Neuropsychiatric Complications of Chronic

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Toronto GeneralHospital, 200 ElizabethStreet, 8N-825,Toronto, ON M5G 2C4,Canada (R. McQuillan,S. V. Jassal).

Correspondence to:S. V. Jassalvanita.jassal@ uhn.on.ca

Neuropsychiatric complications of chronic

kidney diseaseRory 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, 471–479 (2010); published online 22 June 2010; doi:10.1038/nrneph.2010.83

IntroductionAs early as 1858, Addison published an essay suggesting that disturbances in brain function are associated withsymptoms of progressive uremia and chronic kidneydisease (CKD).1 He stated, “Of all the more seriousaffections of the brain arising in connection with renaldisease, the mildest form appears to be that of a tendencyto a state of quiet stupor, varying in degree from a meretorpidity of manner and sluggishness of intellect, to com-plete insensibility to all surrounding objects.”1 Althoughadvanced progressive uremia is now rarely seen owingto the widespread availability of dialysis, an associa-tion remains between earlier stages of CKD and cogni-

tive impairment, depression and susceptibility to acuteconfusional states. These associations are importantclinically, as neuropsychiatric disturbances have beenshown to be associated with increased patient mortality,increased rates of hospitalization and poor adherencewith treatments. This Review discusses the main clinicalneuropsychiatric features associated with renal diseasein three sections: dementia and cognitive impairment,delirium and depression.

Dementia and cognitive impairment

Definition and consequences

Dementia is a clinical state characterized by loss of func-

tion in multiple cognitive domains. The most commonlyused criteria for the diagnosis of dementia are based onthe Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) coding system published by theAmerican Psychiatric Association.2 To be given a diag-nosis of dementia, a patient must experience a declinein memory from previously higher levels of functioning

together with at least one of the following: aphasia,apraxia, agnosia or disturbances in executive function-ing (defined in Box 1). A diagnosis of dementia cannotbe made if def icits occur exclusively during the courseof a delirium. Cognitive impairment must be severeenough to affect a patient’s ability to function in theirwork, personal or social environment. Milder degrees of cognitive impairment, which may not affect day-to-daylife, are sometimes termed ‘mild cognitive impairment’.Dementia seems to be a powerful predictor of mortalityin dialysis patients.3 An analysis of United States RenalData System (USRDS) data found that among hemo-

dialysis patients, dementia was associated with a higherrisk of mortality than were either heart failure or stroke(hazard ratio for death was 1.90 with dementia versus1.28 with heart failure and 1.20 with stroke).3

Prevalence and progression in renal populations

Cognitive impairment and dementia seem to be highlyprevalent in patients with renal disease. Much of theevidence suggests that cognitive impairment is mostcommon among patients who are established on dialy-sis. A 2006 study of prevalent dialysis patients foundthat almost all hemodialysis patients aged ≥55 yearshad some evidence of cognitive impairment, with only

13% of individuals classified as having normal cogni-tion.4 Although comparing the prevalence of cognitiveimpairment across various populations can be difficult—owing to differences in the types of tests used (Table 1)and differences in study design—this study showed thatalmost 40% of hemodialysis patients had severe cognitiveimpairment with features compatible with, in the view ofthe study authors, a diagnosis of dementia. Interestingly,cognitive impairment was documented in the medicalrecords as a comorbid condition in less than 3% of theentire study population.

Cognitive impairment does not, however, occuronly in patients with advanced stages of CKD: it is

Competing interests

S. V. Jassal declares associations with the following companies:Amgen, Baxter, Ortho Biotech. See the article online for fulldetails of the relationships. R. McQuillan declares no competinginterests.

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seen across the whole spectrum of CKD. Much of thedata supporting this observation in the nondialysisCKD population comes from large, population-basedstudies (Table 2). Key studies include the Reasonsfor 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 compari-

sons between these studies are limited by variations inthe populations recruited, tests used, and study design(longitudinal versus cross-sectional), all showed animpressive relationship between reduced kidney func-tion and increased burden of cognitive dysfunction. Thelargest of these studies, the REGARDS study,5 recruited anationally representative sample of over 23,000 US adultsaged ≥45 years. Individuals were tested using a six-itemtest of memory and attention. Individuals were said tohave CKD if their estimated glomerular filtration rate(eGFR) was <60 ml/min/1.73 m2. Using a cross-sectionalapproach, the researchers found that presence of CKDwas associated with a 23% increase in the prevalence of

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

cognitive impairment (even after adjustment for demo-graphic characteristics, prevalent cardiovascular diseaseand cardiovascular risk factors). Exploratory analysessuggested that the association was nonlinear, with thehighest risk of cognitive impairment occurring in thosewith an eGFR <50 ml/min/1.73 m2 and only a modestrisk in those with an eGFR within the range 50–70 ml/min/1.73 m2. A number of longitudinal studies have shedfurther light on the relationship between CKD and cogni-tive function.6–8 Findings from these studies suggestedthat CKD is both a risk factor for the development ofdementia and is also associated with a more rapid declinein cognitive function over time. Details of other studieswith similar findings are summarized in Table 2.

Possible etiologies

Cognitive impairment can be categorized as being ofeither vascular or nonvascular etiology. In a cross-sectional study of 335 homebound individuals aged≥60 years, the presence of albuminuria, a surrogate formicrovascular disease in the kidney, was independently

associated with worse cognitive function.9 Individualswith microalbuminuria had worse performance thanindividuals without microalbuminuria in tests thatassessed executive function, such as the Symbol DigitSubstitution Test and Trail Making Test B, but nobetween-group differences were observed in tests thatprimarily assessed memory. Such a pattern of find-ings is more consistent with a diagnosis of dementia ofthe vascular type than with a diagnosis of Alzheimerdementia, as memory is most often affected in demen-tia of Alzheimer’s type. In this study, albuminuria wasalso found to be associated with increased white matterintensity on MRI, supporting the theory that cerebro-

vascular disease was probably the cause of the cognitiveimpairment. Individuals enrolled in the CardiovascularHealth Study 6 also underwent cranial imaging. Resultsof both cognitive testing and imaging were interpretedby an independent panel who determined whether thedementia was likely to be pure Alzheimer’s type dementiaor vascular-type dementia (with or without features ofAlzheimer disease). The results showed that an increasedserum creatinine level was associated with a 58% increasein the incidence of vascular dementia but with noincrease in the incidence of Alzheimer dementia.

Vascular events such as stroke are intimately linkedwith dementia, with community-based studies in the

general population suggesting that recent stroke isassociated with a ninefold increase in the risk of demen-tia.10 Based on these data, the risk of vascular disease, andcorrespondingly of stroke prevalence, seems to be higherin patients with CKD and patients on dialysis than inthe general population, partly because CKD and vasculardisease share common risk factors (for example, diabetes,hypertension, hypercholesterolemia and increasing age).Some studies suggest, however, that the risk of strokein patients with CKD is higher than can be explainedby the common risk pathways.10–12 Together with theirincreased risk of clinically apparent cerebrovasculardisease, patients with CKD (including those on dialysis)

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 ar ticulate 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 atwhich that is done) is termed ‘psychomotor speed’ or

‘processing speed’.

Executive function

An overall term that refers to the cognitive process that

regulates an individual’s ability to organize thoughts andactivities, prioritize tasks, manage time efficiently and

make decisions; impairment of executive function is seen

in a range of disorders.

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also have a high prevalence of subclinical infarction orleukoaraiosis on neuroimaging.13–15

Nonvascular factors probably also have a role in thehigh prevalence of cognitive impairment seen in patientswith CKD. As in the general population, individuals withapoE4 genotype, thyroid abnormalities, Parkinsondisease and some neurodegenerative disorders are atincreased risk of dementia,16 but it is unknown if therisk of cognitive impairment is increased further whenthese disorders are combined with CKD. Most indivi-

duals with CKD are also at risk of accelerated declinein cognitive function due to specific factors inherent torenal failure, including anemia, hyperparathyroidism,uremia and dialysis disequilibrium. Elias et al.17 notedthat even after adjustment for vascular risk factorsincluding stroke, patients with CKD stage 3 or higherperformed poorly on cognitive testing, suggesting thatother culprits are involved, probably factors associ-ated with CKD itself. Anemia is an independent riskfactor for dementia among individuals aged ≥65 yearsin the general population.18–20 The exact reason forthis increased risk is unclear but common hypothesesare that anemia leads to reduced oxygen delivery and

altered brain metabolism or that the effects are relateddirectly to erythropoietin deficiency. Erythropoietin andits receptors are expressed in the cerebral cortex, cere-bellum, hippocampus, pituitary gland and spinal cord.21 Animal and cellular signaling studies have suggested thaterythropoietin-stimulating agents have neurotrophicand neuroprotective properties.21 In vitro erythro-poietin and its derivatives protect against glutamate- induced cell death, which in turn limits the effects ofhypoxic or traumatic damage.21–25 Early small studies in

patients on dialysis showed that correction of anemiaimproved mental functioning;26–28 however, in morerecent large-scale studies, neither erythropoietin nor itsderivatives have shown the expected beneficial clinicaleffects in CKD populations.29–31 In fact, some studieshave now shown that vascular risk is increased at higherhemoglobin levels in patients with CKD.29–31

The role of parathyroid hormone in normal brainfunction is unclear. Parathyroid hormone receptors arepresent in the brain and good evidence from animalmodels indicates that secondary hyperparathyroidism isassociated with increased intracellular calcium content,which may directly interfere with neurotransmission.32

Table 1 | Examples of psychometric tests used to evaluate cognitive function*

Test Details of test Function(s) assessed

Modified Mini-Mental StateExamination (3MS)

15-item test commonly used in clinical practice Global cognitive function

Trail Making Tests A and B Paper-and-pen test that requires the ability to see and readnumbers and letters

Attention, visual searching, mental processing speed, andthe ability to mentally control simultaneous stimulus patterns

Verbal Fluency Test Verbal test where the patient is asked to name as many

animals as possible in 60 s

Working and semantic memory

Word List Memory Patient is given a list of words and asked to repeatit immediately

Immediate memory

Word List Recall Patient is distracted (usually by performing the next test in thebattery) and then asked to recall the word list previously given

Short-term memory

Boston Naming Test Assesses the ability to name objects shown in a picture;patients experiencing difficulty are given prompts

Inferences can be drawn regarding language facilityand possible localization of cerebral damage

Stroop Test A test using written words and colors in which the patient isasked to name colors or read words as quickly as possible;often the words do not correspond to the color (e.g. the wordgreen would be written in blue ink challenging the patient tocorrectly report the ink color)

Attention, mental speed and mental control

Simple Reaction Time Test A test measuring the time it takes to react to a stimulus Visual-motor speed

Symbol Digit Substitution

Test

Patient is asked to translate symbols into words/letters; can

be done in the opposite direction—where patients must changeletters into symbols—the Digit Symbol Substitution Test)

Visual attention

Serial Digit Learning Test Patient is asked to recall digits in order Learning, recall and concentration

Halstead Category Test Patient is asked to sort images into numeric categories Measures concept learning and examines flexibilityof thinking and openness to learning; a good measure ofoverall brain function

California Verbal LearningTest

Patient is asked to read a list of words and asked to recall themover a series of trials

Several aspects of verbal learning, organization and memory

Letter Number Sequencing Patient is given a list of letters and numbers and askedto repeat them back in numerical and alphabetical order

Auditory working memory

Digit Span Patient is asked to repeat items such as the numbers 1–2–3in reverse sequence

Auditory focused attention and working memory

Digit Vigilance Test Patient is given a page of numbers and asked to cross out the

number 6 wherever it appears

Attention, alertness and mental processing capacity

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

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In 5/6-nephrectomized dogs, parathyroidectomy isassociated with reduced calcium accumulation andnormalization of the electroencephalogram.33 Similarly,treatment with parathyroidectomy or vitamin D ana-

logues has been reported to lead to electroencephalogramimprovements in patients with CKD.32,34–37

Untreated uremia is associated with encephalo-pathy characterized by progressive mental lassitude,which eventually leads to coma and seizures. In 1983,the National Cooperative Dialysis Study showed thatimprovements in cognitive function occurred followingdialysis initiation;38 however, as dialysis is now initiatedat much earlier stages of renal disease, this observationmay not be of current clinical relevance. Although it maystand to reason that more dialysis may decrease uremiaand improve cognitive functioning, the existence of sucha link has yet to be established. The process of dialysis

itself may contribute to a worsening of cognitive impair-ment either by causing large, rapid shifts in fluid andurea (dialysis disequilibrium) or by causing intradialyticcerebral hypoperfusion and hypoxia associated withchanges in circulating volume.39–45 In a cross-sectionalstudy of prevalent dialysis patients, cognitive functionwas worst during a dialysis session and best shortlybefore the dialysis session.46 Indeed, increased dialysisclearance has only been shown to be of modest benefit inone small study that compared nocturnal hemodialysiswith conventional hemodialysis,47 but a study comparingshort (2 h) daily hemodialysis with conventional hemo-dialysis did not find any clear beneficial effects of short

daily hemodialysis on cognitive function.48 Although theimprovements in cognitive function seen with nocturnalhemodialysis might be the result of the increased removalof urea and other toxins, the improvements may equally

be the result of the reduction in rapid fluid and electro-lyte shifts that occur with short daily or conventionalthrice-weekly hemodialysis. A study comparing high-flux and low-flux membranes in patients on hemodialysisshowed little benefit of increased clearance with high-fluxmembranes on neuropsychological function.49 In addi-tion, a cross-sectional study by Murray et al. found thathigher dialysis adequacy (Kt /V >1.2) was actually associ-ated with an increased risk of cognitive impairment.39 This latter observation may be an artifact, however, asimproved dialysis clearance may vary collinearly withfrailty and malnutrition. Consequently, we must concludethat the beneficial effects of more frequent, less intense

dialysis on cognitive function remain unproven. A large,randomized controlled study sponsored by the NIH willhopefully provide more definitive answers.50

Studies comparing the effects of peritoneal dialysis andhemodialysis on cognitive function are limited. As peri-toneal dialysis is less likely than hemodialysis to inducehypotension, the burden of cerebral hypoxia and hypo-perfusion might be expected to be lower with peritonealdialysis. Although some evidence indicates that cerebraloxygenation and carotid blood flow, and consequentlycognitive function, might be better in patients on peri-toneal dialysis than in patients on hemodialysis, thisidea has not been well studied.51,52 Analyses of USRDS

Table 2 | Key studies that examined the relationship between CKD and cognitive impairment

Study Study

design

n Study population Testing method Results

REGARDS

(2008)5

CS 23,000 Nationally r epresentativesample of US adults aged>45 years

Six-item Screener Odds ratio of cognitive impairment 1.23 in patientswith CKD (vs non-CKD)

HERS

(2005)99

CS 1,015 Menopausal women withcoronary artery disease;

mean age 67 years

3MS, Trail Making Test B,Boston Naming Test, Verbal

Fluency Test, Word ListMemory and Word List Recall

5-fold risk of cognitive impairment if eGFR<30 ml/min/1.73 m2; incremental increase in risk

of cognitive impairment with decreasing eGFR

NHANES III

(2007)100

CS 4,849 US adults aged 20–59 years Symbol Digit Substitution,Serial Digit Learning andSimple Reaction Time

Moderate CKD associated with poorer learning,concentration and visual attention

NAME

(2009)101

CS 335 Homebound elders; meanage 73 years

Full neuropsychologicalbattery

Albuminuria (but not GFR) associated with worsecognitive performance (particularly executive function)

Murray et al.

(2006)4

CS 338 Prevalent hemodialysispatients

Battery of tests including3MS and 7 additionalpsychometric tests

37% of hemodialysis patients had severe cognitiveimpairment, 36% had moderate cognitive impairmentand 13% had mild cognitive impairment

Health ABC

(2005)7

LT 3,034 White and black US adults;mean age 74 years

3MS Poorer baseline cognitive function and a more rapiddecline in function among individuals with lower eGFR

CHS (2004)6 LT 3,349 US adults aged >65 yearswithout dementia atbaseline; mean age 75 years

Battery of 12 psychometrictests

Moderate renal insufficiency associated with a 37%increase in the risk of incident dementia over 6 years

Buchman

et al. (2009)8

LT 886 Elderly nursing homeresidents without dementiaat baseline

Collection of 19 cognitivetests

Increased risk of cognitive decline associated with a15 ml/min lower eGFR at baseline (similar to the effectof being 3 years older)

Khatri et al.

(2009)11

LT 2,172 Community-based study ofindividuals mostly aged>70 years; 59% Hispanic

Modified Telephone Interviewfor Cognitive Status

Increased risk of cognitive decline even with mild renalimpairment (eGFR 60–90 ml/min); faster decline inperformance over time in individuals with CKD

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

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data have shown the rate of prevalent dementia to beslightly lower in the peritoneal dialysis population thanin the hemodialysis population, but this finding mightbe explained by implicit differences in patient selectionfor the two modalities.53

Delirium

Definition

Delirium is a transient or acute deterioration in brainfunction that often occurs in association with acuteillness or toxicity. This condition occurs in up to 30% ofelderly hospitalized patients and is associated with pooroutcomes (for example, longer hospitalization and anincreased risk of mortality).54–56 The gold standard defini-tion for delirium comes from the DSM-IV, and lists fourkey features (Box 2).2 Additional features that can accom-pany delirium include psychomotor behavioral disturb-ances such as hypoactivity, hyperactivity with increasedsympathetic activity, and impairment in sleep durationand sleep architecture (that is, sleep stages determinedby polysomnography). Varying degrees of emotional

disturbances, such as fear, depression, euphoria andperplexity, may also be seen.

Predisposing factors

Factors associated with an increased susceptibility todelirium among patients with CKD include the follow-ing: accelerated cerebrovascular disease, a high rate ofsensory loss, polypharmacy, an underlying metabolicdisturbance and rapid solute shifts during dialysis. Inaddition, hospitalization is a common precipitant fordelirium, particularly in individuals with mild cognitiveimpairment. As patients with CKD have high hospitaliza-tion 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 mayfurther predispose individuals with CKD to acute confu-sional states. We have limited further discussion to agentsthat are commonly associated with overdosing and neuro-toxicity in CKD populations, including antibiotics andantiviral agents, opioid analgesics such as morphineand related compounds, and gabapentin, which is usedincreasingly for neuropathic pain. Many other drugs mayalso, however, predispose to delirium.

Morphine toxicity can precipitate delirium, drowsi-ness, and respiratory depression, particularly in the

CKD population.57,58 Although morphine itself is pre-dominantly metabolized by the liver, metabolites such asmorphine-3-glucuronide and morphine-6-glucuronideaccumulate in patients with renal impairment.57,58 Thesemetabolites are at least as potent as their precursors andcan lead to toxicity. By the same token, however, adequatedosing can be challenging as dialysis clears metabolitesto a variable degree depending on drug binding andserum albumin levels.59,60 Sadly, there does not seemto be an easy method to ensure maximal effectivenesswith minimal toxicity, and clinicians are best advised tomaintain a high index of suspicion for adverse effectsthroughout morphine treatment.

Gabapentin is increasingly used for the treatment ofpainful diabetic neuropathy. The clearance of gabapentinis dependent on renal function.57,58 The average half-lifeof gabapentin in uremic patients not on hemodialysis is132 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. Dosereduction is necessary in patients with CKD and thoseon dialysis and recent recommendations in the dialysispopulation are for a 400 mg loading dose followed by200–300 mg after each dialysis session (thrice weeklyassuming thrice-weekly dialysis).61

High levels of aciclovir, valaciclovir and ganciclovircan also lead to neurotoxicity.62–64 Aciclovir is typicallyused for the treatment of the painful cutaneous lesions ofherpes zoster virus infection. This agent can also be givenintravenously to treat the life-threatening conditions ofherpes simplex encephalitis or varicella zoster encepha-litis. Aciclovir is almost entirely cleared by the kidneys

in its unmetabolized form and as the main metabolite9-carboxymethoxymethylguanine (CMMG). Despitedose reductions, aciclovir treatment may be associatedwith delirium in patients with end-stage renal disease(ESRD).62–64 The exact mechanism for delirium associ-ated with aciclovir is unclear, particular as CMMGhas a low volume of distribution, is water soluble, andis easily dialyzed as it has low protein-binding cap-acity.65 Serum levels of aciclovir are often unhelpfulfor monitoring risk of neurotoxicity as they do nottypically correlate with neuropsychiatric manifesta-tions of toxicity. The unpredictability of the occurrenceof drug-related delirium can lead to clinical confusion

as both aciclovir and one of the diseases it is used totreat—herpes simplex encephalitis—are associated withsevere agitation. Adequate dialysis (preferably on a dailyschedule) and discontinuation of aciclovir as soon asclinically possible generally leads to full recovery fromaciclovir-related neurotoxicity.

The cephalosporin group of antibiotics is one of themost commonly used antibiotic types in nephrologyclinical practice. These drugs offer good broad- spectrumcoverage and excellent tissue penetration and are easilyadministered thrice weekly to patients on dialysis. Useof cephalosporins is sometimes, although rarely, compli-cated by neurotoxicity, particularly in older individuals

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.

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on dialysis.66–68 The clinical picture is variable and canrange from a mild delirium through to convulsions, statusepilepticus, choreoathetosis, coma and death. Cefepime,a fourth-generation cephalosporin, is the cephalosporinagent most commonly implicated in neurotoxicity indialysis patients in recent literature. The concentration ofcefepime in the spinal fluid is said to rise in patients withrenal failure due to competitive inhibition of the activetransport of cefepime from the cerebrospinal fluid tothe blood by accumulation of toxic organic acids,increased blood–brain barrier permeability, and lowserum protein binding.66–68 The main mechanism ofcephalosporin neurotoxicity involves a decrease in therelease of γ-aminobutyric acid (GABA), the main inhibi-tory neurotransmitter in the central nervous system.Inhibition of GABA receptors by β-lactams leads to hyper-excitability of neurons and reduces the seizure thresh-old.66–68 In contrast to penicillins, which bind reversibly toGABA, cephalosporins bind irreversibly, which explainstheir greater potential to cause neurotoxicity.66–68

Management of dementia and deliriumThe treatment options for dementia in patients withCKD are similar to those used in the general population:screening, patient and family education, the introductionof nonpharmacological supports and, lastly, pharmaco-logical interventions. The recognition that dementia ishighly prevalent in the CKD population is an importantfirst step in management. The screening of all patientswith CKD is advised but to date no consensus exists as tothe best neuropsychiatric test to employ. Tests of globalcognitive ability are quick and easily administered butare poor at detecting subtle impairment; by contrast, anextensive battery of tests (which is more likely to detect

subtle impairment) may prove too time-consuming inthe clinical setting. As cognitive impairment is probablyat its worst during a dialysis session, attempts should bemade to discuss care plans or treatment changes prior todialysis and not during the session itself.

Although acetylcholinesterase inhibitors seem tobe safe in patients with CKD, their efficacy in demen-tia remains unclear. Studies performed specifically inthe CKD population and in the dialysis population areneeded before their use can be widely recommended.Challenging cases, and individuals whose conditiondeclines rapidly, are often best managed by a psycho-geriatrician who has an interest in, or experience with,

patients on dialysis. Unfortunately, the utility of the various drugs that are available for the management ofdementia in the general population may be limited as thepredominant type of dementia in patients with CKD is ofthe vascular rather than the Alzheimer’s type.

Even mild cognitive changes can precipitate acutedelirium, and recurrent episodes of delirium can accel-erate dementia. The incidence of delirium amonghospitalized patients can be reduced by the use of simplenonpharmacological measures that help to orientatepatients and ensure adequate sleep during hospitaliza-tion.69 For example, informing and reminding patientsof exactly what time they will be taken for dialysis may

help orientation if a clock is clearly visible. Followingroutines closely, such as using the same dialysis spotand the same nursing staff can also help reduce therisk of clinically overt delirium. Rooms should be welllit during the day, and all measures taken to ensure adark and quiet environment at night to facilitate goodsleep. Pharmacological interventions, such as halo-peridol (believed by some to be the preferred drug ofchoice for acute delirium), risperidone and olanzapineshould be used only for short periods of time so as toavoid accumulation and neurotoxicity.69

Depression

Definition

The World Health Organization defines depression as acommon mental disorder that presents with depressedmood, loss of interest or pleasure, feelings of guilt or lowself-worth, disturbed sleep or appetite, low energy, andpoor concentration. Depression is relatively common inpatients with all stages of CKD and in those with ESRD,with most studies from the past decade estimating that

20–30% of such individuals are depressed.70–77 By con-trast, in the general population, depression is presentin 2–4% of individuals in the community and 5–10%of individuals in the primary care setting in the US.78 Depression seems to be more common among patientswith CKD than among those other chronic diseases,affecting approximately 14% of patients with congestiveheart disease and 16% of patients surviving acute myo-cardial infarction.79,80 The risk of depression is maximalaround the time of dialysis initiation.75 Some concern hasbeen expressed that patient-administered questionnairessuch as the Beck Depression Index may overestimatethe prevalence of depression as they may confuse

symptoms of renal failure with the somatic manifesta-tions of depression. Self-report scales have, however,been validated in this population70,73,74 and do correlatewith outcomes.77,81,82

Clinical implications

A diagnosis of depression is associated with poor out-comes in the dialysis population.77,81,82 A 2006 study thatassessed 98 consecutive patients on hemodialysis foundthat the risk of death or hospitalization was more thantwofold greater in the 26 patients with a physician-madediagnosis of depression than it was in patients withoutdepression, a finding that was independent of other

risk factors.73 A larger retrospective study of patients onhemodialysis found that mortality rates were higher inthose who had either a formal diagnosis of depression orreported symptoms of depression than in those withoutdepression.81 An earlier study suggested that a singlescore in the ‘depressed’ range on the Beck DepressionIndex was not predictive of mortality but that averagedhigher scores for depressive symptoms over multipleassessments were significantly associated with increasedmortality.77 This finding supports the case for longitudinalscreening for depression in the dialysis population.

A number of suggestions have been made to explainwhy depression portends an increased risk of mortality

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in the dialysis population. Depressed patients may bemore likely to commit suicide, withdraw from treat-ment or refuse treatment. Nonadherence is a frequentlyencountered problem in clinical practice. In the DialysisOutcomes and Practice Patterns (DOPPS) study, 8% ofUS hemodialysis patients skipped one or more sessionsper month and almost 20% regularly shortened theirsession.83 Such nonadherence was strongly associatedwith adverse outcomes: patients who skipped or short-ened sessions were more likely to die or be hospitalizedthan more adherent patients. Suicide rates among dialy-sis patients are almost 15 times higher than in the generalpopulation and are higher than in patients with cancer.84–86 Depression also seems to be the single most importantpredictive factor for poor adherence to medication inhemodialysis patients.83,87,88 In a 2002 report of theDOPPS study, patients with depression were 1.6 timesmore likely than patients without depression to eitherskip or shorten hemodialysis sessions, independent ofother risk factors.83 Interestingly, patients on peritonealdialysis who report symptoms of depression are also

twice as likely to develop peritonitis than peritonealdialysis patients without depression.89

Another possible explanation for the increasedmortality risk seen in depressed dialysis patients isthe relationship between depression, malnutritionand inflammation. Malnutrition is a clinical sequelae ofinflammation and is more common in dialysis patientswith depression than in dialysis patients without depres-sion.90,91 In addition, inflammation is commonly seen inpatients with CKD,14 and seems to independently drivedepression.92 The combination of these factors, togetherwith the observation that depression can itself upregulateinflammatory mediators, sets up a cycle of depression,

inflammation and malnutrition. A low level of serotonin, which has long been associated with depression, is knownto predispose patients to vascular abnormalities such asreversible platelet aggregation.93,94 These changes can bereversed using medications such as serotonin reuptakeinhibitors (SSRIs),95 but studies confirming that SSRIsare associated with improved survival in dialysis patientsare still lacking.

Treatment

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

as those in the general population, where broadly speak-ing the patient is treated with either cognitive behavioraltherapy or with pharmacotherapy. Further randomizedcontrol trials investigating the efficacy and safety of SSRIsin the ESRD population are greatly needed, but the avail-able literature suggests that these drugs are well toler-ated, safe and effective.76,96,97 Concerns regarding theirsafety are based on pharmacokinetic observations of thepotential for the accumulation of metabolites rather thanactual observed toxicity. More recently, interest in the useof cognitive behavioral therapy in depressed patients ondialysis has increased, and application of this techniquehas shown initial promising results.98

Conclusions

Dementia, delirium and depression are all commonconditions in patients with early stages of CKD andin those with ESRD treated with dialysis. Althoughdementia, delirium and depression are distinct dis-orders, depression can present with features of demen-tia, dementia can predispose to delirium, and delirium

can be predictive of subsequent dementia. The full extentand scope of the neuropsychiatric complications of CKDhave only recently become apparent. Cognitive function,which is now recognized to start to deteriorate early inthe course of renal disease, is impaired in almost 90%of dialysis-dependent patients,40 and impaired cognitivefunction is strongly associated with an increased risk ofmortality. Hemodialysis treatment is far from a panacea;although it may temporarily address the toxic and meta-bolic imbalance in patients with CKD, it does so at theexpense of cerebral perfusion, inducing recurrent cere-bral edema and hypotension. Additional measures forlimiting delirium, detecting and minimizing the effect

of dementia on day-to-day activities and aggressivelytreating 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.

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Neuropsychiatric Complications of Chronic