are defined as the presence of five or more of the following symptoms during the same 2-week period that represent a change from previous functioning (either depressed mood or loss of interest or pleasure is essential): (1) depressed mood; (2) markedly diminished interest or pleasure in (almost) all activities; (3) significant weight loss when not dieting, weight gain, or decrease or increase in appetite; (4) insomnia or hypersomnia; (5) psychomotor agitation or retardation; (6) fatigue or loss of energy; (7) feelings of worthlessness or excessive or inappropriate guilt; (8) diminished ability to think or concentrate, or indecisiveness; and (9) recurrent thoughts of death, recurrent suicidal ideation, or a suicide attempt.

While a psychologist should make the formal diagnosis of depression, screening could be performed by a nephrologist or trained staff using a variety of tools as part of routine clinical practice or in the dialysis unit. A summary of the most widely used assessment tools is presented in Table 13.2.

Table 13.2

Instruments for the screening of depression

Tests	Number of items	Notes
Beck Depression Inventory	21	Three versions available: BDI-I, BDI-IA, BDI-II
Patient Health Questionnaire-9	9
Patient Health Questionnaire-2	2	PHQ-2 serves as a “first-step” approach in screening for depression. It consists of the first two items of the PHQ-9
Hamilton Rating Scale for Depression	17	The original HRSD consisted of 17 items. Other versions include more (up to 29)
Zung Self-Rating Depression Scale	30
Geriatric Depression Scale	30	For use in the elderly
Major Depression Inventory	10	Can be used to generate a diagnosis
Center for Epidemiologic Studies Depression Scale	20	A modified version for use in children is available