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Neuropsychiatric complications of chronic kidney disease

Rory McQuillan and Sarbjit V. Jassal
Abstract | Evidence is emerging that cognitive impairment, delirium and depression are very common in patients with renal disease. All of these conditions are associated with prolonged hospitalization and an increased risk of mortality. A good understanding of these conditions is key to their prevention, early intervention and management. This Review summarizes the clinical features of various forms of cognitive dysfunction that occur in individuals with renal disease and describes the evidence for the high burden of disease in such patients.
McQuillan, R. & Jassal, S. V. Nat. Rev. Nephrol. 6, 471479 (2010); published online 22 June 2010; doi:10.1038/nrneph.2010.83

Introduction

As early as 1858, Addison published an essay suggesting that disturbances in brain function are associated with symptoms of progressive uremia and chronic kidney disease (CKD). 1 He stated, Of all the more serious affections of the brain arising in connection with renal disease, the mildest form appears to be that of a tendency to a state of quiet stupor, varying in degree from a mere torpidity of manner and sluggishness of intellect, to complete insensibility to all surrounding objects.1 Although advanced progressive uremia is now rarely seen owing to the widespread availability of dialysis, an association remains between earlier stages of CKD and cognitive impairment, depression and susceptibility to acute confusional states. These associations are important clinically, as neuropsychiatric disturbances have been shown to be associated with increased patient mortality, increased rates of hospitalization and poor adherence with treatments. This Review discusses the main clinical neuropsychiatric features associated with renal disease in three sections: dementia and cognitive impairment, delirium and depression.

together with at least one of the following: aphasia, apraxia, agnosia or disturbances in executive functioning (defined in Box 1). A diagnosis of dementia cannot be made if deficits occur exclusively during the course of a delirium. Cognitive impairment must be severe enough to affect a patients ability to function in their work, personal or social environment. Milder degrees of cognitive impairment, which may not affect day-to-day life, are sometimes termed mild cognitive impairment. Dementia seems to be a powerful predictor of mortality in dialysis patients.3 An analysis of United States Renal Data System (USRDS) data found that among hemodialysis patients, dementia was associated with a higher risk of mortality than were either heart failure or stroke (hazard ratio for death was 1.90 with dementia versus 1.28 with heart failure and 1.20 with stroke).3

Dementia and cognitive impairment

Definition and consequences Dementia is a clinical state characterized by loss of function in multiple cognitive domains. The most commonly used criteria for the diagnosis of dementia are based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) coding system published by the American Psychiatric Association.2 To be given a diagnosis of dementia, a patient must experience a decline in memory from previously higher levels of functioning
Competing interests S. V. Jassal declares associations with the following companies: Amgen, Baxter, Ortho Biotech. See the article online for full details of the relationships. R. McQuillan declares no competing interests.

Prevalence and progression in renal populations Cognitive impairment and dementia seem to be highly prevalent in patients with renal disease. Much of the evidence suggests that cognitive impairment is most common among patients who are established on dialysis. A 2006 study of prevalent dialysis patients found that almost all hemodialysis patients aged 55 years had some evidence of cognitive impairment, with only 13% of individuals classified as having normal cognition.4 Although comparing the prevalence of cognitive impairment across various populations can be difficult owing to differences in the types of tests used (Table 1) and differences in study designthis study showed that almost 40% of hemodialysis patients had severe cognitive impairment with features compatible with, in the view of the study authors, a diagnosis of dementia. Interestingly, cognitive impairment was documented in the medical records as a comorbid condition in less than 3% of the entire study population. Cognitive impairment does not, however, occur only in patients with advanced stages of CKD: it is

Toronto General Hospital, 200 Elizabeth Street, 8N-825, Toronto, ON M5G 2C4, Canada (R. McQuillan, S. V. Jassal). Correspondence to: S. V. Jassal vanita.jassal@ uhn.on.ca

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Key points
Delirium, depression and cognitive impairment are highly prevalent conditions in patients with chronic kidney disease (CKD) Both the prevalence and the rate of progression of cognitive impairment are inversely associated with the degree of renal function The risk of delirium is increased in patients with CKD and those on dialysis due to the reduced clearance of commonly prescribed drugs and the prolonged hospitalization that occurs in these patients Depression is probably under-recognized and undertreated in the dialysis and CKD population

Box 1 | Common neurological terms Agnosia Partial or total loss of the ability to perform coordinated movements or manipulate objects in the absence of motor or sensory impairment. Aphasia Partial or total loss of the ability to articulate ideas or comprehend spoken or written language resulting from damage to the brain caused by injury or disease. Apraxia Loss of the ability to interpret sensory stimuli such as sounds or images. Domain A term commonly used to describe specific aspects of cognition; for example, if an individual is asked to do a puzzle that involves placing numbers in a sequence, the ability to remember the numbers is working memory whereas the process of sorting them (and the speed at which that is done) is termed psychomotor speed or processing speed. Executive function An overall term that refers to the cognitive process that regulates an individuals ability to organize thoughts and activities, prioritize tasks, manage time efficiently and make decisions; impairment of executive function is seen in a range of disorders.

cognitive impairment (even after adjustment for demographic characteristics, prevalent cardiovascular disease and cardiovascular risk factors). Exploratory analyses suggested that the association was nonlinear, with the highest risk of cognitive impairment occurring in those with an eGFR <50 ml/min/1.73 m2 and only a modest risk in those with an eGFR within the range 5070 ml/ min/1.73 m2. A number of longitudinal studies have shed further light on the relationship between CKD and cognitive function.68 Findings from these studies suggested that CKD is both a risk factor for the development of dementia and is also associated with a more rapid decline in cognitive function over time. Details of other studies with similar findings are summarized in Table 2.

seen across the whole spectrum of CKD. Much of the data supporting this observation in the nondialysis CKD population comes from large, population-based studies (Table 2). Key studies include the Reasons for Geographical and Racial Differences in Stroke (REGARDS) study,5 the Cardiovascular Health Study (CHS),6 and the Health Aging and Body Composition (Health ABC) study.7 Again, although direct comparisons between these studies are limited by variations in the populations recruited, tests used, and study design (longitudinal versus cross-sectional), all showed an impressive relationship between reduced kidney function and increased burden of cognitive dysfunction. The largest of these studies, the REGARDS study,5 recruited a nationally representative sample of over 23,000 US adults aged 45 years. Individuals were tested using a six-item test of memory and attention. Individuals were said to have CKD if their estimated glomerular filtration rate (eGFR) was <60 ml/min/1.73 m2. Using a cross-sectional approach, the researchers found that presence of CKD was associated with a 23% increase in the prevalence of
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Possible etiologies Cognitive impairment can be categorized as being of either vascular or nonvascular etiology. In a crosssectional study of 335 homebound individuals aged 60 years, the presence of albuminuria, a surrogate for microvascular disease in the kidney, was independently associated with worse cognitive function.9 Individuals with microalbuminuria had worse performance than individuals without microalbuminuria in tests that assessed executive function, such as the Symbol Digit Substitution Test and Trail Making Test B, but no between-group differences were observed in tests that primarily assessed memory. Such a pattern of findings is more consistent with a diagnosis of dementia of the vascular type than with a diagnosis of Alzheimer dementia, as memory is most often affected in dementia of Alzheimers type. In this study, albuminuria was also found to be associated with increased white matter intensity on MRI, supporting the theory that cerebrovascular disease was probably the cause of the cognitive impairment. Individuals enrolled in the Cardiovascular Health Study 6 also underwent cranial imaging. Results of both cognitive testing and imaging were interpreted by an independent panel who determined whether the dementia was likely to be pure Alzheimers type dementia or vascular-type dementia (with or without features of Alzheimer disease). The results showed that an increased serum creatinine level was associated with a 58% increase in the incidence of vascular dementia but with no increase in the incidence of Alzheimer dementia. Vascular events such as stroke are intimately linked with dementia, with community-based studies in the general population suggesting that recent stroke is associated with a ninefold increase in the risk of dementia.10 Based on these data, the risk of vascular disease, and correspondingly of stroke prevalence, seems to be higher in patients with CKD and patients on dialysis than in the general population, partly because CKD and vascular disease share common risk factors (for example, diabetes, hypertension, hypercholesterolemia and increasing age). Some studies suggest, however, that the risk of stroke in patients with CKD is higher than can be explained by the common risk pathways.1012 Together with their increased risk of clinically apparent cerebrovascular disease, patients with CKD (including those on dialysis)
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Table 1 | Examples of psychometric tests used to evaluate cognitive function* Test
Modified Mini-Mental State Examination (3MS) Trail Making Tests A and B Verbal Fluency Test Word List Memory Word List Recall Boston Naming Test Stroop Test

Details of test
15-item test commonly used in clinical practice Paper-and-pen test that requires the ability to see and read numbers and letters Verbal test where the patient is asked to name as many animals as possible in 60 s Patient is given a list of words and asked to repeat it immediately Patient is distracted (usually by performing the next test in the battery) and then asked to recall the word list previously given Assesses the ability to name objects shown in a picture; patients experiencing difficulty are given prompts A test using written words and colors in which the patient is asked to name colors or read words as quickly as possible; often the words do not correspond to the color (e.g. the word green would be written in blue ink challenging the patient to correctly report the ink color) A test measuring the time it takes to react to a stimulus Patient is asked to translate symbols into words/letters; can be done in the opposite directionwhere patients must change letters into symbolsthe Digit Symbol Substitution Test) Patient is asked to recall digits in order Patient is asked to sort images into numeric categories

Function(s) assessed
Global cognitive function Attention, visual searching, mental processing speed, and the ability to mentally control simultaneous stimulus patterns Working and semantic memory Immediate memory Short-term memory Inferences can be drawn regarding language facility and possible localization of cerebral damage Attention, mental speed and mental control

Simple Reaction Time Test Symbol Digit Substitution Test Serial Digit Learning Test Halstead Category Test

Visual-motor speed Visual attention

Learning, recall and concentration Measures concept learning and examines flexibility of thinking and openness to learning; a good measure of overall brain function Several aspects of verbal learning, organization and memory Auditory working memory Auditory focused attention and working memory Attention, alertness and mental processing capacity

California Verbal Learning Test Letter Number Sequencing Digit Span Digit Vigilance Test

Patient is asked to read a list of words and asked to recall them over a series of trials Patient is given a list of letters and numbers and asked to repeat them back in numerical and alphabetical order Patient is asked to repeat items such as the numbers 123 in reverse sequence Patient is given a page of numbers and asked to cross out the number 6 wherever it appears

*A battery (combination) of tests is often used together to evaluate the different domains of cognitive function.

also have a high prevalence of subclinical infarction or leukoaraiosis on neuroimaging.1315 Nonvascular factors probably also have a role in the high prevalence of cognitive impairment seen in patients with CKD. As in the general population, individuals with apoE4 genotype, thyroid abnormalities, Parkinson disease and some neurodegenerative disorders are at increased risk of dementia,16 but it is unknown if the risk of cognitive impairment is increased further when these disorders are combined with CKD. Most individuals with CKD are also at risk of accelerated decline in cognitive function due to specific factors inherent to renal failure, including anemia, hyperparathyroidism, uremia and dialysis disequilibrium. Elias et al.17 noted that even after adjustment for vascular risk factors including stroke, patients with CKD stage 3 or higher performed poorly on cognitive testing, suggesting that other culprits are involved, probably factors associated with CKD itself. Anemia is an independent risk factor for dementia among individuals aged 65 years in the general population. 1820 The exact reason for this increased risk is unclear but common hypotheses are that anemia leads to reduced oxygen delivery and
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altered brain metabolism or that the effects are related directly to erythropoietin deficiency. Erythropoietin and its receptors are expressed in the cerebral cortex, cerebellum, hippocampus, pituitary gland and spinal cord.21 Animal and cellular signaling studies have suggested that erythropoietin-stimulating agents have neurotrophic and neuroprotective properties. 21 In vitro erythropoietin and its derivatives protect against glutamateinduced cell death, which in turn limits the effects of hypoxic or traumatic damage.2125 Early small studies in patients on dialysis showed that correction of anemia improved mental functioning; 2628 however, in more recent large-scale studies, neither erythropoietin nor its derivatives have shown the expected beneficial clinical effects in CKD populations.2931 In fact, some studies have now shown that vascular risk is increased at higher hemoglobin levels in patients with CKD.2931 The role of parathyroid hormone in normal brain function is unclear. Parathyroid hormone receptors are present in the brain and good evidence from animal models indicates that secondary hyperparathyroidism is associated with increased intracellular calcium content, which may directly interfere with neurotransmission.32
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Table 2 | Key studies that examined the relationship between CKD and cognitive impairment Study
REGARDS (2008)5 HERS (2005)99

Study design
CS

n
23,000

Study population
Nationally representative sample of US adults aged >45 years Menopausal women with coronary artery disease; mean age 67 years US adults aged 2059 years

Testing method
Six-item Screener

Results
Odds ratio of cognitive impairment 1.23 in patients with CKD (vs non-CKD) 5-fold risk of cognitive impairment if eGFR <30 ml/min/1.73 m2; incremental increase in risk of cognitive impairment with decreasing eGFR Moderate CKD associated with poorer learning, concentration and visual attention Albuminuria (but not GFR) associated with worse cognitive performance (particularly executive function) 37% of hemodialysis patients had severe cognitive impairment, 36% had moderate cognitive impairment and 13% had mild cognitive impairment Poorer baseline cognitive function and a more rapid decline in function among individuals with lower eGFR Moderate renal insufficiency associated with a 37% increase in the risk of incident dementia over 6 years Increased risk of cognitive decline associated with a 15 ml/min lower eGFR at baseline (similar to the effect of being 3 years older) Increased risk of cognitive decline even with mild renal impairment (eGFR 6090 ml/min); faster decline in performance over time in individuals with CKD

CS

1,015

3MS, Trail Making Test B, Boston Naming Test, Verbal Fluency Test, Word List Memory and Word List Recall Symbol Digit Substitution, Serial Digit Learning and Simple Reaction Time Full neuropsychological battery Battery of tests including 3MS and 7 additional psychometric tests 3MS Battery of 12 psychometric tests Collection of 19 cognitive tests Modified Telephone Interview for Cognitive Status

NHANES III (2007)100 NAME (2009)101 Murray et al. (2006)4 Health ABC (2005)7 CHS (2004)6

CS

4,849

CS CS

335 338

Homebound elders; mean age 73 years Prevalent hemodialysis patients White and black US adults; mean age 74 years US adults aged >65 years without dementia at baseline; mean age 75 years Elderly nursing home residents without dementia at baseline Community-based study of individuals mostly aged >70 years; 59% Hispanic

LT LT

3,034 3,349

Buchman et al. (2009)8 Khatri et al. (2009)11

LT

886

LT

2,172

Abbreviations: 3MS, Modified Mini-Mental State Examination; CKD, chronic kidney disease; CS, cross-sectional; eGFR, estimated glomerular filtration rate; LT, longitudinal.

In 5/6-nephrectomized dogs, parathyroidectomy is associated with reduced calcium accumulation and normalization of the electroencephalogram.33 Similarly, treatment with parathyroidectomy or vitamin D analogues has been reported to lead to electroencephalogram improvements in patients with CKD.32,3437 Untreated uremia is associated with encephalopathy characterized by progressive mental lassitude, which eventually leads to coma and seizures. In 1983, the National Cooperative Dialysis Study showed that improvements in cognitive function occurred following dialysis initiation;38 however, as dialysis is now initiated at much earlier stages of renal disease, this observation may not be of current clinical relevance. Although it may stand to reason that more dialysis may decrease uremia and improve cognitive functioning, the existence of such a link has yet to be established. The process of dialysis itself may contribute to a worsening of cognitive impairment either by causing large, rapid shifts in fluid and urea (dialysis disequilibrium) or by causing intradialytic cerebral hypoperfusion and hypoxia associated with changes in circulating volume.3945 In a cross-sectional study of prevalent dialysis patients, cognitive function was worst during a dialysis session and best shortly before the dialysis session.46 Indeed, increased dialysis clearance has only been shown to be of modest benefit in one small study that compared nocturnal hemodialysis with conventional hemodialysis,47 but a study comparing short (2 h) daily hemodialysis with conventional hemodialysis did not find any clear beneficial effects of short
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daily hemodialysis on cognitive function.48 Although the improvements in cognitive function seen with nocturnal hemodialysis might be the result of the increased removal of urea and other toxins, the improvements may equally be the result of the reduction in rapid fluid and electrolyte shifts that occur with short daily or conventional thrice-weekly hemodialysis. A study comparing highflux and low-flux membranes in patients on hemodialysis showed little benefit of increased clearance with high-flux membranes on neuropsychological function.49 In addition, a cross-sectional study by Murray et al. found that higher dialysis adequacy (Kt/V >1.2) was actually associated with an increased risk of cognitive impairment.39 This latter observation may be an artifact, however, as improved dialysis clearance may vary collinearly with frailty and malnutrition. Consequently, we must conclude that the beneficial effects of more frequent, less intense dialysis on cognitive function remain unproven. A large, randomized controlled study sponsored by the NIH will hopefully provide more definitive answers.50 Studies comparing the effects of peritoneal dialysis and hemodialysis on cognitive function are limited. As peritoneal dialysis is less likely than hemodialysis to induce hypotension, the burden of cerebral hypoxia and hypoperfusion might be expected to be lower with peritoneal dialysis. Although some evidence indicates that cerebral oxygenation and carotid blood flow, and consequently cognitive function, might be better in patients on peritoneal dialysis than in patients on hemodialysis, this idea has not been well studied.51,52 Analyses of USRDS
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data have shown the rate of prevalent dementia to be slightly lower in the peritoneal dialysis population than in the hemodialysis population, but this finding might be explained by implicit differences in patient selection for the two modalities.53
Box 2 | Four key features of delirium according to DSM-IV2
A disturbance of consciousness with reduced ability to focus, sustain, or shift attention A change in cognition or the development of a perceptual disturbance that is not better accounted for by a pre-existing, established, or evolving dementia The disturbance develops over a short period of time, and tends to fluctuate during the course of the day Findings on history, physical examination, or laboratory testing that the disturbance is caused by a medical condition, substance intoxication, or medication side effect
Abbreviation: DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Fourth Edition 2000 American Psychiatric Association.

Delirium
Definition Delirium is a transient or acute deterioration in brain function that often occurs in association with acute illness or toxicity. This condition occurs in up to 30% of elderly hospitalized patients and is associated with poor outcomes (for example, longer hospitalization and an increased risk of mortality).5456 The gold standard definition for delirium comes from the DSM-IV, and lists four key features (Box 2).2 Additional features that can accompany delirium include psychomotor behavioral disturbances such as hypoactivity, hyperactivity with increased sympathetic activity, and impairment in sleep duration and sleep architecture (that is, sleep stages determined by polysomnography). Varying degrees of emotional disturb ances, such as fear, depression, euphoria and perplexity, may also be seen. Predisposing factors Factors associated with an increased susceptibility to delirium among patients with CKD include the following: accelerated cerebrovascular disease, a high rate of sensory loss, polypharmacy, an underlying metabolic disturbance and rapid solute shifts during dialysis. In addition, hospitalization is a common precipitant for delirium, particularly in individuals with mild cognitive impairment. As patients with CKD have high hospitalization rates, it is likely that patients with CKD experience higher rates of delirium than is currently appreciated. Changes in drug metabolism and the clearance of certain drugs and their potentially toxic metabolites may further predispose individuals with CKD to acute confusional states. We have limited further discussion to agents that are commonly associated with overdosing and neurotoxicity in CKD populations, including antibiotics and antiviral agents, opioid analgesics such as morphine and related compounds, and gabapentin, which is used increasingly for neuropathic pain. Many other drugs may also, however, predispose to delirium. Morphine toxicity can precipitate delirium, drowsiness, and respiratory depression, particularly in the CKD population.57,58 Although morphine itself is predominantly metabolized by the liver, metabolites such as morphine-3-glucuronide and morphine-6-glucuronide accumulate in patients with renal impairment.57,58 These metabolites are at least as potent as their precursors and can lead to toxicity. By the same token, however, adequate dosing can be challenging as dialysis clears metabolites to a variable degree depending on drug binding and serum albumin levels.59,60 Sadly, there does not seem to be an easy method to ensure maximal effectiveness with minimal toxicity, and clinicians are best advised to maintain a high index of suspicion for adverse effects throughout morphine treatment.
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Gabapentin is increasingly used for the treatment of painful diabetic neuropathy. The clearance of gabapentin is dependent on renal function.57,58 The average half-life of gabapentin in uremic patients not on hemodialysis is 132 h, but it is rapidly cleared in patients on dialysis.57,58 Gabapentin-related neurotoxicity manifests as an altered level of consciousness, dizziness and/or vomiting. Dose reduction is necessary in patients with CKD and those on dialysis and recent recommendations in the dialysis population are for a 400 mg loading dose followed by 200300 mg after each dialysis session (thrice weekly assuming thrice-weekly dialysis).61 High levels of aciclovir, valaciclovir and ganciclovir can also lead to neurotoxicity.6264 Aciclovir is typically used for the treatment of the painful cutaneous lesions of herpes zoster virus infection. This agent can also be given intravenously to treat the life-threatening conditions of herpes simplex encephalitis or varicella zoster encephalitis. Aciclovir is almost entirely cleared by the kidneys in its unmetabolized form and as the main metabolite 9-carboxymethoxymethylguanine (CMMG). Despite dose reductions, aciclovir treatment may be associated with delirium in patients with end-stage renal disease (ESRD).6264 The exact mechanism for delirium associated with aciclovir is unclear, particular as CMMG has a low volume of distribution, is water soluble, and is easily dialyzed as it has low protein-binding capacity.65 Serum levels of aciclovir are often unhelpful for monitoring risk of neuro toxicity as they do not typically corre late with neuropsychiatric manifestations of toxicity. The unpredictability of the occurrence of drug-related delirium can lead to clinical confusion as both aciclovir and one of the diseases it is used to treatherpes simplex encephalitisare associated with severe agitation. Adequate dialysis (preferably on a daily schedule) and discontinuation of aciclovir as soon as clinically possible generally leads to full recovery from aciclovir-related neurotoxicity. The cephalosporin group of antibiotics is one of the most commonly used antibiotic types in nephrology clinical practice. These drugs offer good broad-spectrum coverage and excellent tissue penetration and are easily administered thrice weekly to patients on dialysis. Use of cephalosporins is sometimes, although rarely, complicated by neurotoxicity, particularly in older individuals
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on dialysis.6668 The clinical picture is variable and can range from a mild delirium through to convulsions, status epilepticus, choreoathetosis, coma and death. Cefepime, a fourth-generation cephalosporin, is the cephalosporin agent most commonly implicated in neurotoxicity in dialysis patients in recent literature. The concentration of cefepime in the spinal fluid is said to rise in patients with renal failure due to competitive inhibition of the active transport of cefepime from the cerebrospinal fluid to the blood by accumulation of toxic organic acids, increased bloodbrain barrier perme ability, and low serum protein binding.6668 The main mechanism of cephalosporin neurotoxicity involves a decrease in the release of -aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system. Inhibition of GABA receptors by -lactams leads to hyperexcitability of neurons and reduces the seizure threshold.6668 In contrast to penicillins, which bind reversibly to GABA, cephalosporins bind irreversibly, which explains their greater potential to cause neurotoxicity.6668 help orientation if a clock is clearly visible. Following routines closely, such as using the same dialysis spot and the same nursing staff can also help reduce the risk of clinically overt delirium. Rooms should be well lit during the day, and all measures taken to ensure a dark and quiet environment at night to facilitate good sleep. Pharmacological interventions, such as haloperidol (believed by some to be the preferred drug of choice for acute delirium), risperidone and olanzapine should be used only for short periods of time so as to avoid accumulation and neurotoxicity.69

Depression
Definition The World Health Organization defines depression as a common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration. Depression is relatively common in patients with all stages of CKD and in those with ESRD, with most studies from the past decade estimating that 2030% of such individuals are depressed.7077 By contrast, in the general population, depression is present in 24% of individuals in the community and 510% of individuals in the primary care setting in the US.78 Depression seems to be more common among patients with CKD than among those other chronic diseases, affecting approximately 14% of patients with congestive heart disease and 16% of patients surviving acute myocardial infarction.79,80 The risk of depression is maximal around the time of dialysis initiation.75 Some concern has been expressed that patient-administered questionnaires such as the Beck Depression Index may overestimate the prevalence of depression as they may confuse symptoms of renal failure with the somatic manifestations of depression. Self-report scales have, however, been validated in this population70,73,74 and do correlate with outcomes.77,81,82 Clinical implications A diagnosis of depression is associated with poor outcomes in the dialysis population.77,81,82 A 2006 study that assessed 98 consecutive patients on hemodialysis found that the risk of death or hospitalization was more than twofold greater in the 26 patients with a physician-made diagnosis of depression than it was in patients without depression, a finding that was independent of other risk factors.73 A larger retrospective study of patients on hemodialysis found that mortality rates were higher in those who had either a formal diagnosis of depression or reported symptoms of depression than in those without depression.81 An earlier study suggested that a single score in the depressed range on the Beck Depression Index was not predictive of mortality but that averaged higher scores for depressive symptoms over multiple assessments were significantly associated with increased mortality.77 This finding supports the case for longitudinal screening for depression in the dialysis population. A number of suggestions have been made to explain why depression portends an increased risk of mortality
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Management of dementia and delirium

The treatment options for dementia in patients with CKD are similar to those used in the general population: screening, patient and family education, the introduction of nonpharmacological supports and, lastly, pharmacological interventions. The recognition that dementia is highly prevalent in the CKD population is an important first step in management. The screening of all patients with CKD is advised but to date no consensus exists as to the best neuropsychiatric test to employ. Tests of global cognitive ability are quick and easily administered but are poor at detecting subtle impairment; by contrast, an extensive battery of tests (which is more likely to detect subtle impairment) may prove too time-consuming in the clinical setting. As cognitive impairment is probably at its worst during a dialysis session, attempts should be made to discuss care plans or treatment changes prior to dialysis and not during the session itself. Although acetylcholinesterase inhibitors seem to be safe in patients with CKD, their efficacy in dementia remains unclear. Studies performed specifically in the CKD population and in the dialysis population are needed before their use can be widely recommended. Challenging cases, and individuals whose condition declines rapidly, are often best managed by a psychogeriatrician who has an interest in, or experience with, patients on dialysis. Unfortunately, the utility of the various drugs that are available for the management of dementia in the general population may be limited as the predominant type of dementia in patients with CKD is of the vascular rather than the Alzheimers type. Even mild cognitive changes can precipitate acute delirium, and recurrent episodes of delirium can accelerate dementia. The incidence of delirium among hospitalized patients can be reduced by the use of simple nonpharmacological measures that help to orientate patients and ensure adequate sleep during hospitalization.69 For example, informing and reminding patients of exactly what time they will be taken for dialysis may
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in the dialysis population. Depressed patients may be more likely to commit suicide, withdraw from treatment or refuse treatment. Nonadherence is a frequently encountered problem in clinical practice. In the Dialysis Outcomes and Practice Patterns (DOPPS) study, 8% of US hemodialysis patients skipped one or more sessions per month and almost 20% regularly shortened their session.83 Such nonadherence was strongly associated with adverse outcomes: patients who skipped or shortened sessions were more likely to die or be hospitalized than more adherent patients. Suicide rates among dialysis patients are almost 15 times higher than in the general population and are higher than in patients with cancer.8486 Depression also seems to be the single most important predictive factor for poor adherence to medication in hemodialysis patients. 83,87,88 In a 2002 report of the DOPPS study, patients with depression were 1.6 times more likely than patients without depression to either skip or shorten hemodialysis sessions, independent of other risk factors.83 Interestingly, patients on peritoneal dialysis who report symptoms of depression are also twice as likely to develop peritonitis than peritoneal dialysis patients without depression.89 Another possible explanation for the increased mortal ity risk seen in depressed dialysis patients is the relationship between depression, malnutrition and inflammation. Malnutrition is a clinical sequelae of inflammation and is more common in dialysis patients with depression than in dialysis patients without depression.90,91 In addition, inflammation is commonly seen in patients with CKD,14 and seems to independently drive depression.92 The combination of these factors, together with the observation that depression can itself upregulate inflammatory mediators, sets up a cycle of depression, inflammation and malnutrition. A low level of serotonin, which has long been associated with depression, is known to predispose patients to vascular abnormalities such as reversible platelet aggregation.93,94 These changes can be reversed using medications such as serotonin reuptake inhibitors (SSRIs),95 but studies confirming that SSRIs are associated with improved survival in dialysis patients are still lacking. as those in the general population, where broadly speaking the patient is treated with either cognitive behavioral therapy or with pharmacotherapy. Further randomized control trials investigating the efficacy and safety of SSRIs in the ESRD population are greatly needed, but the available literature suggests that these drugs are well tolerated, safe and effective.76,96,97 Concerns regarding their safety are based on pharmacokinetic observations of the potential for the accumulation of metabolites rather than actual observed toxicity. More recently, interest in the use of cognitive behavioral therapy in depressed patients on dialysis has increased, and application of this technique has shown initial promising results.98

Conclusions

Dementia, delirium and depression are all common conditions in patients with early stages of CKD and in those with ESRD treated with dialysis. Although dementia, delirium and depression are distinct disorders, depression can present with features of dementia, dementia can predispose to delirium, and delirium can be predictive of subsequent dementia. The full extent and scope of the neuropsychiatric complications of CKD have only recently become apparent. Cognitive function, which is now recognized to start to deteriorate early in the course of renal disease, is impaired in almost 90% of dialysis-dependent patients,40 and impaired cognitive function is strongly associated with an increased risk of mortality. Hemodialysis treatment is far from a panacea; although it may temporarily address the toxic and metabolic imbalance in patients with CKD, it does so at the expense of cerebral perfusion, inducing recurrent cerebral edema and hypotension. Additional measures for limiting delirium, detecting and minimizing the effect of dementia on day-to-day activities and aggressively treating depression are needed.
Review criteria
The information referenced in this Review was compiled by performing MEDLINE searches using the terms dementia, cognitive impairment and depression combined with the terms chronic kidney disease, hemodialysis and peritoneal dialysis. Further references were found by reviewing the reference lists of recent studies. Only articles written in English or German were included.

Treatment Once a patient with CKD has been diagnosed with depression, the treatment options are largely the same
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