mini-review systematic review of structural and functional

Mini-Review

Systematic Review of Structural and FunctionalNeuroimaging Findings in Children and Adults withCKD

Divya G. Moodalbail,* Kathryn A. Reiser,* John A. Detre,†‡ Robert T. Schultz,* John D. Herrington,*Christos Davatzikos,‡ Jimit J. Doshi,‡ Guray Erus,‡ Hua-Shan Liu,†‡ Jerilynn Radcliffe,* Susan L. Furth,*§

and Stephen R. Hooper|

SummaryCKD has been linked with cognitive deficits and affective disorders in multiple studies. Analysis of structural andfunctional neuroimaging in adults and childrenwith kidney diseasemay provide additional important insights intothe pathobiology of this relationship. This paper comprehensively reviews neuroimaging studies in both childrenand adults. Major databases (PsychLit, MEDLINE, WorldCat, ArticleFirst, PubMed, Ovid MEDLINE) weresearched using consistent search terms, and studies published between 1975 and 2012 were included if theirsamples focused on CKD as the primary disease process. Exclusion criteria included case reports, chapters, andreview articles. This systematic process yielded 43 studies for inclusion (30 in adults, 13 in children). Findings fromthis review identified several clear trends: (1) presence of cerebral atrophy and cerebral density changes inpatients with CKD; (2) cerebral vascular disease, including deep white matter hyperintensities, white matterlesions, cerebral microbleeds, silent cerebral infarction, and cortical infarction, in patients with CKD; and (3)similarities in regional cerebral blood flow between patients with CKD and those with affective disorders. Thesefindings document the importance of neuroimaging procedures in understanding the effect of CKD on brainstructure, function, and associated behaviors. Results provide a developmental linkage between childhood andadulthood,with respect to the effect of CKDon brain functioning across the lifespan,with strong implications for acerebrovascular mechanism contributing to this developmental linkage. Use of neuroimaging methods to cor-roborate manifest neuropsychological deficits or perhaps to indicate preventive actions may prove useful toindividuals with CKD.

Clin J Am Soc Nephrol 8: 1429–1448, 2013. doi: 10.2215/CJN.11601112

IntroductionKidney function may affect brain function on manylevels, ranging from developmental alterations andvascular injury to disorders of metabolism. There isincreasing interest in understanding the neurologicbasis of cognitive and affective dysfunction in childrenand adults with kidney disease that is evident inneurobehavioral findings across the lifespan (e.g.,increased rates of neurocognitive impairments in chil-dren; increased rates of dementia in adults). Neuro-imaging methods provide a noninvasive means ofexamining brain structure and function (1) and repre-sent an important approach for further elucidating thekidney-brain connection in individuals with CKD.

Sixteen years ago, Butler et al. (2) touted the benefitsof using magnetic resonance angiography as a screen-ing tool for cerebral aneurysms and subarachnoidhemorrhage in patients with autosomal dominantpolycystic kidney disease (ADPKD). Similarly, Burnand Bates (3) reviewed neurologic presentations inpatients with a wide range of kidney diseases (e.g.,Von Hippel-Lindau disease) from genetic predisposi-tion to tumors to direct and indirect effects of kidneydisease on brain functioning.

To date, several comprehensive reviews have ex-amined the neuroimaging literature in individualswith CKD. Aǧildere et al. (4) provided one of the firstreviews of the neurologic complications of ESRD inpatients undergoing hemodialysis (HD) assessed byuse of magnetic resonance imaging (MRI). These in-vestigators highlighted the importance of MRI, in-cluding T2-weighted, fluid-attenuated inversionrecovery, and proton density images, as a tool forclinical investigation of ESRD-associated neurologicsymptoms. They reported that patients with ESRD,particularly those receiving HD, have high rates ofneurologic complications compared with healthy con-trols. They surveyed the use of MRI in combinationwith new and conventional imaging methods fordiagnosing white matter changes, cerebral atrophy,osmotic demyelination syndrome, dialysis encepha-lopathy, hypertensive encephalopathy, intracranialhemorrhage, cerebral ischemia and infarction, infec-tion, and sinus thrombosis.Brouns and De Deyn (5) also reviewed the causes

and presentations of neurologic complications in ure-mic patients with ESRD. They noted that dialysis andrenal transplantation themselves may precipitate

*Department ofPediatrics, TheChildren’s Hospital ofPhiladelphia,Philadelphia,Pennsylvania;†Department ofNeurology,‡Department ofRadiology, and§Department ofEpidemiology,Perelman School ofMedicine at theUniversity ofPennsylvania,Philadelphia,Pennsylvania; and|Department ofPsychiatry andCarolina Institute forDevelopmentalDisabilities,University of NorthCarolina School ofMedicine, ChapelHill, North Carolina

Correspondence:Dr. Divya G.Moodalbail, TheChildren’s Hospital ofPhiladelphia, 34thStreet and CivicCenter Boulevard,Philadelphia, PA19104. Email: [email protected]

www.cjasn.org Vol 8 August, 2013 Copyright © 2013 by the American Society of Nephrology 1429

mailto:[email protected]



neurologic symptoms and that treatment and maintenancefor patients with ESRD should address both renal andneurologic components. More recently, Lakadamyali andErgün (6) reviewed brain MRI findings for diagnosis ofacute neurologic complications in patients with ESRD un-dergoing HD. They noted that symptoms may be causeddirectly by CKD itself, HD, or a combination of the two.Cerebral ischemia and infarction, intracerebral hemor-rhage, posterior reversible encephalopathy syndrome, os-motic demyelination syndrome, cerebral infection,gadolinium accumulation, sinus vein thrombosis, and di-alysis disequilibrium syndrome are all reported as beingdetected via MRI. Vogels et al. (7) reviewed the associationbetween CKD and brain lesions as noted on MRI and com-puted tomography (CT). They reported association ofCKD with brain atrophy, silent cerebral infarction, andwhite matter lesions (WMLs).Taken together, these earlier reviews describe the neu-

rologic complications that can stem from CKD. Impor-tantly, however, none of these reviews provide findingspertaining to children. In addition, the earlier reviewsfocused on specific neurologic complications from CKDand did not provide a broad overview of the neuroimagingliterature related to CKD.This paper provides an updated review of neuroimaging

in kidney disease, focusing on quantitative findings fromboth structural and functional neuroimaging studies inchildren and adults. The primary objective is to provide acontemporary summary of the available studies. Analysisof structural and functional neuroimaging in adults andchildren with kidney disease will provide additionalimportant insights into the pathobiology of CKD.

MethodsA systematic review of major search databases was

conducted to compile a comprehensive list of studies thatused neuroimaging techniques in individuals with CKDand were published between 1975 and 2012. Three re-viewers systematically reviewed databases, including Psy-chLit, Ovid MEDLINE, MEDLINE, WorldCat, PubMed,and ArticleFirst. Designated search terms included MRIAND chronic kidney disease, computed tomography AND he-mofiltration, polycystic kidney AND brain AND magnetic res-onance imaging, dialysis AND single-photon emissioncomputed tomography (SPECT), dialysis AND MRI, dialysisAND regional cerebral blood flow (rCBF), rCBF AND CKD,CKD AND CT, dialysis AND transcranial Doppler, dialysisAND cerebral magnetic resonance imaging, neurologic impair-ment in CKD, neuroimaging AND CKD, and diffusion tensorimaging (DTI) AND CKD. Studies were included in the re-view if (1) the sample focused on CKD (defined by an esti-mated GFR [eGFR] ,60 ml/min per 1.73 m2 for$3 months)as the primary disease process and (2) the study producedquantitative statistics. Exclusion criteria included case re-ports, book chapters, and previous review articles.Use of the search terms in this systematic process

produced 1462 possible articles, and an additional 9 re-cords were identified through other sources (e.g., citationsincluded in the ascertained articles). Removal of the dupli-cate articles resulted in a pool of 1264 potential articles forinclusion. Application of the inclusion and exclusion

criteria produced 43 articles for inclusion in the review.These studies comprised 30 studies in adults (20 structural,10 functional) and 13 studies in children (13 structural).The selection and identification process for candidate stud-ies can be seen in Figure 1.

ResultsAdult Neuroimaging StudiesThirty studies included adults with CKD in their neuro-

imaging protocols: 20 structural and 10 functional. Thesestudies span a time frame from 1987 (8) to 2011 (9–11). Thestudy designs included retrospective, cross-sectional, case-control, and prospective approaches to data collection. Sam-ple sizes ranged widely, and the composition of the CKDsamples reflected significant heterogeneity across studies.Other studies examined AKI (e.g., Ronco et al. 12); however,our review focuses on CKD. For the structural neuroimagingstudies, the primary technique used was MRI, with severalstudies using CT. For the functional neuroimaging studies,the primary techniques used were SPECT, transcranialDoppler ultrasonography, and rCBF using 133Xe inhalation.

Findings in Adult Structural Neuroimaging StudiesIn adults, more severe kidney disease has been associ-

ated with abnormal structural findings. One study hasdocumented the presence of intracranial arachnoid cysts inADPKD (13), but more studies examined MRI findings inpatients undergoing various renal replacement therapies(RRTs) and have reported the presence of cerebral atrophyand decreased cerebral density in both white and graymatter (9,14–21). Walters et al. (18) showed that five HDpatients had postdialysis increases in cerebral volumecompared with five controls. Savazzi et al. (20) foundhigh correlations between atrophy on CT and MRI andpredialytic BP. Yoshimitsu et al. (19) also studied MRI inHD patients and reported significantly more lacunae andmore advanced periventricular hyperintensity thanmatched controls. In one of the largest studies conductedto date (187 kidney transplant and 29 liver transplant cases),Aǧildere et al. (16) found that roughly one third of adultrenal transplant recipients had neuroradiologic findings onMRI, including nearly 20% of patients with hemisphericsulcal and ventricular dilatation.Similar findings have been uncovered in patients not

receiving RRT. In neuroimaging studies conducted to date,with sample sizes ranging from 52 to 625 adult cases withCKD, high rates of structural abnormalities were detectedwith MRI, including WMLs (22). In a study by Wada et al.(23), elderly patients with CKD (defined by low eGFR[,60 ml/min per 1.73 m2] or a urinary albumin-to-creati-nine ratio .30 mg/g) evidenced more lacunar infarcts andhigher grades of WMLs. After adjustment for hypertensionand diabetes, CKD continued to remain an independentrisk factor for cerebrovascular disease–related lesions. Sev-eral other investigators have reported similar findings (24–27). Using DTI, Kim et al. (9) showed subtle WMLs in asmall sample of patients receiving peritoneal dialysis (PD).Cerebral small vessel disease has also been studied in the

adult CKD population. Kobayashi et al. (28) found thatdecreased kidney function was a risk factor for silent la-cunar infarcts. The prevalence of silent cerebral infarction

1430 Clinical Journal of the American Society of Nephrology

also has been reported to be significantly higher in HD pa-tients than in controls (17). Kobayashi et al. (29) also foundan independent association between silent cerebral infarc-tion and decreased kidney function, and silent cerebral in-farction independently predicted outcomes, including strokeand dementia. Other investigators have asserted that WMLsreflect possible ischemic brain damage and generalized vas-cular damage, and both are independently associated withvascular nephropathy in patients with CKD (22). In patientswith CKD, high rates of cerebral microbleeds have also beendocumented, with rates ranging from about 26% (30) to 61%(29). These microbleeds tended to be more prevalent in malepatients, those with hypertension, those with advanced age,and those with worsening kidney function as defined byeGFR, with no relation to the use of antiplatelet or anti-thrombotic therapy (15,30,31). Table 1 summarizes the adultstructural neuroimaging studies in CKD.

Findings in Adult Functional Neuroimaging StudiesFunctional neuroimaging studies use methods to detect

structural brain abnormalities and localized neural activity

in reaction to executing certain specific sensory, motor, andcognitive tasks. These studies are sensitive to changes inrCBF and blood flow velocity in targeted brain regions.Seven of the 10 studies included in this review focused onpatients receiving HD or PD. In one of the oldest imagingstudies conducted with adults, which used 133Xe inhala-tion, Gottlieb et al. (8) found that predialysis rCBF valuesdid not differ from those in age-matched controls; how-ever, after HD, there was a mild but significant reductionin rCBF. This reduction was not associated with cognitiveimpairment or neurologic symptoms. Using transcranialDoppler ultrasonography, several studies have docu-mented similar findings. Prohovnik et al. (32) showedthat 19 HD patients had reduced rCBF between sessions.Other investigators have reported similar findings (33,34),with blood flow reductions noted in the middle cerebralartery and the basilar artery after HD (35). However, somestudies report contrary findings, suggesting that cerebralblood flow does not change significantly during or afterHD (36). Many functional neuroimaging studies also haveused SPECT in their examination of blood flow velocities

Figure 1. | Systematic review of neuroimaging data in CKD. *Studies where CKD was not the primary disease process of interest, but otherassociated disease processes (e.g., stroke) were screened for in large populations of patients with CKD. Reproduced with permission fromMoher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: ThePRISMA statement. PLoS Med 6: e1000097, 2009.

Clin J Am Soc Nephrol 8: 1429–1448, August, 2013 Neuroimaging in CKD, Moodalbail et al. 1431

Tab

le1.

Adultstructuralneu

roim

agingstudiesin

CKD

(n=20)

Autho

rsSa

mpleDescription

Stud

yDesign

Imag

ingTechn

ique

MainFind

ings

Nag

anuma

etal.(20

12)

n=17

9HD

patien

ts;m

ean

age,

58.2

yr(ran

ge,2

3–86

yr)

n=58

healthycontrols;m

ean

age,

55.9

yr(ran

ge,4

1–77

)

Cross-section

alMRI(T1-,T

2-weigh

ted

andFL

AIR

)The

prev

alen

ceof

WMHswas

sign

ificantly

high

erin

HD

patien

tsthan

healthype

rson

s.In

theHD

patien

ts,

multiple

logisticregression

analysisshow

edthat

indep

enden

tand

sign

ificant

factorsassociated

withthe

presen

ceof

PVH

wereag

e,femalesex,

andsystolic

BPan

dthoseassociated

withthepresen

ceof

DSW

MH

wereag

e,femalesex,

systolicBP,

andbo

dymassindex.

Kim et

al.(20

11)

n=4pa

tien

tswithESR

Don

PD$

3yr;3

men

and1

wom

an;m

eanag

e,39

.75yr

n=6controls;4

men

and2

wom

en;m

eanag

e,44

.17yr

Cross-section

alDTI

DTIfind

ings

wereinve

stigated

inpa

tien

tswithESR

Dwho

show

edno

specificlesion

son

conv

ention

albrainMRI.

DTItractograp

hyshow

edthat

all4

patien

tsha

d.1

lesion

.PatientswithESR

Dshow

edab

norm

alitieson

DTIthat

wereassociated

withcogn

ition;

howev

er,the

ydid

notsh

owsign

ificant

cogn

itiveab

norm

alities.

Kob

ayashi

etal.(20

10)

n=14

2pa

tien

tswithCKD;

96meanan

d46

wom

en;

meanag

e,64

.7yr

Prospective

coho

rtMRI(T1-,T

2-,

andproton

den

sity–weigh

ted

imag

es)

Atb

aseline,87

patien

tsha

dSB

I.During

2-yr

follo

w-up,

43pa

tien

ts(30.3%

)dev

elop

edthefollo

wingprim

ary

outcom

es:d

oublingof

SCrleve

l,dialysistherap

y,an

ddeath

from

card

iova

scular

caus

es.S

BIwas

anindep

enden

tpredictorof

outcom

es;eGFR

decreased

morein

patien

tswithSB

Ithan

inthosewitho

utS

BI.

Shim

aetal.(20

10)

n=16

2pa

tien

tswithCKD,

stag

es1–

5;85

withdiabe

tes,

77witho

utd

iabe

tes;92

men

and70

wom

en;m

eanag

e,64

.9yr

n=24

controls;1

4men

and10

wom

en;

meanag

e,59

.7yr

Cross-section

alMRI(T1-,T

2-,F

LAIR

,an

dT2*-w

eigh

ted

imag

es)

CMBswerefoun

din

35pa

tien

tswithCKD

(25.6%

)but

notincontrols.C

MBsweremoreprev

alen

tin

men

,thosewithhigh

erBP,tho

sewithad

vanc

edag

e,an

dthosewithpo

orkidne

yfunc

tion

.The

rewas

anassociationbe

tweentheprev

alen

ceof

CMBsan

dad

vanc

ingCKD

stag

e(P,0.01

).eG

FRwas

associated

withtheprev

alen

ceof

CMBsindep

enden

tofa

ge,

sex,

andhy

perten

sion

;how

ever,n

orelation

ship

was

seen

betw

eenCMBsan

ddiabe

tesmellitus

anddyslip

idem

ia.

Yak

ushiji

etal.(20

10)

n=61

0Japan

esead

ultswith

CKD;3

02men

and30

8wom

en;m

eanag

e,56

.4yr

Cross-section

alMRI(T1-,T

2-,a

ndFL

AIR

weigh

ted

imag

es)

Cereb

rala

trop

hywas

foun

din

25(4.1%)cases.Age

,male

sex,

hypertens

ion,

kidne

yfunc

tion

,WMH,a

ndlacu

naewereassociated

withcerebral

atroph

y.eG

FR,

60ml/min

per1.73

m2was

associated

withcerebral

atroph

y.Treatmen

tofC

KD

may

controla

ge-related

deg

enerativeprocesses

ofthebrain.

Kob

ayashi

etal.(20

09)

n=33

5pa

tien

tswithCKD

n=40

patien

tswithEHTan

dno

CKD;n

otag

e-match

edOve

rall:

226men

and14

9wom

en;m

eanag

e,63

.5yr

Cross-section

alMRI(T1-,T

2-,

andproton

den

sity–weigh

ted

imag

es)

SBIs

wereseen

56.5%

ofpa

tien

ts.H

ypertens

ive

neph

rosclerosisan

dad

vanc

ingeG

FRstatewere

associated

withSB

I.eG

FRwas

relatedto

SBI,in

additionto

agean

dBP(P=0.02

5).

Patien

tswithCKD

shou

ldun

dergo

active

detection

ofSB

Ian

dmoreintens

iveprev

entive

man

agem

ent,especially

forhy

perten

sion

.


Tab

le1.(Continued

)

Autho

rsSa

mpleDescription

Stud

yDesign

Imag

ingTechn

ique

MainFind

ings

Ikram

etal.(20

08)

n=48

4pa

tien

tsin

theRotterd

amStudy;

meaneG

FR,

54.8

ml/min

per1.73

m2 ;23

9men

and24

5wom

en;m

ean

age,

73.4

yr

Cross-section

alMRI(T1-,T

2-an

dproton

den

sity–weigh

ted

imag

es)

Volum

esof

WMLan

dpresen

ceof

lacu

narinfarcts

reflected

cerebral

smallv

esseld

isease.P

ersons

withlower

GFR

had

less

deepwhite

mattervo

lumean

dW

ML.G

FRwas

not

associated

withgray

mattervo

lumeor

loba

rwhite

mattervo

lume.

Impa

ired

kidne

yfunc

tion

was

associated

withcerebral

smallv

esseld

isease.

Wad

aetal.(20

08)

n=62

5community-based

Japan

eseelderly;3

59men

and26

6wom

en;m

ean

age,

62.7

yr

Cross-section

alMRI(T1-,T

2-,a

ndFL

AIR

-weigh

ted

imag

es)

Patien

tswithlower

eGFR

show

edmorelacu

narinfarcts

andhigh

ergrad

esof

WML.T

hemeangrad

esof

WML

orthemeannu

mbe

rsof

lacu

narinfarction

inthe

patien

tswithalbu

minuriaweregreaterthan

thosein

patien

tswitho

utalbu

minuria.A

fter

exclusion

ofpa

tien

tswithstag

e2hy

pertens

ionor

diabe

tes,CKD

remaine

dan

indep

enden

triskforCVD-related

lesion

s.Kha

tri

etal.(20

07)

n=61

5pa

tien

tswithCKD

from

NorthernMan

hattan

Stud

y;24

6men

and36

9wom

en;

meanag

e,70

yr

Cross-section

alMRI(FLAIR

imag

es)

Creatinineclearanc

e15

–60

ml/min

was

associated

with

increasedlog-white

matterhy

perintensityvo

lumeas

was

eGFR

15–60

ml/min.F

indings

high

light

the

impo

rtan

ceof

CKD

asapo

ssible

determinan

tof

cerebrov

ascu

lardisease

and/or

asamarke

rof

microan

giop

athy

.Kim et

al.(20

07)

n=57

PDpa

tien

ts;3

4men

and

23wom

en;m

eanag

e,48

.4yr

n=57

match

edhy

perten

sive

controlswithno

rmal

rena

lfunc

tion

;34men

and23

wom

en;m

eanag

e,51

.9yr

Cross-section

alMRI(T1-,T

2-,a

ndFL

AIR

-weigh

ted

imag

es)

The

prev

alen

ceof

leuko

araiosiswas

sign

ificantly

greater

inpa

tien

tson

PDthan

controls(P,0.00

1).H

ighe

rT2sign

alintens

itieswereseen

inthePD

patien

tsthan

incontrols,p

articu

larlyin

thean

terior

circulationof

thebrainwithrelative

sparingof

thepo

steriorfossa.

ESR

D,o

lder

age,

andpo

orcontrolo

fBPweresign

ificant

pred

ictors

ofleuk

oaraiosis.

Watan

abe

(200

7)n=

80HD

patien

ts;3

4men

and

46wom

en;m

eanag

e,62

.9yr

Cross-section

alMRI(T2-weigh

ted

imag

es)

CMBswerefoun

din

28pa

tien

ts(35%

).The

duration

ofHD

did

notsign

ificantly

affect

theap

pearan

ceof

theCMBs.

Old

intracereb

ralh

emorrhag

eswereseen

in7pa

tien

ts,

5of

who

m(71%

)had

CMBs.The

freq

uenc

yof

old

intracereb

ralh

emorrhag

eswas

sign

ificantly

high

erin

thepa

tien

tswithCMBsthan

inthosewitho

utC

MBs

(P=0.48

),an

dthepa

tien

tswitholdintracereb

ral

hemorrhag

esha

dsign

ificantly

moreCMBsthan

the

patien

tswitho

utthem

(P=0.00

65).The

high

ratioof

patien

tswithCMBswas

considered

toha

vebe

encaused

notb

ymainten

ance

HD

butby

othe

rfactors,su

chas

hype

rten

sion

.


Tab

le1.(Continued

)

Autho

rsSa

mpleDescription

Stud

yDesign

Imag

ingTechn

ique

MainFind

ings

Aǧildere

etal.(20

06)

n=18

7kidne

ytran

splant

cases;

ofcaseswithne

urorad

iologic

find

ings;3

6men

and20

wom

en;m

eanag

e,39

.3yr

n=29

liver

tran

splant

cases;22

men

and7wom

en;m

ean

age,

29.4

yr

Retrosp

ective

MRI(T-2

weigh

ted

andproton

den

sity–or

FLAIR

-and

T1-weigh

ted

sequ

ences)

Neu

roradiologicfind

ings

wereclassified

into

3grou

ps:

Group

1was

relatedto

tran

splantation.

Ove

rall,

30%

ofkidne

ytran

splant

recipientsha

dne

uroradiologic

find

ings:3

patien

ts(1.6%)h

adpo

steriorreve

rsible

encepha

lopa

thysynd

rome;2pa

tien

ts(1.1%)h

adtube

rculosisgran

ulom

as;1

patien

t(0.5%

)had

osmotic

dem

yelin

ationsynd

rome;1pa

tien

t(0.5%

)had

aNocardiaab

scess;an

d1(0.5%)h

adfocalcereb

ritis.

Group

2was

relatedto

chronicpa

renc

hymal

disease.

Includingkidne

yan

dliv

ertran

splant

recipien

ts,

38pa

tien

ts(20.3%

)had

brainatroph

y;37

(20%

),white

matterch

ange

s;3(1.6%),sinu

sthrombo

sis;

8(4.3%),lacu

narinfarct;1(0.5%),rena

losteod

ystrop

hyin

thecran

ialb

ones;a

nd4(2.2%),

intracranial

hemorrhag

esecond

aryto

ESR

D.

Group

3was

relatedto

neithe

rtran

splant

norch

ronic

parenc

hymal

disease:3

patien

ts(1.6%)h

adintracranial

lipom

as;1

(0.5%),mesialtem

poralsclerosis;a

nd1

(0.5%),an

anterior

white

matteran

eurysm

inrena

ltran

splant

patien

ts.

Martine

z-Vea

etal.(20

06)

n=52

patien

tswithCKD

stag

es3an

d4witho

utdiabe

tes;

SCr,2.03

–7.91

mg/

dl;38

men

and14

wom

en;m

ean

age,

49yr

n=32

controls;2

1men

and11

wom

en;m

eanag

e,49

yr

Cross-section

alMRI(T1-,T

2-,a

ndFL

AIR

-weigh

ted

imag

es)

WMLweremoreprev

alen

tintheCKD

grou

pthan

incontrols(33%

versus6%

;P=0.00

8).W

MLweremore

common

inpa

tien

tswho

wereolder;h

adrena

ldisease

causedby

card

iova

scular

disease

orva

scular

neph

ropathy

;and

hadhigh

ersystolicBP,

greater

pulsepressu

re,large

rleftve

ntricu

larmassindex,

greaterleve

lsof

C-reactiveprotein,

andhigh

errates

ofan

tihy

perten

sive

drugprescription

s.Stag

ean

dduration

ofCKD

wereno

trelated

tothepresen

ceof

WML.O

nlyva

scular

neph

ropathy

(P=0.03

)pred

ictedan

increasedrisk

forW

ML,sug

gesting

that

WMLreflectische

micbraindam

agecaused

byge

neraliz

edva

scular

dam

age.


Tab

le1.(Continued

)

Autho

rsSa

mpleDescription

Stud

yDesign

Imag

ingTechn

ique

MainFind

ings

Kob

ayashi

etal.(20

04)

n=51

patien

tswithCKD;m

ean

SCr,2.01

mg/

dl;29

men

and

22wom

en;m

eanag

e,52

.7yr

n=80

controlp

atientswith

EHTbu

tno

CKD;4

7men

and

33wom

en;m

eanag

e,58

.8yr

Cross-section

alMRI

Lacun

aeprev

alen

cewas

25%

inpa

tien

tswithaCcr

.40

ml/min

per1.73

m2 ,85

%in

patien

tswithaCcr

,40

ml/min

per1.73

m2 ,an

d29

%in

patien

tswithessential

hype

rten

sion

withno

rmal

rena

lfunc

tion

.Patientswith

lacu

naeha

dsign

ificantly

lower

hematocrits

associated

withincreasedfibrinog

enan

dlip

oprotein

leve

lscompa

redwiththosewitho

utlacun

ae.P

lasm

atotal

homocysteinean

dinsu

linleve

lsat

2hr

aftera

75-g

gluc

osetoleranc

etest

correlated

withlacu

nae.

Isch

emic

heartc

hang

eson

echo

card

iograp

hyan

dthicke

nedcarotidintima-med

iathickn

essweremore

freq

uent

inpa

tien

tswithlacu

nae.The

best

contribu

ting

factor

forlacu

narinfarcts

was

declin

ein

Ccr.D

ecreased

rena

lfunc

tion

isarisk

factor

forsilent

lacu

narinfarcts.

Nak

atan

ietal.(20

03)

n=12

3HD

patien

ts;8

0men

and

43wom

en;m

eanag

e,55

.6yr

n=52

healthycontrols;2

9men

and23

wom

en;m

ean

age,

51.7

yr

Cross-section

alMRI(T1-,T

2-,

andproton

den

sity–weigh

ted

imag

es)

The

prev

alen

ceof

SCIwas

sign

ificantly

high

erin

HD

patien

tsthan

inhe

althycontrols(P,0.00

01).Fo

rbo

thgrou

ps,indep

enden

triskfactorsforSC

Iwerech

ronic

rena

lfailure,h

ypertens

ion,

smok

ing,

andag

e.In

the

HD

grou

p,a

gean

dsm

okingwereindep

enden

trisk

factorsof

SCI(P,0.00

01),whe

reas

HD

duration

and

hype

rten

sion

wereno

t.The

find

ings

indicatethat

chronicrena

lfailure

maintaine

dby

HD

increasesthe

prev

alen

ceof

SCIan

dthat

agean

dsm

okingarerelated

toSC

Iin

HD

patien

ts.

Walters

etal.(20

01)

n=5HD

patien

ts;3

men

and2

wom

en;m

eanag

e,44

.2yr

n=5he

althycontrols;2

men

and3wom

en;m

eanag

e,67

.4yr

Cross-section

alMRI(T1-weigh

ted

imag

es)

Potentialcereb

ralv

olum

ech

ange

causedby

HD

was

quan

tified

byMRIim

med

iately

before

and

afterHD.P

atientsha

dan

increase

incerebral

volume

afterHD,w

hich

averag

ed32

.8ml(SE

M,7

.4ml).

Con

trolsav

erag

ed1.4ml(SE

M,0

.6ml).N

opa

tien

tha

dsign

ificant

neurolog

icsymptom

s.Yoshimitsu

etal.(20

00)

n=55

HD

patien

ts;3

5men

and

20wom

en;m

eanag

e,52

yrn=

35controls;1

8men

and17

wom

en;m

eanag

e,42

yr

Cross-section

alMRI

HD

patien

tsshow

edmorelacu

naean

dmoread

vanc

edPV

Hthan

controls.T

heVBR,the

numbe

rof

lacu

nae,

andtheseve

rity

ofPV

Htend

edto

increase

with

agein

HD.V

BRsat

alla

gegrou

psweresign

ificantly

high

erin

HD

recipientsthan

incontrols(7.0%

versus3.7%

atthefourth

decad

eof

life;8.4%

versus5.9%

atthefifthdecad

e;9.6%

versus

5.4%

atthesixthdecad

e;an

d11

.6%

versus

6.3%

attheseve

nthdecad

e).B

oththenu

mbe

rof

lacu

naean

dtheseve

rity

ofPV

Hweresign

ificantly

correlated

toVBRin

HD

recipien

ts.


Tab

le1.(Continued

)

Autho

rsSa

mpleDescription

Stud

yDesign

Imag

ingTechn

ique

MainFind

ings

Sava

zzi

etal.(19

99)

n=25

regu

larHD

treatm

ent

patien

ts;1

9men

and6wom

en;

meanag

e,50

.3yr

Retrosp

ective

CT(n=25

)and

MRI(n=

17)

Nosign

ificant

correlationwas

found

betw

eenthedeg

ree

ofatrophy

andtheurem

ia-altered

labo

ratory

measu

resof

creatinine

,hem

atocrit,ch

olesterol,

triglyceride,albu

min,P

TH,calcium

,and

inorga

nic

phospha

te.N

orelation

ship

betw

eendeg

reeof

atrophy

andnu

mbe

rof

mon

thsthepa

tien

tsha

dbe

enon

HD

ortimethat

passed

betw

eenthe

find

ingof

Ccr

,30

ml/min

per1.73

m2an

dthestart

ofHD.L

arge

correlations

werefound

betw

een

CA

andpred

ialyticBPan

dbe

tweenCA

andthe

duration

ofhy

perten

sion

.Hyp

ertens

ionseem

sto

berelatedto

cerebral

parenc

hymal

dam

agean

dsh

ould

becorrected.

Fazeka

setal.(19

95)

n=30

patien

tswithCHD;2

1men

and9wom

en;m

ean

age,

58yr

n=30

controlsmatch

edfor

age,

sex,

andmajor

cerebrov

ascu

larrisk

factors;

23men

and7wom

en;

meanag

e,60

yr

Cross-section

alMRI(T1-

and

T2-weigh

ted

andax

ial

mixed

-inten

sity

imag

es)

The

brains

ofpa

tien

tswithCHD

show

edsign

ificantly

moreatrophy

onvisu

alrating

andsemiqua

ntitative

morph

ometricmeasu

res.Multiple

lacu

nesor

confl

uent

white

matterhy

perinten

sities

pred

ominated

in33

%of

patien

ts.M

arke

dcogn

itiveim

pairmen

twas

associated

withmoreextens

iveen

largem

ento

fthe

thirdve

ntricle

(P,0.04

)and

thetempo

ralh

orns

(P,0.02

)bu

tno

twiththepresen

ceof

cerebral

isch

emiclesion

sor

any

differenc

ein

labo

ratory

data.

The

seresu

ltscall

attentionto

ave

ryhigh

rate

ofcerebral

dam

agein

individua

lsun

dergo

ingCHD

andsu

ggestbrain

deg

enerationof

toxic-metab

oliccause

that

isassociated

withseve

recogn

itiveim

pairmen

t.Schiev

ink

etal.(19

95)

n=24

7pa

tien

tswithADPKD;

96men

and15

1wom

en;

meanag

e,44

yrn=

247controlsmatch

edfor

agean

dsex

Retrosp

ective

MRI(180

cases)

orCT(67cases)

Une

xpectedly

high

numbe

rof

patien

tswithADPK

Dha

dintracranial

arachn

oidcysts.The

cystswerefoun

din

20pa

tien

ts(8.1%)v

ersu

s2controls

(0.8%)(P,0.00

01).Multiple

intracranial

arachn

oid

cystswerefoun

din

2pa

tien

ts.P

inealcysts

werefoun

din

2pa

tien

ts(0.8%)a

ndch

oroidplexuscy

stswere

foun

din

3pa

tien

ts(1.2%),bu

tthiswas

notdifferent

from

controls.N

oneof

theintracranial

cystswere

symptom

aticor

treatedsu

rgically.

HD,h

emod

ialysis:MRI,mag

neticresona

nceim

aging;

FLAIR,fl

uid-atten

uated

inve

rsionrecove

ry;W

MH,w

hite

matterhy

perinten

sities;P

VH,p

eriven

tricular

hype

rinten

sity;D

SWMH,d

eep

andsu

bcorticalw

hite

matterhy

perinten

sity;P

D,p

eriton

eald

ialysis;DTI,diffusion

-ten

sorim

aging;

SBI,silent

braininfarct;eG

FR,estim

ated

GFR

;CMB,cereb

ralm

icrobleeds;EHT,essen

tial

hype

rten

sion

;WML,w

hite

matterlesion

s;HD,h

emod

ialysis;SC

r,serum

creatinine

;Ccr,creatinineclearanc

e;SC

I,silent

cerebral

infarct;VBR,v

entricular-brain

ratio;

CT,com

putedto-

mog

raph

y;PT

H,p

arathy

roid

horm

one;CA,cereb

rala

trop

hy;C

HD,coron

aryhe

artd

isease;A

DPK

D,a

utosom

aldom

inan

tpolyc

ystickidne

ydisease.


Tab

le2.

Adultfunctional

neu

roim

agingstudiesin

CKD

(n=10)

Authors

SampleDescription

StudyDesign

Imag

ingTechn

ique

MainFind

ings

Nam

etal.(20

11)

n=14

patien

tswithstag

e5

CKD,eGFR

,15

ml/min

per

1.73

m2or

perm

anen

tren

alreplacemen

tthe

rapy;

10men

and4wom

en;m

eanag

e,54

yr

Prospe

ctive

99mTcECD

SPECT

HDRSan

dSP

ECTweread

ministered

before

starting

dialysisan

d6moafter

dialysisinitiation

.rCBFwas

compa

red

betw

eenpa

tien

tswho

seHDRSscore

decreased

by.25

%an

dthosewho

seHDRSscores

decreased

by,25

%or

thosewithan

increase

inHDRSscore.

Adecreaseof

.25

%in

HDRSwas

correlated

withhigh

erpe

rfusion

inthe

leftmiddle

tempo

ralg

yrus(P=0.05

)an

dhigh

errC

BFin

therigh

tpa

rahipp

ocam

palg

yrus

(P=0.04

).Less

reduc

tion

inHDRSwas

correlated

with

decreased

rCBFin

theleftsu

perior

fron

talg

yrus

(P=0.03

)and

righ

torbitofron

talcortex(P=0.05

).Trycetal.(20

11)

n=23

nond

ialyzedpa

tien

tswith

CKD

stag

es4an

d5;

15men

and

8wom

en;m

eanag

e,48

.4yr

n=15

dialyzedpa

tien

ts;1

0men

and5wom

en;m

eanag

e,52

.5yr

n=23

match

edhe

althycontrols;

9men

and14

wom

en;

meanag

e,52

.5yr

Cross-section

al1 H

-MRS

MRSalteration

swerepred

ominan

tly

foun

din

thewhite

matter.Con

centration

sof

creatinine

-con

tainingcompo

und

sweredecreased

indialyzedan

dno

ndialyzedpa

tien

ts.C

holin

econc

entration

(and

combine

dN-acetylasp

artate

and

N-acetylasp

artylglutamateconc

entration)

werereduc

edin

dialyzedpa

tien

ts.

Disturban

cein

mem

ory/

learning

and

attentionwereob

served

inbo

thpa

tien

tgroup

s,bu

tattentiondefi

cits

weremoreseve

rein

dialyzedpa

tien

ts.

Patien

tswithCKD

witho

utclinical

sign

sof

urem

icen

ceph

alop

athy

show

edmetab

olicdisturban

cesin

distinc

tbrain

region

san

dcogn

itive

impa

irmen

ts.H

Dwas

accompan

ied

bymoreseve

recogn

itivedysfunc

tion

andmetab

olic

alteration

sthan

CKD

alon

e.A

nega

tive

effect

ofHD

oncogn

itivefunc

tion

mus

tbecons

idered

.


Tab

le2.(Continued

)

Authors

SampleDescription

StudyDesign

Imag

ingTechn

ique

MainFind

ings

Kim

etal.(20

08)

n=27

patien

tswithCKD,

pred

ialyticstag

e4–

5;mean

GFR

,9.1

ml/min

per1.73

m2 ;

16men

and11

wom

en;

meanag

e,51

.9yr

Prospe

ctive

Tc-99

ECD

SPECT

rCBFan

ddep

ressivemoo

dwerene

gative

lycorrelated

intherigh

tins

ula,

posterior

cing

ulated

gyrus,an

dleftsu

perior

tempo

ral

gyrusan

dpo

sitive

lycorrelated

intheleft

fusiform

gyrus.rC

BFan

dinsomniawere

nega

tive

lycorrelated

intherigh

tmiddle

fron

talg

yrus

,bila

teralcingu

latedgy

ri,right

insu

la,right

putamen

,and

righ

tinferior

parietal

lobu

lean

dpo

sitive

lycorrelated

inleftfusiform

gyrusan

dbilateralcereb

ellar

tonsils.rCBFan

dan

xietywerene

gative

lycorrelated

intheleftinferior

fron

talg

yrus

,righ

tsupe

rior

fron

talg

yrus

,right

middle

tempo

ralg

yrus,righ

tsupe

rior

tempo

ralg

yrus

,an

dleftsu

perior

fron

talg

yrus

andpo

sitive

lycorrelated

intherigh

tlingu

algy

rusan

drigh

tpa

rahipp

ocam

palg

yrus

.The

patterns

were

simila

rto

thosewithMD

witho

utCKD.

Proh

ovniketal.(20

07)

n=19

HD

patien

ts;a

llmen

;meanag

e,63

yrn=

5PD

patien

ts;a

llmen

;meanag

e,63

yrn=

14controls;1

1men

and

3wom

en;m

eanag

e,61

yr

Prospe

ctive

MP-RAGE,A

SL,a

ndT1-MRIsequ

ences

plus

ICA

Dop

pler

ultrason

ograph

yan

dcerebral

oxim

etry

HD

patien

tsshow

edbilateralcereb

ralatrop

hyin

thecaudatenu

cleu

san

dmidbrainassociated

withlong

erdurationof

dialysis.Cereb

ral

oxyg

enationan

dcarotidbloo

dflow

werelow

before

dialysiscompa

redwith

controls.C

erebral

oxyg

enationim

prov

edon

lyslightly

afterHD,w

hile

carotid

bloo

dflow

norm

alized

.PD

patientsshow

edva

lues

betw

eenthoseof

HD

patientsan

dcontrols.

Durationof

HDwas

associated

with

glob

algray

mattervo

lume,chan

geof

bloo

dflow

during

dialysis,and

baselin

erSO

2.HD

patientsap

pear

toha

velow

CBF

betw

eensessions.

Skinne

retal.(20

05)

n=12

HD

patien

ts;6

men

and

6wom

en;m

eanag

e,44

yrCase-control

Transcran

ialD

oppler

ultrason

ograph

yMCA

FV,d

ynam

icpressu

reau

toregu

lation

,an

dCRCO

2weremeasu

redbe

fore

andafter

HD.M

CA

FVdecreased

from

57cm

zs21

before

to46

cmzs

21afterHD

(P,0.01

).The

THRRwas

1.29

(0.13)

before

HD

anddid

notch

ange

sign

ificantly

afterHD.C

RCO

2was

21.7

kPa2

1be

fore

HD

andremaine

dun

chan

gedafterw

ard(20.9kP

a21 ).M

CA

FVdecreased

sign

ificantly

afterHD.D

ynam

icpressu

reau

toregu

lation

andCRCO

2remain

norm

alin

patien

tswithCRFan

dareno

talteredsign

ificantly

byHD.


Tab

le2.(Continued

)

Authors

SampleDescription

StudyDesign

Imag

ingTechn

ique

MainFind

ings

Steafnidisetal.(20

05)

n=18

HD

patien

ts;1

0men

and

8wom

en;m

eanag

e,62

yrCross-section

alTranscran

ialD

oppler

ultrason

ograph

yBeforeHD,the

MFV

intheMCA

was

within

norm

alrang

ean

ddep

enden

tonpa

tien

t’s

age,

butduring

HD

itdecreased

sign

ificantly.T

hisdecreasein

MFV

was

relatedto

ultrafi

ltration

volume,bloo

dvo

lume,an

dpe

rcen

tcha

ngeof

the

hematocritof

thearterial

bloo

dox

ygen

conten

tand

oftheplasmafibrinog

enleve

ls.

The

MFV

intheMCA

decreased

continuou

slyduring

HD.

Metry

etal.(20

02)

n=18

HD

patien

ts;1

3men

and

5wom

en;a

gerang

e,46

–82

yrCross-section

alTranscran

ialD

oppler

ultrason

ograph

yThe

effect

ofhe

mod

ynam

ican

drheo

logic

chan

geson

MFV

was

exam

ined

during

HD

through

continuo

uson

linemon

itoring.

After

HD,h

ematocrita

ndbloo

dan

dplasma

viscosityincreasedsign

ificantly.T

hech

ange

inMFV

was

notsign

ificantly

different

from

zero

andcorrelated

sign

ificantly

withch

ange

inhe

matocrit.

During

HD,the

meanarterial

pressu

rein

15pa

tien

tsmov

edinto

theno

rmal

rang

e,whe

reas

3pa

tien

tsdev

elop

edhy

potens

ion

andtheirMAPdecreased

.Cha

ngein

MFV

was

notsign

ificant.C

BFdoe

sno

tap

pear

tobe

dim

inishe

dsign

ificantly

during

HD.

Lassetal.(19

99)

n=17

patien

tswithESR

Dor

undergo

ingdialysis;13

men

and4wom

en;m

eanag

e,60

yr

Prospe

ctive

Tc-99

HMPA

OSP

ECT

Reg

iona

lcereb

ralp

erfusion

imag

ingwas

performed

,and

activity

inthefron

tala

ndtempo

rallob

eswas

compa

redby

quan

tification

agains

tthe

ipsilaterala

ndcontralateralcereb

ellum

using

three-dim

ension

alsu

rfacemap

ping

.Discretecortical

defects

consistent

with

infarcts

wereseen

in14

patien

ts(82%

).The

defects

werefound

inalllob

ules.T

hemean

righ

tand

leftfron

tal-to-cereb

ellarratios

wereno

tsign

ificantly

different

from

therigh

tan

dlefttempo

ral-to-cereb

ellarratios,a

ndbo

thwerewithinno

rmally

accepted

rang

es,

sugg

esting

noev

iden

ceof

Alzhe

imer-typ

edem

entia.


Tab

le2.(Continued

)

Authors

SampleDescription

StudyDesign

Imag

ingTechn

ique

MainFind

ings

Hataetal.(19

94)

n=27

HD

patien

ts;1

3men

and

14wom

en;m

eanag

e,52

.4yr

Case-control

Transcran

ial

Dop

pler

ultrason

ograph

y

Blood

FVswereob

tained

from

theMCA

and

theba

silarartery

immed

iately

before

and

afterHD.T

here

was

asign

ificant

reduc

tion

intheMFV

intheMCA

(P,0.01

)an

dthe

basilarartery

(P,0.01

)after

HD.A

nega

tive

correlationwas

observed

betw

eenthe

relative

chan

gein

MFV

andtheloss

ofweigh

tafter

HD,the

amou

ntof

fluid

remov

ed,a

ndtheincrease

inhe

matocritin

themiddle

cerebral

artery

andtheba

silar

artery.H

Dan

dtheassociated

physiologic

chan

gescansign

ificantly

affect

cerebral

circulation

.Trans

cran

ialD

oppler

ultrason

ograph

ycaneffectivelymon

itor

rapid

chan

gesin

thecerebral

circulation

during

HD.

Gottliebetal.(19

87)

n=9pa

tien

tsun

dergo

ing

long

-term

HD;4

men

and

5wom

en;m

eanag

e,50

yrn=

44men

tally

and

neurologically

healthy

controls;a

gerang

e,49

–79

yr

Cross-section

al13

3 Xeinha

lation

tech

niqu

eto

measu

rerC

BF

rCBFwas

measu

redbe

fore

andafterHD.

Pred

ialysisrC

BFva

lues

did

notdiffer

from

thosein

controls.A

fter

HD,rCBF

decreased

byameanof

7%(P=0.02

).Po

st-H

DrC

BFreduc

tion

was

notassociated

withne

urolog

icor

cogn

itivedysfunc

tion

.Cau

sesof

HD-ind

uced

rCBFdecreases

are

unkn

own,

butincreasedbloo

dviscosity

andbioche

mical

chan

ges(e.g.,urea

reduc

tion

,blood

alka

linization)

aresu

spected.

eGFR

,estim

ated

GFR

;ECD,ethylcy

steina

tedim

mer;S

PECT,single-ph

oton

emission

compu

tedtomog

raphy

;HDRS,

Ham

ilton

Dep

ressionRatingScale;rC

BF,

region

alcerebral

bloo

dflow

;MRS,mag

neticresona

ncesp

ectroscopy

;HD,h

emod

ialysis;MD,m

ajor

dep

ression;

PD,p

eriton

eald

ialysis;MP-RAGE,m

agne

tiza

tion

prep

ared

rapid

grad

ient

echo

;ASL

,arterialspinlabe

ling;

MRI,mag

neticresona

nceim

aging;

ICA,interna

lcarotid

artery;rSO

2,region

alox

ygen

saturation

;MCA,m

iddle

cerebral

artery;F

V,fl

owve

locity;C

RCO

2,carbon

dioxidereactivity;T

HRR,

tran

sien

thyp

erem

icresp

onse

ratio;

MFV

,meanflow

velocity;H

MPA

O,h

exam

ethy

lpropylen

eamineox

ime.


Tab

le3.

Ped

iatric

structuralneu

roim

agingstudiesin

CKD

(n=13)

Authors

SampleDescription

StudyDesign

Imag

ing

Techn

ique

Used

MainFind

ings

Ishiku

raetal.(20

06)

n=20

rena

lpatients;13

boys

and7girls;meanag

e,8.7yr

n=10

kidne

ytran

splant

patien

ts(7

withidiopathic

neph

riticsynd

rome,2with

acute

poststreptococcalG

N,

1withdiffuse

mesan

gial

sclerosis)

Retrosp

ective

coho

rtstud

yCTan

dMRI

Inmostp

atients,radiologicab

norm

alities

extend

edto

thegray

matter(17of

20pa

tien

ts),

fron

tala

ndtempo

rallob

es,a

ndthecerebe

llum

(16pa

tien

ts).Po

steriorreve

rsible

encepha

lopa

thy

synd

romeshou

ldbe

susp

ectedin

pediatric

kidne

ytran

splant

recipien

tsan

dpa

tien

tswithkidne

ydisease

ifthey

have

asu

dden

episod

eof

neurolog

icsymptom

s,ev

enifim

agingfind

ings

areno

trestricted

tothesubcortical

white

matterof

theoccipitalregion.

Valan

neetal.(20

04)

n=33

rena

ltrans

plan

trecipients

who

received

arena

lallo

graft

before

age5yr;2

2bo

ysan

d11

girls;ag

erang

e,6–

11yr

Cross-section

alstud

yCTan

dMRI

Brain

MRIwas

performed

aftertran

splantation.

Pretrans

plan

tCTscan

sof

26pa

tien

tswere

availableforcompa

rison;

18pa

tien

ts(54%

)ha

disch

emiclesion

sin

theva

scular

border

zone

s.Mild

lesion

swereseen

in10

patien

ts,

mod

eratein

6,an

dseve

rein

2.Other

find

ings

wererare.B

rain

lesion

sof

thepa

tien

tsdid

not

correlatewithun

derlyingdisease

butwere

relatedto

adverseclinical

even

tsbefore

tran

splant.

Qvist

etal.(20

02)

n=33

scho

ol-age

child

renwho

received

rena

ltrans

plan

tfor

ESR

Dwhe

nag

e,5yr;2

2bo

ysan

d11

girls;7ch

ildren

attend

ingsp

ecialsch

ool,6

received

remed

ialins

truction,

20in

regu

larinstruction

Prospective

stud

yPretrans

plan

tCT;

post-trans

plant

MRI

Prev

alen

ceof

cerebral

atrophy

aftertran

splant

was

15%;5

5%of

sampleha

dwatersh

edisch

emiclesion

s(5

ofthe7in

specialsch

ool,

5of

6in

remed

ialteach

ing,

8of

20receiving

regu

larinstruction).B

rain

infarcts

wereseen

in6of

7ch

ildrenwho

wereattend

ingsp

ecial

scho

ol.C

hildrenattend

ingsp

ecialsch

oolh

adahigh

errate

ofprem

aturity,h

ypertens

ive

crises

(P=0.00

2),a

ndseizures(P=0.03

),with

man

yof

theseev

ents

occu

rringduring

dialysis.

Elzou

iki(19

94)

n=15

patien

tswho

dev

elop

edCKD

atbirthor

duringfirsty

ear

oflife;13

boys

and2girls;mean

follo

w-uppe

riod

,50mo

Prospective

coho

rtstud

yCT;E

EG;n

erve

cond

uction

velocity;A

BER

Allpa

tien

tsha

dano

rmal

neurologicexam

ination

apartfrom

hypo

tonia.

Five

hadmicrocepha

ly.

The

rewas

acorrelationbe

tweenmalnu

trition

inthefirst2ye

arsof

lifean

dmicroceph

aly.

Dev

elop

men

tald

elay

was

presen

tin3pa

tien

tswithmicrocepha

ly.B

rain

atroph

ywas

seen

inon

ly3of

13pa

tien

ts.E

EG

resu

ltswereab

norm

alin

6pa

tien

ts.O

nly1pa

tien

thad

dim

inishe

dne

rvecond

uctionve

locity;a

llpa

tien

tsha

da

norm

alABER.N

oneof

thepa

tien

tsdev

elop

edprog

ressiveen

cepha

lopa

thyor

recu

rren

tseizures.A

polic

yof

nooral

aluminum

therap

yan

dearlynu

tritiona

lsupp

ortleadsto

better

neurolog

icou

tcom

ein

child

renwithearlyCKD.


Tab

le3.(Continued

)

Authors

SampleDescription

StudyDesign

Imag

ing

Techn

ique

Used

MainFind

ings

Pueshe

letal.(19

91)

n=3pa

tien

tswithLow

esynd

rome

Cross-section

alstud

yMRI

The

stud

yem

pha

sizedtheCNSan

drena

lpa

tholog

yof

Low

esynd

rome.MRIshow

eddiffuse

high

T2sign

alsin

thepe

rive

ntricu

lar

region

,ind

icatingsign

ificant

white

matter

destruction,

which

may

contribu

teto

the

intelle

ctua

ldisab

ility,seizu

redisorder,

hypo

tonia,

andarefl

exia

seen

inLow

e’ssynd

rome.

Cocha

tetal.(19

86)

n=10

patien

tswithcystinosis;

meanag

e,14

.2yr

n=10

compa

risoncaseswith

prim

aryrena

ldisease

butno

cerebral

abno

rmalities;

meanag

e,11

.8yr

Case-control

stud

yCT

Bothgrou

psinclud

eddialyzedch

ildrenor

tran

splant

recipien

tswitho

uts

ignificant

differenc

ein

leng

thof

ESR

Dman

agem

ent.

Cranial

CTsh

owed

brainatroph

yin

cystinotic

patien

tsch

aracterizedby

enlargem

ento

fcortical

sulciin80

%of

casesve

rsus

only

20%

from

thecompa

risongrou

p.

Steinb

ergetal.(19

85)

n=22

patien

tswithCKD

(6with

stab

leCKD,1

4on

dialysis,2

post-trans

plant);ag

erang

e,2–

18yr

Cross-section

alstud

yCT

Brain

atrophy

was

presen

tin13

patien

ts(59%

),pa

rticularly

forpa

tien

tsreceivingHD.T

wo

patien

tsha

dcortical

infarcts,a

nd1ha

da

hypo

den

searea

intheba

salg

anglia.M

etab

olic

deran

gemen

tsan

d/or

theaccu

mulationof

toxic

substanc

esdue

tourem

icstatemay

berelated

tobrainatrophy

inyo

ungpa

tien

tswithCKD.

Recurrent

osmoticch

ange

sof

thebrainduring

HD

may

contribu

teto

thepresen

ceof

brainatroph

y.Kretzschm

aretal.(19

83)

n=22

HD

patien

tsProspective

stud

yCT

Cranial

CTwas

performed

before

andafterHD

inallp

atientsan

din

halfof

thosepa

tien

ts8mo

later.In

halfof

cases,brainatrophy

was

reco

gnizab

le,w

ithdecreased

absorption

ofcerebral

parenc

hymaafterHD

in73

%of

the

cases.Thisfind

ingispa

rtly

explaine

dby

cerebral

edem

aor

hydration

.Schn

aper

etal.(19

83)

n=15

patien

tswithESR

D,n

one

withSL

E;5

boys

and10

girls;ag

erang

e,3.5–

20yr;d

ialysis(n=14

)an

d/or

rena

ltrans

plan

t(n=

13)

Prospective

stud

yCT

Corticala

trop

hywas

seen

in8casesan

dve

ntricu

laren

largem

entinan

additiona

l2.

Corticala

trop

hywas

notassociated

withclinical

sign

sor

symptom

s.The

meanleng

thof

timethe

patien

tsreceived

long

-term

HD

was

twiceas

long

inpa

tien

tswithatroph

y(30.8mo)

asin

thosewithno

rmal

scan

s(14.6mo).T

heleng

thof

timethat

patien

tsreceived

dialysis

contribu

tedto

thecortical

atroph

y.


Tab

le3.(Continued

)

Authors

SampleDescription

StudyDesign

Imag

ing

Techn

ique

Used

MainFind

ings

Dettorietal.(19

82)

n=48

patien

tswithESR

D;2

8bo

ysan

d35

girls;ag

erang

e,6–

71yr;

38receivingdialysis

n=15

patien

tswithCKD

Case-controlstudy

CT

Nomorpho

logicmod

ification

swereob

served

.Sign

ificant

chan

gesin

den

sity

weredem

onstrated

afteradialysissessionin

thepo

pulation

treated

interm

ittently.P

atientswithESR

Dwho

were

undergo

ingCAPD

alway

sha

dno

rmal

den

sity

values.C

ereb

rald

ensity

chan

gesrelatedon

lyto

interm

ittent

dialytictreatm

ent.

LaGreca

(198

2)n=

30pa

tien

tson

HD

orPD

;16

boys

and14

girls;ag

erang

e,10

–59

yrn=

10no

rmal

controls

Case-controlstudy

CT

CTof

thehe

adwas

cond

uctedbe

fore,immed

iately

after,an

d6hr

afterdialysis.Den

sity

did

not

decreasein

healthype

rson

sor

inpa

tien

tson

continuou

sPD

.The

absenc

eof

den

sity

variations

inCAPD

was

explaine

dby

agrad

ual

stab

ledeliveryof

fluid

columns

andsolutes.

Papag

eorgiouetal.(19

82)

n=25

patien

tswithESR

D;1

4bo

ysan

d11

girls;meanag

e,50

yrn=

45HD

patien

ts;2

1bo

ysan

d24

girls;meanag

e,46

yrn=

20he

althycontrols;1

0bo

ysan

d10

girls;meanag

e,55

yr

Case-controlstudy

CT

Non

eof

thepa

tien

tsha

dclinical

sign

sof

urem

icen

cepha

lopa

thy.

Ven

triclesweresign

ificantly

enlarged

inbo

thgrou

pscompa

redwiththe

controls,w

iththegreatest

enlargem

entinthe

patien

tsun

dergo

ingHD.V

entricular

enlargem

ente

xpresses

thedeg

reeof

brain

atrophy

,which

inESR

Dmay

bedue

tothe

metab

olic

factorsof

rena

ldisease

andin

HD

toalum

inum

toxicity.

Passer

(197

7)n=

33rena

lpatients;meanSC

r,11

.6mg/

dl;ag

erang

e,4–

72yr

Healthy

controlswereag

ematch

edto

rena

lgroup

and

rand

omly

selected

from

radiologicfiles

Case-controlstudy

CT

Patien

tsun

derwen

tCTas

partof

theirpred

ialysis

evaluation.

Normal

controlswerescan

nedfor

head

ache

sor

trau

maticinjury

tothehe

ad.

Cereb

rala

trop

hywas

presen

tinen

d-stage

urem

ia.D

egreeof

atroph

ycorrelated

with

theag

eat

onseto

fend

-stage

urem

iaan

dwas

mostm

arke

dduring

theyo

unge

rag

esof

cerebral

dev

elop

men

t.

CT,com

putedtomog

raphy

;MRI,mag

neticresona

nceim

aging;

EEG,electroen

ceph

alog

raphy

;ABERau

ditorybrainstem

evok

edresp

onse;C

NS,

centraln

ervo

ussystem

;HD,h

emod

ialysis;

SLE,systemic

lupu

serythe

matosus

;CAPD

,con

tinu

ousam

bulatory

peritone

aldialysis;PD

,periton

eald

ialysis;SC

r,serum

creatinine

.


Table 4. Summary of common findings across the neuroimaging studies

Common Theme (Total n=43)CKD Populations Studied

Non-ESRD Dialysis Post-Transplant

Cerebral atrophy and cerebral density changesFazekas et al. (1995) [A] XSavazzi et al. (1999) [A] XYoshimutu et al. (2000) [A] XWalters et al. (2001) [A] XAǧildere et al. (2006) [A] XProhovnik et al. (2007) [A] XYakushiji (2010) [A] XPasser (1977) [P] XDettori et al. (1982) [P] X XLa Greca et al. (1982) [P] XPapageorgiou et al. (1982) [P] X XKretzschmar et al. (1983) [P] XSchnaper et al. (1983) [P] XSteinberg et al. (1985) [P] X X XCochat et al. (1986) [P] X XElzouiki et al. (1994) [P] X

Cerebral vascular abnormalitiesWhite matter lesions/abnormalitiesPueshel et al. (1991) [A] XAǧildere et al. (2006) [A] XMartinez-Vea et al. (2006) [A] XKhatri et al. (2007) [A] XKim et al. (2007) [A] XWatanabe et al. (2007) [A] XIkram et al. (2008) [A] XWada et al. (2008) [A] XShima et al. (2010) [A] XKim et al. (2011) [A] XNaganuma et al. (2011) [A] XNam et al. (2011) [A] X XTryc et al. (2011) [A] X XNaganuma et al. (2012) [A] XIshikura et al. (2006) [P] X X

Silent cerebral infarctionNakatani et al. (2003) [A] XKobayashi et al. (2009) [A] XKobayashi et al. (2010) [A] X

Cortical infarctsLass et al. (1999) [A] X X XQvist et al. (2002) [A] XKobayashi et al. (2004) [A] XValanne et al. (2004) [A] X

Effect of hemodialysis on cerebral circulation/oxygenationGottlieb et al. (1987) [A] XHata et al. (1994) [A] XMetry et al. (2002) [A] XSkinner et al. (2005) [A] XSteafnidis et al. (2005) [A] XProhovnik et al. (2007) [A] X

Depression and kidney diseaseKim t al. (2007) [A] XKim et al. (2008) [A] XNam et al. (2011) [A] X X

OtherIntracranial cystsSchievink et al. (1995) [A] X

A, adult study; P, pediatric study.


in adults with CKD. Lass et al. (37) documented discretecortical defects consistent with infarcts in 82% of their het-erogeneous patient sample (patients with CKD and thoseundergoing dialysis), with the defects being observable ineach of the lobules.Although magnetic resonance spectroscopy does not

assess rCBF, it provides indices that help elucidate neuro-chemical functions within the brain. To date one study hasassessed magnetic resonance spectroscopy in adults withCKD. Using magnetic resonance spectroscopy in HDpatients, patients with stage 4 and 5 CKD, and matchedhealthy controls, Tryc et al. (11) reported reduced brainactivity, as defined by targeted neurometabolites relatedto healthy brain functioning (i.e., choline, N-acetylaspartate,and N-acetylaspartylglutamate), in HD patients. Addition-ally, memory/learning and attention impairments were ob-served in both nondialyzed and dialyzed patients with CKD,but more severe cognitive dysfunction and neurometabolicalterations were seen in HD patients than in those withCKD stages 4 and 5.Finally, the relationship between CKD and depression in

adults also has received attention in the neuroimagingliterature. Kim et al. (14) demonstrated that in 27 patientswith CKD, rCBF patterns correlated with symptom clus-ters of depressive mood. These findings were similar tothose in individuals with major depressive disorder with-out CKD (38) and patients with Parkinson disease and de-pression (39). More recently, Nam et al. (10) studied 14patients with CKD before and 6 months after HD andfound correlations between reduced levels of depression,higher perfusion in the left middle temporal gyrus, andhigher rCBF in the right parahippocampal gyrus. Theselatter findings implicate the importance of the kidney-brain connection not only in the neurologic aspect of cog-nition and learning but also in the affective presentation ofmany individuals with CKD, particularly with respect tothe appearance of affective disorders.Table 2 summarizes the adult functional neuroimaging

studies in CKD.

Pediatric Neuroimaging StudiesThirteen studies included children with CKD in their

neuroimaging protocols. Unlike the adult studies, all of thepediatric studies to date have been of a structural nature.These studies span from 1977 (40) to 2006 (41). The studydesigns included retrospective, cross-sectional, case-control,and prospective approaches to data collection. Samplesizes ranged widely, with the composition of the CKDsamples reflecting significant heterogeneity across studies.For the structural neuroimaging studies, all of the pediat-ric investigations used CT, and several studies also usedMRI.

Findings in Pediatric Structural Neuroimaging StudiesAs with adults, cerebral atrophy has been noted in

children with ESRD, and this appears to be more prevalentin the HD population. Passer (40) was one of the first fewto publish neuroimaging findings in ESRD. Thirty-threepatients with ESRD secondary to various causes under-went head CT as part of their predialysis evaluation.This group of patients ranged widely in age and included

children. Cerebral atrophy was noted in ESRD, with thedegree of atrophy correlating with the age of onset. Similarfindings have been reported by other investigators (42–44)using solely pediatric samples; Qvist et al. (45) documentedthe presence of cerebral atrophy even after transplant in15% of their cases.Papageorgiou et al. (46) conducted a similar comparative

study of brain atrophy in patients with CKD and thoseundergoing long-term HD age 16–70 years comparedwith age-matched controls. None of the patients had clin-ical signs of uremic encephalopathy. Compared with theirage-matched controls, the renal patients had significantlyenlarged ventricles, with the greatest enlargement noted inthe HD group. Using a small sample of pediatric patientswho developed CKD at birth, Elzouki and colleagues (47)found that approximately 23% showed cerebral atrophy.Enlarged ventricles, a correlate of brain atrophy, have alsobeen reported by investigators studying primarily pediat-ric samples; estimates were significantly higher andranged from 59% (44) to 67% (43). In addition, enlargedcortical sulci have been reported on cranial CT in up to80% of pediatric cases with cystinosis (48). Widening ofcerebrospinal fluid spaces secondary to brain atrophy(42), with lower cerebral density, has been typically asso-ciated with HD (43,49) in comparison with patients receiv-ing continuous ambulatory PD (50). In general, theliterature suggested that although brain atrophy was evi-dent in patients with stable CKD and those receiving con-tinuous ambulatory PD, it was definitely more frequent inHD patients.In addition to cerebral atrophy, brain lesions have also

been documented using both CT and MRI. Specifically,Ishikura et al. (41) studied 20 cases of posterior reversibleencephalopathy syndrome. In most patients, radiologic ab-normalities extended to the gray matter (85%), particularlyin the frontal and temporal lobes, and the cerebellum.Moreover, ischemic lesions have been documented in thevascular border zones at a rate of about 54% in childrenwho received a renal transplant before 5 years of age(45,51). Cortical infarcts have been documented aftertransplant as well (44,45). These findings, however, alsoshowed the presence of various neurologic deficits (e.g.,brain infarcts, cerebral atrophy) and other factors (e.g.,history of hemodynamic crisis, prematurity, congenital ne-phrosis), including hypercoagulability related to long-termPD before transplantation, suggesting a priori brain insultsduring the first 5 years of life (51).Table 3 summarizes the pediatric structural neuroimag-

ing studies in CKD.

DiscussionThis review of the neuroimaging literature in CKD

provides a contemporary examination of one importantfacet of the kidney-brain connection: namely, structuraland functional neuroimaging studies in CKD. This reviewcomplements earlier reviews conducted on this topic but toour knowledge is the first to include both pediatric andadult studies and to focus on the structural and functionalfindings in the brain.This review focused on understanding potential linkages

between kidney disease and brain structural and functional


integrity across the lifespan. As can be seen in Table 4,several clear findings emerged. In addition to clusteringstudies under four major themes, Table 4 shows the sam-ple composition for these studies. The three substantivethemes are presented below.

Cerebral Atrophy and Cerebral Density Changes Are Foundin Children and Adults With CKDBoth cerebral atrophy and cerebral density changes have

been noted in CKD, particularly with more severe kidneydisease. These findings were seen more frequently in bothchild and adult patients on intermittent dialysis treatments(long-term HD, intermittent PD) than in patients with CKD(who were not receiving dialysis) or patients undergoingcontinuous veno-venous hemofiltration (CVVH). Thesechanges were present in adults but were more markedduring the periods of cerebral development in children.These findings were not necessarily associated with thepresence of neurologic signs or symptoms, but up to 59% ofthese cases were noted to have brain atrophy (44). Recurrentosmotic changes of the brain during HD and aluminum tox-icity (in older studies) were associated with a greater risk forbrain atrophy in HD patients. The degree of brain atrophyalso has been related to predialytic BP and the duration ofhypertension. Even after transplantation, the prevalence ofcerebral atrophy is at least 15%–20%.Similarly, significant changes in cerebral density have

been discovered in both children and adults with CKD,with changes reported after HD but not after CVVH. Thesefindings favor continuous RRTs, such as CVVH, to avoidthis effect; however, this is not a viable treatment option forlong-term outpatient dialysis therapy. In general, thesefindings support the ongoing study of more frequent and/or intensive dialysis regimens, in place of HD three times aweek (52).

Signs of Cerebral Vascular Disease Are Seen in Children andAdults with CKDBoth kidney and brain are highly vascularized organs

and may share sensitivity to vascular disease. Accordingly,the brains of patients with CKD tend to show confluentdeep white matter hyperintensities, WMLs, cerebral micro-bleeds, and territorial cerebral infarcts. ESRD, chronologicage, and hypertension appear to be significant predictors ofthe presence of abnormal subcortical white matter. Thesefindings indicate how kidney disease and its sequelae leadto cerebrovascular disease through microangiopathy (23).Further, vascular nephropathy was found to be the mostimportant factor related to the presence of these lesions,suggesting that WMLs may reflect ischemic brain damagesecondary to generalized vascular damage. Conversely,stage and duration of CKD have not been linked to thepresence of WMLs.CKD has been related to small vessel disease–related

lesions. Lower eGFR levels and albuminuria were associ-ated with more lacunar infarcts and higher grades ofWMLs and less white matter volume. These findingswere present after adjustment for age, sex, and cardiovas-cular factors and when individuals with stage 2 hyperten-sion, cardiovascular risk factors, or diabetes were excludedfrom examination (23,25). Similarly, the incidence of

cerebral microbleeds appears to be high in patients receiv-ing maintenance HD, with rates hovering around 25%–

35% (31). These findings point to poor renal functionas a significant risk factor for cerebral microbleeds aswell as for future cerebrovascular events. It is interestingto know that although no relationship between anticoagu-lants and cerebral microbleeds has been uncovered inadults, this relationship has not been studied in pediatricpatients.Further evidence from these studies points to the pres-

ence of cerebral infarctions as being present in CKD, serv-ing as yet another marker of possible cerebrovasculardisease. The prevalence of silent cerebral infarctions hasbeen shown to be at least 50% in patients with ESRD (40).Among causes of CKD, hypertensive nephrosclerosishad a strong association with silent brain infarctions,and lower/declining eGFR, chronologic age, and hyper-tension were independently associated with a higher prev-alence of silent brain infarction. Taken together, theseneuroimaging findings point to CKD as an independentrisk factor for these infarctions and provide a strong link-age to the risk for cerebrovascular disease.Finally, in adults receiving HD, blood flow velocities in

the middle cerebral artery and the basilar artery immedi-ately before and after HD are significantly reduced afterdialysis treatment (32). Functional imaging techniques,such as transcranial Doppler ultrasonography, should beconsidered to monitor rapid changes in cerebral circula-tion during HD treatments. To date, no studies have in-vestigated blood flow velocities in children with CKD,although such studies may provide early clues for the laterappearance of cerebrovascular disease.

Functional Brain Imaging Techniques Show CirculatoryPatterns Consistent with Affective DisordersFor adults, the available neuroimaging studies suggest

that rCBF patterns in CKD are similar to those seen inpatients with major depressive disorder without CKD.Conversely, improvement in depressive symptoms hasbeen associated with higher perfusion in the left middletemporal gyrus and higher rCBF in the right parahippo-campal gyrus (10,14). To date, no such studies have beenconducted with children and adolescents with CKD.

SummaryThis comprehensive review has analyzed structural and

functional neuroimaging in adults and children withkidney disease. This review points to several key evidence-based findings supporting the ongoing study of the kidney-brain connection, with noteworthy findings indicating thepresence of cortical atrophy and other structural differencesin both children and adults with CKD, particularly withincreasing disease burden and the need for RRT, and whilecontrolling for other disease-related factors. The findingsalso provided evidence suggesting developmental continu-ity of cerebrovascular involvement in both children andadults with CKD. These latter studies point to cerebrovas-cular disease as one primary mechanism for the appearanceof abnormal brain structure, impaired brain functions, andperhaps increasing cognitive impairments across the life-span.


Despite the overarching nature of the available studies,it is important to note that our systematic review alsorevealed several limitations that moderate the strength ofthe findings. The corpus of studies spans approximately 35years, with 30 of the 43 studies involving adults. Thenumber of pediatric studies is increasing, but to date nopublished functional imaging studies have directly exam-ined brain function in children and adolescents with CKD.Further, many of the earlier pediatric studies actuallyinclude both adults and children in their samples, thusobscuring the effects of CKD in child brain structure andfunction. Study designs ranged widely but largely usedcross-sectional approaches to patient ascertainment; thisraises issues of how CKD, and its changing degree ofseverity, interacts with neurodevelopmental aspect of brainstructure and function over time. Additionally, very fewlongitudinal studies have been conducted with adults orchildren. Only a small subset of the included studiesfocused on functional neuroimaging. Finally, most of thestudies were conducted with small and/or heterogeneoussamples of individuals with CKD and RRT, although therewere some notable exceptions in the structural neuro-imaging literature for adults.In the future, it will be of interest to expand studies

to link complications of CKD, such as hypertension andbone mineral disorder, with neuroimaging. One such studyof interest is the ongoing, National Institutes of Health–sponsored SPRINT-MIND (Systolic Blood Pressure In-tervention Trial-Memory and Cognition in DecreasedHypertension) study, which will determine whether alower systolic BP goal will further reduce the risk of car-diovascular and kidney disease or age-related cognitivedecline. Future pediatric study designs should aim at re-cruiting pure CKD population (with no history of prema-turity, underlying central nervous system abnormalities,or genetic disorders) because that will permit study of thekidney-brain connection with perhaps more careful consid-eration. The use of neuroimaging procedures as part of rou-tine clinical care requires ongoing investigation, but thesefindings do point to the use of such procedures for casesshowing neurologic symptoms. Their use from a preventivestance for young patients with CKD also holds promise withrespect to managing their cerebrovascular health and asso-ciated neurologic morbidity across the lifespan.

AcknowledgmentsThis study was supported by the Pennsylvania Department of

Health: Commonwealth Universal Research Enhancement (CURE)Program, Health Research Formula Grant Award SFY 2010-14awarded to The Children’s Hospital of Philadelphia.

DisclosuresS.R.H. reported researchand travel support received fromEliLilly

and The Children’s Hospital of Philadelphia. The other authors hadno conflicts to report.

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