Known unknowns - examining the burden of neurocognitive ... · opposed to HD (1.0% Vs 2.7% and 3.9% Vs 7.3% by 1 and 3 years post dialysis initiation respectively)(41). Through more

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e'Known unknowns - examining the burden of neurocognitive

impairment in the end-stage renal failure population'

Authors:

Scott Wilson1,2,3, Arup Dhar1,2, Peter Tregaskis1, Gavin Lambert4, David Barton1,2,3, Rowan

Walker1,2

1. Alfred Health

2. Monash University

3. Baker IDI

4. Swinburne University

Corresponding Author:

Dr Scott Wilson, Nephrologist, Alfred Health, 55 Commercial Rd, Prahran MELBOURNE

e: [email protected] ; t: (03) 9076 2580 ; f: (03) 9076 3494

Declarations relevant to this project : None

Keywords: Cognitive Dysfunction, Dementia, Renal Dialysis

The burden of neurocognitive impairment (NCI) in patients receiving maintenance dialysis

represents a spectrum of deficits across multiple cognitive domains which are associated

with hospitalisation, reduced quality-of-life, mortality and forced decision-making around

dialysis withdrawal. Point prevalence data suggests that dialysis patients manifest NCI at

rates 3-5 fold higher than the general population with executive function the most

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/nep.13223

This article is protected by copyright. All rights reserved.

mailto:[email protected]

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ecommonly affected cognitive domain. The unique physiology of the renal failure state and

maintenance dialysis appears to drive an excess of vascular dementia subtype compared to

the general population where classical Alzheimer’s disease predominates. Despite the

absence of evidence based cost-effective therapies for NCI, detecting it in this population

creates opportunity to proactively personalise care through education, supported decision

making and targeted communication strategies to cover specific areas of deficit and help

define goals of care. This review discusses NCI in the dialysis setting, including developments

in the definition of neurocognitive impairment, dialysis-specific epidemiology across

modalities, screening strategies and opportunities for dialysis providers in this space.

Introduction

Improvements in life expectancy have driven a demographic transition and contributed to a

rising prevalence of dementia worldwide. Most developed nations report a standardised

population dementia rate of 5-8%(1). Despite a recognised minimum prevalence at least 3-

to 5-fold that of the general population, the burden of neurocognitive disease in patients

receiving maintenance dialysis is poorly understood. Clinically obvious cognitive deficits may

impact dialysis provision across a number of aspects including behavioural concerns,

reduced therapeutic engagement, ability to self-care, adherence to therapy and associated

lifestyle restrictions. The consequence of impairment in these domains may impact on the

quality of dialysis delivered and ultimately technique and patient survival. Less apparent but

equally important effects of more subtle neurocognitive disease reflect insight and decision

making capacity, including that beyond the medical sphere, progressing toward loss of

independence and transfer of the care burden to external carer supports. Timely


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erecognition of cognitive deficits represent an opportunity for proactive patient centred care,

in particular tailored communication and advanced care planning well before any

progression into established dementia. Here we review the current epidemiologic data,

commonly applied screening methodologies and clinical implications associated with

cognitive impairment in dialysis-dependent populations.

Diagnostic Definitions and Pathophysiology

Neurocognitive Impairment (NCI) is a summative term covering persistent deficits from a

range of potential cognitive domains occurring along a continuum of severity. A formal

diagnosis of dementia traditionally sits at its most extreme. The latest iteration of the

Diagnostic and Statistical Manual (DSM-V) has re-named the condition 'major

neurocognitive disorder' (NCD)(2), partly in an attempt to reduce the stigma burden of a

dementia diagnosis and expand the category to disorders in those of younger age. Presently

however, the term 'dementia' remains in common clinical and academic use. Dementia

represents a persistent and progressive cognitive dysfunction from baseline characterised

by deficits in one or more of the domains of learning and memory, language, complex

attention, perceptual motor function, social cognition and executive function.

The most subtle and precursory form of NCI is Mild Cognitive Impairment (MCI) - a

detectably reduced cortical function to a degree beyond ageing associated norms but short

of fulfilling formal diagnostic criteria for dementia. Whilst the course of MCI may be

variable, including potential regression toward more normal cognitive testing outcomes


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eover time, a diagnosis of MCI has been strongly associated with progression to dementia at

a rate of 4 to 12% per year(3-6).

In the general population, Alzheimer's type is the most common form of dementia

accounting for approximately 60% of diagnoses, followed by vascular dementia in

approximately 30% (7, 8). A singular diagnosis is however rarely straightforward due to

substantial overlap in risk factors, clinical presentation and radiological findings between the

two entities. There is general acknowledgement that the co-existence of either disease is

both common and may adversely modify the typical trajectory of the other(9). Data from

dialysis-dependent populations suggests a different pattern of epidemiology with

substantially greater frequency of vascular dementia such that the prevalence rises to

become equal to or greater than Alzheimer's diagnoses(10, 11).

Observational studies have found independent associations between the presence of 25-

hydroxyvitamin D deficiency, hyperparathyroidism, untreated anaemia, cardiovascular

disease and prior stroke with dialysis-associated MCI(12-16). Associations with the

parathyroid axis have been reinforced with postoperative improvements in cognitive and

memory domains observed in patients undergoing surgery for secondary

hyperparathyroidism(17), though only in small studies. It is hoped that prospective

longitudinal studies such as the Brain IN Kidney disease (BRINK) cohort may provide deeper

mechanistic insights in future(18).

At a structural level, paired brain MRI and cognitive testing in HD and non-dialysis

dependent patients have shown significant reductions in grey matter volume which

correlates with lower cognitive testing scores, particularly in the executive domain(19, 20).

The basis for excess grey matter atrophy and vascular-related NCI holds strong parallels with


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edialysis associated micro-circulatory threat to other organ systems. This cohort appears to

represent a persistently vulnerable microcirculatory phenotype where the drivers of

cumulative vascular disease extend beyond traditional atherothrombotic mechanisms of the

general population to convey 'renal-failure-specific' risk(21). This may be exacerbated by the

process of dialysis itself even in the setting of nominally 'adequate' renal replacement as

described biochemically by small-solute clearance.

Nontraditional risk factors such as disordered calcium-phosphate metabolism, chronic

volume overload, uremia, oxidative stress, albuminuria, hyperuricemia and sustained

activation of the renin:angiotensin system are implicated in progression of vascular disease

(22-26) and may contribute to the progression of MCI. Cross-sectional analysis has shown

the duration of dialysis therapy to be strongly associated with the severity of vascular

disease (27), demonstrating that maintenance dialysis does little to ameliorate or reverse

the evolution to a progressively more ‘abnormal’ cardiovascular state. Functional end-organ

perfusion studies during haemodialysis (HD) have demonstrated that conventional HD

treatment acutely creates an environment of repeated microcirculatory ischaemic injury,

even in the absence of macroscopically demonstrable arteriopathy(28, 29). Regaining

dialysis independence and (at least) partial restoration of physiology through renal

transplantation may see domain specific improvements in cognitive test scores though

typically not returning to levels matching general population controls(30).

Epidemiology across Dialysis Cohorts

Against a background prevalence of approximately 5-8% in the general western

population(1) studies in dialysis cohorts tend to use point prevalence single-phase


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emethodology, typically unadjusted for co-morbid disease or dialysis vintage, to indicate an

approximately 3-5 fold increase in the frequency of NCI.. Rather than an absolute

association with dialysis this likely, in part, reflects a disease burden accumulated through

the time-course of chronic kidney disease toward end-stage. In support of this hypothesis,

linear increases in cross-sectional prevalence of NCI across falling levels of estimated GFR

have been demonstrated(31, 32).

A recent systematic review found evidence of significantly worse overall cognition in HD

patients than the general population but was restricted in terms of further conclusions,

largely due to marked inconsistency in cognitive assessment metrics(33). Unadjusted

registry level analysis of diagnostic codes in the HD-DOPPS collective indicates a

progressively incremental association with each decade in age beyond 59 years to a

minimum prevalence of 18% by 90 years old(34). More targeted screening of prevalent HD

cohorts in ambulatory and clinical trial environments has demonstrated a consistent

relationship with age however much greater prevalence rates up to 30% in patients aged

>65 years and just over half of patients dialysing beyond 85 years.

Deficits in the executive function domain (covering attention control, behavioural inhibition

and working memory) appear as the dominant pattern of NCI(16, 35). Higher executive

function scores are associated with lower mortality risk in a prevalent HD cohort followed

for several years(36). It appears that both MMSE and executive function scores continue to

drop off over time, a process hastened by advancing age, whereas the memory domain may

stabilise or improve subtly with dialysis(36, 37). Stratification between a global reduction in

cognition and specific detectable impairment in executive function preserves the

relationship with advancing age but identifies the phenomenon much more frequently in


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eyounger HD patients such that those between 21 and 54 years have detectable NCI at a rate

significantly greater than those over 65 years in the general population(38). Although data

remains relatively sparse, small cohort studies in HD patients with 'normal' range MMSE

scores >24 demonstrate significant reductions in executive function when compared to

normative population data(39, 40) indicating the incidence of subclinical NCI may be

substantially higher than generally recognised.

The impact of dialysis modality

Notwithstanding potential variation in dialysis prescription and delivery, the available data

superficially suggests a slight excess of NCI in patients undergoing HD as opposed to

peritoneal dialysis (PD). Consistent with extensive research comparing modalities across

non-cognitive aspects, studies of NCI differences between modalities are confounded by

reverse epidemiology, factors associated with initial modality selection, local

transplantation practice and the nature of screening methodology applied. A retrospective

USRDS and Medicare claims investigation found approximately half the cumulative

incidence of ICD9 dementia-associated diagnostic codes in patients commencing PD as

opposed to HD (1.0% Vs 2.7% and 3.9% Vs 7.3% by 1 and 3 years post dialysis initiation

respectively)(41). Through more specific screening in Hong-Kong patients commencing PD,

the administration of the Montreal Cognitive Assessment (MOCA) tool during PD training

identified NCI in 29%, with a four-fold increase amongst those patients over 65 years. In

addition to age, terminating education below secondary level and a history of hypertension

or peripheral vascular disease was associated with the detection of NCI(42). Cross-sectional

analysis comparing a formal neuropsychological test battery in english-speaking patients

established on PD, HD or healthy volunteers found an odds ratio for NCI compared to


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econtrol of 2.58 and 3.1 for PD and HD respectively, against a control NCI rate significantly

higher than commonly reported(43). National health-insurance registry analysis from

Taiwan following clinician confirmed diagnosis of dementia yielded a significantly higher

cumulative incidence (crude HR 1.24 for HD vs PD) across 8 years of follow-up however saw

the modality effect ameliorated after adjustment for age, sex, socioeconomic factor and

urbanisation levels(44). In terms of prospective data, a single study has compared age and

demographically matched HD and PD patients at two timepoints: dialysis initiation and 12

months post, finding a subtle improvement in cognitive function for the PD group(45).

Mechanistic explanations for potential modality effect have not been studied and remain

the subject of speculation.

Screening

The complexity of identifying a specific deficit across a spectrum of potential cognitive

domains highlights the need for robust screening methodology which appropriately

examines all requisite areas. The most commonly applied tools are summarised in Table 1.

Short-form diagnostic screens may be applied either in isolation or more effectively in

combination to identify deficits across multiple areas of cognition. In the clinical dialysis

context, the utility of screening tests are a balance of sensitivity and specificity against the

time and specific resources required to administer. No specific screening tool covers all

requisite cognitive domains nor have any been specifically validated in dialysis patients

against a clinical diagnosis of NCI. Comparisons between studies have been confounded by

the wide range of measures applied and the more recent observation that significant intra-

individual variability may be seen in attention and executive function depending upon the

timing of administration with respect to the dialysis cycle(46, 47). Despite a strong


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eassociation with progressive age, screening strategies based on age alone may fail to

capture a significant number of patients with detectable NCI, particularly executive function

deficits in younger patients. Given the frequency of impairment in executive function in this

population, screening strategies should incorporate specific coverage of this domain,

implying a global screening strategy may be more appropriate if the intention is to intervene

using a patient-centred supportive approach. There is no data or consensus to guide

frequency of repeat screening in prevalent dialysis populations though a pragmatic

approach might be annual or semi-annual testing to balance natural history, service

logistics, patient amenability and to mitigate survey fatigue and testing learning effect.

Implications & Perspectives

In that the real prevalence of clinically significant NCI amongst patients receiving dialysis is

likely underestimated as a function of systematic bias, the true magnitude of consequent

implications for dialysis patients and services remains largely unrecognised. World Health

Organisation Global Burden of Disease estimates in the general population rank dementia in

the top 5 contributors to disability adjusted life years burden and the second greatest

contributor to years lived with disability in those aged over 60 years(48). The secondary

impacts on family, carers and healthcare workers are particularly unknown, specifically at

lower levels of NCI where impacts are difficult to quantify and the condition commonly

unrecognised. The applicability of these observations to the co-morbid renal failure context

is similarly challenging, though likely amplified where a chronic, time-consuming

maintenance therapy and persistent illness state already see significantly reduced life

expectancies with care requirements grossly higher than the general population(49, 50).

Studies in non-renal failure clinical trial populations have observed those with executive


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edysfunction in particular are up to three times less likely to complete trial followup

compared to patients with isolated memory or global cognitive deficits(51). Common

manifestations of this phenomenon are typically subtle rather than outright resistive;

cancelling appointments, multiple attempts to reschedule appointments and tendencies

toward vague excuses(52) – many of which are common behaviours observed in dialysis

units. Whilst a patient-centred approach to this problem frequent involves empathy,

flexibility and tailored communication strategies the impact on adherence to therapy or

clinical trial engagement are important.

In conventional centre-based HD cohorts, the presence of a dementia diagnosis has been

significantly associated with the risk of hospitalisation, all-cause mortality and forced

decision making around dialysis withdrawal(53-56). Data from home-based dialysis

therapies, where clinically obvious NCI is a typically a barrier to entry and concerns

regarding independence, technique and patient survival are magnified, is much more

limited. A single one-year prospective cohort study of 114 PD patients found those with

confirmed NCI report significantly higher requirements for assistance with dialytic and day-

to-day care though demonstrated no difference in terms of PD-associated peritonitis

rates(42). The risk of developing NCI once established on a home-based therapy, or the

hypothesis that this dialysis choice might be in some way protective, is challenged by

selection biases inherent to home-dialysis and has not been explored.

The natural trajectory of NCI in patients undergoing home dialysis overall is unknown, as is

the relative interplay of dialysis modality and modification to dialysis prescription over time.

In clinical trial patients undergoing HD, escalation of delivered dialysis dose yielded

significant improvements in markers of small solute clearance and fluid volume control


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ethough no significant effect on the degree of NCI over 12 months as measured by 3MS or

Trail-making B methodology(57). This data should be cautiously interpreted however as, in

the absence of context and with a reasonable expectation of NCI progression drawn from

general population studies(58), a relative lack of change might be speculatively inferred to

represent a slowing in the rate of NCI decline.

Variation in reported prevalence, particularly the substantial under-reporting of coding

record based analyses compared with formally screened patient samples indicates that NCI

is neither well recognised nor documented in the provision of routine dialytic care. Without

general awareness, validated screening strategies, acknowledgement of the benefits of

diagnosis or resource for intervention there appears no immediate catalyst for change. This

would be consistent with known barriers to implementation of patient-centred practise in

contemporary dialysis settings(59).

In the absence of evidence based and cost-effective treatments for dementia, consideration

of the condition in terms of deficits facilitates opportunity for proactive resource

engagement and support tailored to specific patient needs. Given the heterogeneity of

presentations the clinical conceptualisation of NCI might be more usefully inverted and

considered in functional deficit terms rather than as a firm diagnostic label of itself. The

detection of NCI in a dialysis patient might then be viewed optimistically as an opportunity

to supportively enhance patient-centred care rather than through a prism of therapeutic

nihilism.

Acknowledging that contemporary dementia management interventions neither provide

cure nor significant likelihood of functional improvement, formalising a diagnosis of NCI may

aid nephrologists to better define goals of dialytic care and more suitably inform advanced


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ecare planning conversations. Clarity around specific cognitive deficits in particular supports

an evaluation of dialysis modality safety and may assist in-centre behavioural management

day-to-day. If identified in the pre-dialysis phase, NCI represents an opportunity for

discussion of nondialytic treatment, time-limited trials of dialysis with set timelines for

ongoing re-evaluation(60) or, in more milder manifestations, assist supported decision

making, dialysis education and surrogate decision-maker engagement.

Future Research Priorities

Whilst both common and a driver of adverse outcome, NCI in patients undergoing

maintenance dialysis remains a deceptively unclear subject. Validation of appropriate

screening tools for the dialysis environment and clear disease epidemiology specific to this

population through uniform criteria are crucial first steps. Against this framework, a

thorough understanding of the burden of NCI would encompass temporal variation in

domain assessments across the longitudinal trajectory of time on dialysis. Given the

statistical power and duration of observation required, there may be a role for registry-level

contribution to achieve the scale necessary to build the knowledge foundation.

Relationships between the effect of modality choice on the development and rate of

progression and the reciprocal impact of NCI on the efficacy of dialysis delivered represent

the next logical progression of study. Subsequent identification of potentially modifiable

factors or interventions might allow arrest or reversal of decline. Whilst presently the

recognition of NCI in a dialysis patient tends to be opportunistic at the point of the obviously

clinically apparent, the future is hopefully a path toward understanding and ultimately a

drive to improvement in the dialysis experience for patients and caregivers.

References


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eTable 1. Characteristics of cognitive tools in order of increasing complexity

Cognitive Tool

Time to Administer (Minutes)

Domains evaluated

Advantages Disadvantages Validated in ESKD

Clock Drawing Task

1 Visuospatial, executive function

Quick and easily administered. Minimal staff training time required

Multiple domains not assessed.

No

Frontal Assessment Battery

10 Abstraction, fluency, impulsivity, primitive reflexes

Discriminates between dementia types

Non frontal lobes minimally assessed .

No

Mini Mental State Examination (MMSE)

10 Orientation, Registration, Attention, Recall, Language, Visuospatial.

Well known to clinicians

30 point score and may not detect subtle deficits. Does not assess frontal lobe.

No

Montreal Cognitive Assessment (MoCA)

10 Orientation, recall, attention, visuospatial, verbal fluency, executive function.

Language neutral

30 point score and therefore does not detect subtle changes.

No

Addenbrooke’s Cognitive Examination Revised (ACER)

15 Attention, orientation, memory, fluency, language, visuospatial.

Detects mild cognitive impairment.

False positives in those of non-English speaking background.

No

Cogstate® 60 Processing speed, attention, visual learning, working memory.

Culture and education neutral. No learning effect. Automated calculation of results.

False positives in those with poor computer skills.

No

Wechsler Adult Intelligence Scales IV (WAIS-IV)

60 Verbal comprehension, perceptual reasoning, working memory, processing speed.

Provides detailed intelligence scores. Multiple domains scored.

Requires trained psychologist to administer. Lengthy scoring time of ~2 hours.

No


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Known unknowns - examining the burden of neurocognitive ... · opposed to HD (1.0% Vs 2.7% and 3.9% Vs 7.3% by 1 and 3 years post dialysis initiation respectively)(41). Through more