Neurologicalcomplicationsofrenaldialysisandtransplantation

KushanKarunaratne1,DavidTaube2,RichardPerry1,3,NofalKhalil4,PareshMalhotra1,3*

1DepartmentofNeurology,ImperialCollegeHealthcareNHSTrust,London,UnitedKingdom.

2DepartmentofRenalandTransplantationMedicine,WestLondonRenalandTransplantCentre,ImperialCollegeKidneyandTransplantInstitute,London,UnitedKingdom.

3DivisionofBrainSciences,ImperialCollegeLondon,UK

4DepartmentofNeurophysiology,ImperialCollegeHealthcareNHSTrust,London,UnitedKingdom.

*Correspondingauthor.

Correspondence:DrPareshMalhotra,DepartmentofNeurology,HammersmithHospital,DuCaneRoad,London,W12OHS.Telephonenumber–02033117286

Email–p.malhotra@imperial.ac.uk

Wordcount-4740

ABSTRACT

Neurologicalcomplicationswithrenalreplacementtherapycontribute

significantlytomorbidityandmortalityinpatientswithrenalfailure.Alllevelsof

thenervoussystemcanbeaffected,andcanbeclassifiedascentralorperipheral.

Mostneurologicaldisturbancesassociatedwiththeuraemicstatefailtorespond

fullytorenalreplacementtherapyandfurthercomplicationsarespecifically

associatedwithdialysisandtransplantation.Amulti-disciplinaryapproach

involvingbothnephrologistsandneurologistsiscriticalindiagnosisand

effectivemanagementofthesedisordersintheseparticularlyvulnerablegroups

ofpatients.

Keywords–Haemodialysis,Dialysis,Renaltransplant,Neurological

complications

INTRODUCTION

InthemostrecentUKrenalregistryreport,itwasnotedthattherewere

approximately60,000patientsreceivingrenalreplacementtherapyattheendof

2014with7,411patientshavingstartedrenalreplacementtherapyoverthe

courseofthatyear(1).Transplantationwasthemostcommontreatment

modality(53%);haemodialysiswasusedin41%andperitonealdialysisin6%of

renalreplacementtherapypatients(1).Thekidneyandtransplantserviceat

ImperialCollegeHealthcareNHSTrust,predominantlybasedatHammersmith

Hospital,looksafterover3500patientsonrenalreplacementtherapy.Inour

experienceasizeableproportionoftheseindividualsdevelopneurological

problems.Althoughthesecansometimesrelatetosystemicconditions,

particularlydiabetesmellitusandautoimmunediseases,whichcanleaddirectly

tobothneurologicalandkidneydisease,theyareoftensecondarytothe

introductionofdialysisorsubsequenttorenaltransplantation.Thus,herewe

focusonneurologicalpresentationsinpatientsreceivingrenalreplacement

therapy(fordescriptionsofneurologicalpresentationsinchronickidneydisease

seeKellyetal)(2).

Despitethetherapeuticadvancesofdialysisandtransplantation,thewell-

describedneurologicalcomplicationsofuraemiasuchasencephalopathy,

neuropathyandmyopathyremainaseriousconcernandcanleadtofunctional

impairment(3).Althoughtherearechangesinthespectrumofneurological

diseaseinthetransitionfrompre-dialysistodialysis,aconsiderableproportion

ofchronicuraemiccomplicationsremain.Theunderlyingreasonsforthisarenot

clear,butsomehavepostulatedtheinabilitytoclear‘middlemolecules’(arange

oftoxinsconsistingmostlyoflowmolecularweightpeptidesandproteins;300-

12000Kilodaltons)withstandarddialysis(4).Theintroductionofdialysiscan

alsoleadtoanumberofnewneurologicalproblemsinthesepatients(SeeTable

1).Withprogressionfromdialysistorenaltransplantation,immunosuppressive

therapyengendersavarietyofneurologicaldisturbances(5).Fromourown

experience,itisimportanttonotethatneurologicalpresentationsinrenal

replacementtherapypatientsareoftenmultifactorial,andmorethanone

problemmayneedtobeaddressed.

NEUROLOGICALCOMPLICATIONSASSOCIATEDWITHDIALYSIS

PeritonealDialysisversusHaemodialysis

Themajorityofneurologicaldialysiscomplicationsareobservedinboth

haemodialysisandperitonealdialysis.However,thosecomplicationsassociated

withhaemodynamicinstabilityaremorelikelytooccurinthoseundergoing

haemodialysis.Thereisalsosomeevidencetosuggestthatdialysisheadacheis

lessfrequent,inperitonealdialysis,althoughtheunderlyingmechanisms

explainingthisdifferencearenotyetclear(6).

Table1

Neurologicalcomplicationssecondarytodialysis

Centralnervoussystem Cerebralhaemorrhage

Cerebralthrombosis

Centralpontinemyelinolysis

Wernicke’sencephalopathy

Dialysisdementia

Cognitiveimpairment

Disequilibriumsyndrome

Anteriorischaemicopticneuropathy

Posteriorreversibleencephalopathysyndrome

Peripheralnervoussystem

Vascularaccessrelatednerveinjury

Carpaltunnelsyndrome

Peripheralneuropathy

Others Haemodialysisheadache

Dialysisinducedhypotension

Drugtoxicity

Centralnervoussystem

Cerebralhaemorrhage

Intracerebralhaemorrhages(ICHs)causesignificantmorbidityandmortalityin

haemodialysispatients(3).Combinationsofchronicuraemia,intradialytic

anticoagulation,inadequatecontrolofhypertensionandconcurrentuseofblood

thinnerssuchasaspirinincreasetheriskofhaemorrhagicevents.Uraemia

resultsinplateletdysfunctionaswellasabnormalinteractionsbetweenplatelets

andthevesselwall,increasingbleedingtendency(7).Haemodialysisonlypartly

correctsthispathophysiologicalabnormality.Techniquesusedtolimitsystemic

bleedingriskincluderegionalanticoagulationandminimalheparinuse(8).

PatientswhohavesufferedarecentICH,areactivelybleedingfromanothersite

orareatahighriskofbleedingcanundergodialysiswithoutanticoagulation

(heparin-freedialysis).

Aretrospectivestudyinourcentrewithover2500patientsonmaintenance

haemodialysis,foundtheprevalenceofnon-traumaticsubduralhaemorrhage

was0.4%withanoverallannualincidenceof189per100000patients(9).No

associationwasfoundwithcomorbiditiessuchashypertensionanddiabetes,or

theuseofanti-plateletandanticoagulantmedication(9).

Cerebralthrombosis

Cerebralvenoussinusthrombosis(CVST)isarelativelyuncommonneurological

complicationindialysispatients.Althoughdialysispatientshavenumerous

predisposingfactorstodevelopCVST,heparinanticoagulationusedwith

haemodialysismostlikelyhasaprotectiveeffect.Ifthereisanyclinicalsuspicion

ofCVST,magneticresonanceimaging(MRI)venogramisthepreferableimaging

method(10).Ifdiagnosisisconfirmeditisadvisabletocommunicatewiththe

haematologyteamwithregardstoacuteandlong-termanticoagulationtherapy

asdialysispatientsareatahigherriskofhaemorrhagicevents.Ifno

contraindications,wewouldsuggestacutetreatmentwiththerapeuticdoselow

molecularweightheparin.

Centralpontinemyelinolysis

Rapidplasmaosmoticfluctuationsduringhaemodialysiscanresultincentral

pontinemyelinolysisalsoknownasosmoticdemyelinationsyndrome(11).

Patientswithchronichyponatraemiaandelevatedserumosmolalityaremore

likelytodevelopthiscomplication.Initialsymptomssuchasdysarthria,

dysphagiaandlimbweaknesscanmimicastroke.Characteristicoedemais

observedintheponsandextrapontineregionsonMRIscans.Cautionmustbe

exercisedwithslowcorrectionofsodiumlevels(6-8mmol/day)byreducing

dialysatelevelsofsodiumandslowingrateofbloodflowduringdialysis(3).

Wernicke’sencephalopathy

Thisisaparticularlychallengingclinicaldiagnosis,giventhenumerous

differentialdiagnosesrelatedtoencephalopathyinhaemodialysispatients

(examplesincludehypertensiveencephalopathy,drugtoxicity,electrolyteand

metabolicderangementanddialysisencephalopathy)(12).Wernicke’s

encephalopathymanifestsduetoacombinationofpoornutritionalstate

commonlyobservedindialysispatients,andincreasedlossofwater-soluble

vitaminsduringhaemodialysis.Althoughclassicallycharacterisedbythetriadof

confusion,ataxiaandophthalmoplegia,atypicalfeaturessuchaschorea,

peripheralneuropathyandmyoclonushavealsobeenobserved(13).Assessment

andadvicefromrenal-specificdieticiansisprudenttoimprovenutritionalstate.

Thereisnowidelyavailablebiochemicalassaywhichaidsdiagnosis,soclinicians

shouldalwaysconsiderthisreversibleconditioninpatientsundergoingdialysis,

andtreatempiricallywithparenteralvitaminreplacementifinanydoubt.

Dialysisdementia

Dialysis-associateddementiahasbeendescribed‘asanepidemicthatcameand

went’,withaluminiumneurotoxicitywidelyrecognisedasthecausativefactor

(14).

Cognitiveimpairment

Anincreasedincidenceofcognitiveimpairmentanddementiaisobservedin

patientswithESRDcomparedtothegeneralpopulation(15).Thereisevidence

thatcognitiveimpairmentstartstooccuronceestimatedglomerularfiltration

rate(eGFR)islessthan60ml/minandfastereGFRdeclineisassociatedwith

globalcognitivedeterioration(16).However,comparedtothegeneral

population,cognitiveimpairmentsecondarytovasculardiseaseisthoughttobe

moreprevalentthanAlzheimer’sdiseaseinhaemodialysispatients(15).High

ratesofcardiovascularriskfactorscontributetodevelopmentofcerebrovascular

disease.Manystudieshavealsonotedthehigherprevalenceofcognitive

impairmentinhaemodialysispatientscomparedtoperitonealdialysispatients

(17,18).Rapidfluctuationsinbloodpressure,electrolytesandosmolalitywith

haemodialysismaycausecerebralischaemicinjuryleadingtocognitive

impairment.Althoughperitonealdialysisdoesnotresultinsuchrapidchanges,

thehighglucosebaseddialysateleadingtosecondarymetabolicdisordersis

thoughttocontributetocognitiveimpairment(15).

Disequilibriumsyndrome

Cerebraloedemaandraisedintracranialpressurehavebeenimplicatedin

dialysis-relateddisequilibriumsyndrome(3).Firstdescribedover50yearsago,

butnowveryrare,itcanpresentinanypatientundergoinghaemodialysisbut

mostcommonlyoccursafterthefirstsessionofdialysis.Initialsymptomscan

rangefromheadache,muscletwitching,restlessnessandnausea.Progressionof

cerebraloedemacanresultincomaanddeath.Thesimplestmethodtoprevent

disequilibriumsyndromeistoperformhaemofiltrationinsteadofhaemodialysis.

Thisensuresareductionintherateofchangeofosmolalitiescomparedto

haemodialysisassoluteisremovedthroughconvectionratherthandiffusion.If

usinghaemodialysis,slowlyreducingbloodureaconcentrations,takingagentle

approachwithnewdialysispatients,andusinghighsodiumcontaining

dialysatesorotherosmoticagentshavebeenrecommendedtoreducetheriskof

occurrence(19).

Anteriorischaemicopticneuropathy

Anteriorischaemicopticneuropathycanberelatedtohaemodialysisdueto

vascularcompromisetotheprelaminaropticnerve.Riskfactorssuchasco-

existinganaemiaanddialysis-inducedhypotensionhavebeenlinkedwiththis

condition(20).

Posteriorreversibleencephalopathysyndrome

Posteriorreversibleencephalopathysyndrome(PRES)isaneurologicaldisorder

predominantlyaffectingcerebralwhitematterandisoftenassociatedwitha

rapidincreaseinbloodpressure.PREScanalso,rarely,beassociatedwith

systemicautoimmunediseasessuchassystemiclupus.Thisclinico-radiologic

entitycommonlypresentswithsymptomssuchasheadache,visualdisturbances,

alteredmentalstateandseizures.MRIfindingsareessentialfordiagnosisand

typically(butnotexclusively)showvasogenicoedemainthedeepwhitematter

oftheoccipitalandparietallobes.Earlyrecognitionandaggressiveblood

pressurecontroliscrucialinmanagementofthisreversibleneurological

complicationtopreventpermanentneurologicaldeficits(3).

Peripheralnervoussystem

Peripheralnervoussystemdisordersareoftendirectlyrelatedtohaemodialysis

andcaninvolvemonoandpolyneuropathies.Mononeuropathiesaremainly

relatedtocreationofarteriovenousfistulae.

Vascularaccessrelatednerveinjury

Surgicalnerveinjuryrelatedtoarteriovenousfistulaecanoccurinthe

immediatepost-operativeperiodorinthemorechronicsetting.Theproximityof

themediannervetothebrachialarterymakesitsusceptibleduringformationof

brachio-cephalicfistulae.Disablingmediannervecompressionhasbeen

reportedfollowingahaematomaandapseudoaneurysmformationrelatingto

surgery(21).Pseudoaneurysmsformduetorepeatedcannulation,androtation

ofpuncturesiteshelpstoavoidthis.Nervecompressionrelatedtosurgical

arteriovenousfistulaeformationshouldberegardedasasurgicalemergencyto

preventlong-termdisability.

Ischaemicneuropathyfollowingarteriovenousfistulaesurgeryhasalsobeen

showntoaffectthemediannervewithonestudyreportingthefrequency

rangingfrom1-10%(22,23).Itisthoughttobeaformof‘stealphenomenon’,

wherethevascularaccesssitedepletesbloodsupplytothedistalnervecausing

axonalloss(23).Riskfactorsincludeddiabetesandsevereperipheralvascular

disease.Ifdiagnosed,distalperfusionshouldbeestablishedwithoutdelayand

thismayrequireclosureofthearteriovenousfistulae.

Carpaltunnelsyndrome

Carpaltunnelsyndromecommonlyoccursinhaemodialysispatients.Local

amyloiddeposition,venoushypertensiondistaltothearteriovenousfistulae,

uraemicdamagetomediannerveandincreasedextracellularvolumeleadingto

nerveischaemiahavebeenimplicated(21,24).Studiescomparingresultsof

surgicaltreatmentinidiopathiccarpaltunnelsyndromeanddialysisrelated

carpaltunnelsyndromesuggestthatcarpaltunnelsyndromerecurrence,higher

postoperativecomplicationratesandlongerrecoveryaremorecommonin

dialysisrelatedcarpaltunnelsyndromecomparedtoidiopathiccarpaltunnel

syndrome(25).

Peripheralneuropathy

Peripheralneuropathyrelatedtouraemicpolyneuropathyisoneofthemost

commonneurologicalcomplicationsassociatedinpre-dialysisanddialysis

patients(2,3).Unfortunatelyhaemodialysisitselfrarelyimprovesneuropathy.In

milderformspatientsusuallyreportdistalparaesthesiaepredominantly

affectingthelowerlimbs.Lossofvibrationsenseandabsentanklereflexesare

foundonneurologicalexamination.Moresevereformscanpresentwith

weakness.Neurophysiologytypicallyshowsalength-dependentpredominantly

axonalmixedsensorymotorneuropathy(3).

Itcanbedifficulttodifferentiateuraemicneuropathyfromothercausesof

peripheralneuropathyindialysispatientsduetolikelyco-existingcomorbidities

suchassystemicvasculitisanddiabetesmellitus(3).Insuchcases

neurophysiologicalfindingsaloneareinsufficienttodistinguishonefromthe

otherandtheclinicalhistoryplaysthemostusefulrole.Forinstancearapidly

progressivemotorneuropathyisunlikelytoberelatedtouraemicneuropathy.

FolicacidandBVitaminsupplementation,andtheuseofneuropathicpain

agentscanbeusefulassymptomatictherapy(althoughnoteriskofpossibledrug

toxicityasbelow).Non-uraemicperipheralneuropathiesshouldalsobe

considered

Others

Haemodialysisheadache

Thistransientheadache,thoughttoberelatedtointradialytichypotensionand

changesinureaandmagnesiumlevels,isreportedtofrequentlyoccurtowards

theendofhaemodialysissessionsandhasanincidenceof5%(3).Itisoften

describedasabilateralthrobbingornon-pulsatingheadacheusuallylastingless

than4hours.Diagnosticcriteria(internationalheadacheclassificationsystem)

include:>2episodesofacuteheadachewitheachepisodedevelopingduringa

dialysissession,worseningheadacheduringdialysisandheadacheresolution

within72hoursofcompletingdialysis.Followingsuccessfulrenal

transplantationtheheadachemustcompletelycease.

Fewstudiesareavailabletoprovideevidencetosupportspecifictreatments.

Angiotensiveconvertingenzymeinhibitorsandmagnesiumsupplementation

havebeensuggestedaspotentialtherapies(26).

Dialysisinducedhypotension

Symptomatichypotensionisacommonintradialyticcomplication,and

increasinglyrecognisedasaseriousproblemwiththeincreasingnumberof

elderlyanddiabeticpatientsundergoinghaemodialysis.Itcanresultincerebral

hypoperfusionandischaemia.Riskfactorsinadditiontorapidultrafiltration

includecardiovascularrisks.Therapeuticstrategiesincludeclosesupervision

andmonitoringbydialysisstaffandpharmacologicalmanagementofco-existing

cardiovascularandautonomicneuropathy(27).

Drugtoxicity

Oneofthemostcommoncausesofneurologicalproblemsinpatientswithrenal

failure(pre-dialysisanddialysis)isdrugtoxicity,particularlypenicillins,

ciprofloxacin,acyclovir,gabapentin,pregabalin,benzodiazepinesandopioidsas

thesedrugs(andoftentheiractivemetabolites)arerenallyexcretedandpoorly

removedbydialysis,particularlyifproteinbound(28,29).

Forthesedrugs,doseadjustmentsareoftenmadebyreducingthedose,

increasingtheintervalbetweendoses,orboth.Itmaybesafetoadminister

drugswithawidetherapeuticindexwithoutadosereduction,ifthedrugis

unlikelytocauseharmalthoughthedrugconcentrationmaybehigher.However,

indrugswithalowtherapeuticindex,significantdoseadjustmentsmaybe

required.

Inallcasesanapproachmustbetakentodeterminetheimportanceofstable

serumdrugconcentrations,whilstmonitoringforadverseeffects.Thereare

manyaccessiblesourcesforreferencefordoseadjustmentsinrenalfailure.The

RenalDosingDatabaseiseasilyaccessibleonline

(http://www.globalrph.com/index_renal.htm)andprovidesguidanceforboth

renal(basedoncreatinineclearance)andhaemodialysisdosing.Ifindoubt,the

renalunitpharmacistisagoodsourceforadviceandguidance.

NEUROLOGICALCOMPLICATIONSRELATEDTORENALTRANSPLANTATION

Overthepastdecaderobustevidencesuggeststhesuperiorityofrenal

transplantationcomparedtohaemodialysiswithimprovements,bothinsurvival

andqualityoflife(30,31).Advancesinperi-operativecare,surgicaltechniques

andpostoperativemanagementhavereducedthemorbidityandmortalityof

transplantrecipients.Despitethis,recipientsareatahighriskofdeveloping

neurologicaldisorders(5).

Theaetiologyofmostpost-transplantneurologicaldisordersrelatesto

immunosuppressivemedication.Someofthese,suchasopportunisticinfections,

arewell-describedbutinourexperiencethesemedicationshaveaverywide

rangeofpotentialtoxicities,notallofwhichhavebeenfrequentlyreportedinthe

literature.

OpportunisticCNSinfections,cerebrovasculareventsanddenovoCNS

neoplasmsarealsomorefrequentinthispopulation(SeeTable2).Calcineurin

inhibitorsareamongstthemostrecognisedimmunosuppressivedrugscausing

neurotoxicitywithcomplicationsrangingfromfinetremortoseizures.Rapid

identificationoftheunderlyingdisorderanddiseaseprocessparticularlywith

neuroimaging,electrodiagnostictests

(Figure3),laboratorytestsincludingcerebrospinalfluid(CSF)analysisto

complementhistoryandclinicalfindingsarecrucialinthesepatients.

Table2

Commonneurologicalcomplicationsrelatedtorenaltransplantation

Centralnervoussystem Infections

Toxicityofimmunosuppressivetherapy

Posteriorreversibleencephalopathysyndrome

PrimaryCNSlymphoproliferativedisease

Cerebrovasculardisease

Peripheralnervoussystem

PeripheralNeuropathyPostoperativenerveinjury

Centralnervoussystem

Infection

Infectionistheleadingcauseofmortalityandmorbidityinrenaltransplant

patientsandmostcommoninthefirst12monthsfollowingtransplantation(32).

Earlydiagnosisandtreatmentiscrucial.Effectsofimmunosuppressivetherapy

oftenhinderthemanifestationoftypicalsignsandsymptoms,leadingtochanges

inpresentationanddifficultyindiagnosis.Hencethethresholdforsuspecting

CNSinfectionintransplantpatientsmustbelowerthaninthe

immunocompetentpatient,andthesemustbedifferentiatedfromCNSvasculitis

orsystemiclupuserythematosus(SLE)inpatientswithsystemicformsofthese

diseases(whetherornottheyhavepreviouslyhadCNSinvolvement).

ThemostreliablesymptomsuggestiveofCNSinfectioninthetransplantpatient

isheadacheinthepresenceofanunexplainedfever.Alteredmentalstatus,focal

neurologicalsignsandmeningismmaybesuppressedbytheanti-inflammatory

propertiesofimmunosuppressivemedications.Allrecipientspresentingwith

anyofthesesymptomsshouldhaveanMRIscanwithgadoliniumcontrast

followedbylumbarpuncture(providednocontraindications).Magnetic

resonanceimagingisthemostsensitivemodalitytodemonstrateleptomeningeal

enhancement,cerebritis,hydrocephalusandabscesses(33).

Timeframepost-transplantisanimportantfactorrelatingtoCNSinfection

susceptibility.Inthefirstmonth,opportunisticpathogenssuchasgram-negative

bacteria,staphylococcalspecies,AspergillusfumigatusandMycobacterium

tuberculosisarecommon.ThereisalwayspotentialforCNSinfectionstobe

transmittedfromdonortorecipient,andalthoughrare,cliniciansmustbeaware

ofsuchoccurrences.

Betweenoneandsixmonths,atpeaklevelsofimmunosuppression,thereis

increasedsusceptibilitytoorganismssuchasCytomegalovirus(CMV),Epstein-

Barrvirus(EBV),Humanherpesvirusesandatypicalbacterialorganismssuchas

Listeriamonocytogenes(34).Inthisintermediateposttransplantperiod,

infectionscanprecipitateorganrejectionleadingtoaviciouscycleofincreasing

immunosuppressivetherapytopreventrejection,inturnprecipitatingdifficulty

controllingtheinfectiveprocess.

After6monthsthereisgenerallyadecreasedriskofCNSinfectionwithmost

casesreportedasCryptococcusneoformans,EBVandJCvirus(34).

NeuroimagingwithMRIiscrucialindiagnosis.AspergillusandToxoplasma

commonlypresentasmasslesionswithringenhancement.CNSaspergillosisis

alsooftenassociatedwithhaemorrhagiccerebralinfarctionaswellas

pulmonaryinvolvement.ListeriaandCryptococcus,Epstein-Barrvirusand

Varicella-zostervirusmostcommonlyareresponsibleformeningeal

enhancementwhilstCMVcausesventricularenhancement(34).

Inadditiontoneuroimaging,lumbarpunctureisalsocriticalinestablishing

diagnosis.WesuggestsendingCSFformicrobiology,cultureandsensitivities,

proteinlevel,glucose(CSFandblood)level,extendedviralPCR,cytology,

Cryptococcalantigen,TBPCR,Bacterial16SrDNA-PCRandanadequatesample

forstorageintheeventfurthertestsarerequired.

CerebrospinalfluidPCRissensitiveandspecificfororganismssuchasEBV,CMV,

VZVandJCvirus.PositiveCSFcultureismoreusefulindiagnosisofCryptococcus

neoformansandMycobacteriumtuberculosis.

Whilstinvestigatingtherapidlydeterioratingpatient,wesuggestempirical

treatmentwithCeftriaxoneandAcyclovirandwouldrecommendingdiscussion

withtheinfectiousdiseasesand/ormicrobiologybeforeandafterinitialtest

resultsareavailable.

Table3

OrganismsresponsibleforCNSinfectionsintransplantpatentsandtreatmentoptions

Organism Microbialtherapyoptions

Bacterial Listeriamonocytogenes

Ampicillin+Gentamycin

Ampicillin+Ceftriaxone+Vancomycin

Cryptococcusneoformans

AmphotericinB+Fluconazole/Flucytosine

NocardiaAsteroides Trimethoprim/sulfamethoxazole

Toxoplasmagondii Pyrimethamine,Sulfadiazine+Folinicacid

Mycobacterium Rifampicin,Isoniazid,Ethambutalol+

Tuberculosis Pyridoxine,Amikacin,Dexamethasone

Viral VaricellaZoster Acyclovir

Humanherpesvirus6 Ganciclovir

Herpessimplex Acyclovir

Toxicityofimmunosuppressivetherapy

Numerousimmunosuppressivedrugsareusedfollowingtransplantationto

preventorganrejectionandtheseareassociatedwithanumberofneurotoxic

effects(Table4).Suddenexposureofthenervoussystemtotoxicsubstancesand

thenarrowtherapeuticwindowincreasestheriskofneurotoxicity.Protocolsfor

bothinductionandmaintenanceofimmunosuppressionvaryaccordingto

centreswithmostusingacombinationof1)glucocorticoidsandcalcineurin

inhibitorsorpurinesynthesisinhibitorsor2)monoclonalantibodiesand

calcineurininhibitors.

Themostwellrecognisedneurotoxiceffectsaredocumentedwithcalcineurin

inhibitorsexpressedinseveralareasofthebrain(35,36).Amajorityof

transplantrecipientssufferfrommildneurologicalsymptomsespeciallyinthe

firstfewweeksfollowinginitiationoftherapy.Commonsymptomsincludefine

restingandactiontremors,headaches,paraesthesiaandmoodchanges.More

serioussymptomscanincludeseizures,ataxiaandmotordeficits.

Inourcentretacrolimusisthemostcommonlyusedimmunosuppressiveagent.

Thecommonestneurotoxicsideeffectswehavenoticedarefinerestingand

actiontremors.Druglevelmonitoringisimportantduetothenarrow

therapeuticindex.Althoughmanysideeffectsaredoserelated,inourexperience

druglevelsarenotalwaysraisedevenifthereisclinicaltoxicity(SeeFigure2).

Table4

Immunosuppressivemedicationandcommonassociatedneurotoxiceffects

Cytomegalovirus Ganciclovir/foscarnet

Epstein-BarrVirus (Noantiviraltreatmentavailable)

Fungal Aspergillusfumigatus AmphotericinB/fluconazole

Histoplasmacapsulatum

Itraconazole+-AmphotericinB

Parasitic Strongyloidessteroralis Ivermectin

Class Commonneurotoxiceffects

Corticosteroids Acute-Insomnia,moodchanges,psychosis,delirium

Chronic–Proximalmyopathy

Purinesynthesisinhibitors Usuallynone,rarelyheadache

Calcineurininhibitors PRES,akineticmutism,toxicencephalopathy,seizures

Headache,tremor,paraesthesia,moodchanges

Antimetabolites,Targetofrapamycininhibitorsandbiologicagentsareonlyrarelyassociatedwithneurotoxiceffects(seeFigure2)

Posteriorreversibleencephalopathysyndrome

PRES(Seesectionabove)isalsoacomplicationofimmunosuppressivetherapy

andcanleadtopermanentneurologicaldeficitsifmisdiagnosedorinadequately

managed(37).NeurotoxiceffectsofcalcineurininhibitorsresultinginPRESmay

occurattherapeuticdruglevelsandevenintheabsenceofhypertension.Inmost

casesreducingdoseorwithdrawaloftheoffendingimmunosuppressivetherapy

(andcontrolofanyfurtherexacerbatingfactor(e.g.hypertension))canprevent

permanentimpairment.Electrolytemonitoringandreplacement(including

magnesium),treatmentofhypertensionandacuterenalfailureandsupportive

therapyarethemainstaysofmanagement.Intheacutesettinganti-epileptic

drugsmayberequired(38).

PrimaryCNSlymphoproliferativedisease

Post-transplantlymphoproliferativediseaseisawell-knowncomplication

developinginimmunosuppressedtransplantrecipients.ThevastmajorityareB-

Cellphenotype,whichareEBVdriven.Patientscommonlypresentwith

headaches,seizures,alteredmentalstateandexaminationmayrevealfocal

neurologicaldeficits.

Boththetypeandlevelofimmunosuppressionareassociatedwithriskin

developingthisdisorder.Onestudyshowed,comparedtothegeneralpublic,

renaltransplantrecipientshavebeenreportedtohavearelativeriskof12.6of

developingpost-transplantlymphoproliferativedisease(39).Treatmentwith

anti-thymocyteglobulinorMuromonab-CD3forinduction,orasanagentto

preventacuterejection,hasbeenshowntoincreasepost-transplant

lymphoproliferativediseaseriskbyapproximately9-fold(39).Treatmentwith

calcineurininhibitorsincreasedtheriskapproximatelytwofold(39).

Althoughpost-transplantlymphoproliferativediseasecanaffectanyorgan,CNS

involvementhasbeenreportedin10-15%ofcases(39).AdditionallyCNS

lymphomawasfoundtobemorecommonfollowingrenaltransplantation

comparedtoheartandlungtransplantrecipients.Prognosislargelydependedof

extentofdiseasedisseminationand5-yearsurvivalwas38%(40).

Cerebrovasculardisease

Cardiovascularandcerebrovasculardisordersremaintheleadingcauseof

mortalityresultingin‘deathwithafunctioningallograft’(41).Moststudies

reportanincreasedriskofischaemicstokescomparedtohaemorrhagicstrokes

butmortalityishigherwithhaemorrhagicevents(42,43).Riskfactorsfor

haemorrhagicstrokeincludediabetesmellitus,polycystickidneydisease(PKD),

leftventricularhypertrophyandhighsystolicbloodpressure(42).

Aretrospectiveanalysisofover1000patientsfromourunitfoundthatthat

4.53%ofindividualswhoreceivedakidneyaloneorasimultaneouspancreas

andkidneytransplanthadastrokepost-transplant(41).Predictorsofstroke

wereage,diabetes,corticosteroiduseandsimultaneouspancreasandkidney

transplant.

Transplantspecificriskfactorsforstrokewereidentifiedasgraftfailure,

immunosuppression,longdurationondialysispre-transplant,anddeceased

donortransplantation(41).However,ithasbeenobservedthattransplantleads

toanoverallimprovementincerebrovascularriskcomparedtodialysis

patients(43).

Peripheralnervoussystem

Neuropathy

Peripheralnervesaresusceptibletothetoxiceffectsofimmunosuppressive

medicationduetotheabsenceofprotectivemechanismssuchastheblood-brain

barrier.AnAustralianstudydemonstratedabnormalitiesinnervefunction

inducedbycalcineurininhibitors(44).Ahigherprevalenceofclinical

manifestationsofneuropathywerenotedinthecalcineurininhibitortherapy

group(68%)comparedtothecalcineurininhibitorfree-group(37%,)where

sirolimusandmycophenolatewereusedincombinationoreitheras

monotherapy.Furtherthereweresignificantdifferencesinnerveexcitability

parameterssuggestiveofmembranedepolarisation.

Neuropathycouldalsobeduetopre-existinguraemiarelatednervedamageor

asanewmanifestationduetograftfailurerelateduraemia.Itcanoftenbe

difficulttodifferentiatebetweenuraemicneuropathyandcalcineurininhibitor

inducedperipheralneuropathy.Inourexperiencewithuraemicneuropathy,

motorsymptomsandsignstendtoonlyoccurwhenuraemicneuropathyisvery

advanced.

Post-operativenerveinjury

Sensoryandmotorimpairmentfollowingrenaltransplantationisrelatively

commonwithlateralcutaneousnerveofthethighandfemoralnervesmostly

affected(45).

Instrumentrelatedinjuryislikelythemostcommonexplanationeventhough

thesurgicalsiteisusuallydistantfromthepathoflateralcutaneousnerveofthe

thighandfemoralnerves.Postoperativehaematomaandcompressiondueto

retractorscanalsocausenervepalsy.Localstealsyndromeresultinginfemoral

nerveischaemiahasalsobeenpostulatedinacutefemoralnervepalsy(46).

Thesechangesareusuallytemporary.

Usefulneurologicalinvestigationsisrenaldialysisandtransplantpatients

Inthesesusceptiblegroupsofpatients,earlyidentificationandprompt

treatmentofthediseaseprocessiscrucial.Particularlywithimmunosuppressed

patients,symptomsandsignsmaybemaskedduetotherapyandtheremusta

lowthresholdfordiagnosticinvestigations(Table5).

Computedtomographyandmagneticresonanceimaging

MRIisthemostusefuldiagnosticinvestigationinearlydetectionof

cerebrovasculardiseaseindialysisandtransplantpatients,andisthepreferred

imagingmodality.

Patientsreceivingdialysistreatmentshouldbescheduledtoundergodialysisas

soonaspractical,preferablywithin24hoursfollowingadministrationof

Table5

Neurologicalinvestigationsinrenaldialysisandtransplantpatients

Investigations Indication

Imaging

Computedtomography

Magneticresonanceimaging

Unwellpatientinacutesetting

Stroke

SuspectedCNSinfectionsorfocallesion

Encephalopathy

PrimaryCNSmalignancy

UltrasoundDoppler Suspectedischaemicneuropathy

Electrophysiologicaltests

Electroencephalogram

Encephalopathy

Episodicconfusion

Nerveconductionstudies

Suspectedmononeuropathyorpolyneuropathy

Fatiguableweakness(Repetitivenervestimulation)

Electromyography SuspectedmyopathyorNeuromuscularjunctionpathology

gadoliniumcontrast.Intransplantpatients,creatininelevelsshouldbeclosely

monitoredandineventofacutedeteriorationofrenalfunction,provisionsfor

haemodialysisorhaemofiltrationshouldbeinplace.Thedevelopmentof

nephrogenicsystemicsclerosisisrareandnotusuallyseenwiththenewerforms

ofgadolinium(47).Itshouldbenotedthatalargenumberofpatientswith

chronickidneydiseasehavesignificantcerebralsmallvesseldisease.

MRIhoweverhasmanylimitations,particularlyintheacutelyunwelland

restlesspatient.Theseincludescanneravailabilityandimagedegradationdueto

movementartefact.InthesesituationsCTisveryusefultoruleoutcerebral

haemorrhages,hydrocephalusandspaceoccupyinglesions.CTarteriogramsand

venogramsarealsousefulforacutevascularimagingandinthediagnosisof

venoussinusthrombosis(Figure1).

Electroencephalogram

Electroencephalogram(EEG)canbehelpfulinpatientswithimpaired

consciousnessoralteredmentalstatusandisparticularlyofuseinearly

detectionofdialysisdementia,metabolicencephalopathyassociatedwithrenal

failureandseizuresoccurringinsevereencephalopathy(48).Triphasicwaves

anddiffuseslowactivityareobservedinsuchencephalopathies(48).Inacute

uraemicencephalopathy,EEGchangesareusuallymoresevereandmayhelpto

distinguishfromseizure-relatedimpairmentofconsciousness(48).Correlations

betweendegreeofEEGslowingandlevelofserumcreatininemayalsobeseen

(48).

Lumbarpuncture

Cerebrospinalfluidanalysisisusefulinpatientswithnew-onsetsevere

headache,alteredmentation,seizuresandessentialintheaccuratediagnosisof

CNSinfectionsandmalignancies.Inmanydialysispatientswithalteredmental

stateandnofever,lumbarpuncturewillnotbenecessaryasclinical

improvementusuallydevelopswithin48hours.Intracranialhypotension

secondarytohaemodialysiscanbeconfirmedbymeasuringCSFpressure.CSFin

uraemiamaybeabnormalwithapleocytosisandraisedproteinlevelin

approximately50%ofpatients(49).History,examinationandinvestigations

needtobeconsideredintheinterpretationofabnormalCSFresults(forinstance

whendistinguishinguraemicencephalopathyfromaCNSinfection).Although

thereistheoreticalincreasedriskassociatedwithlumbarpuncturebecauseof

bleedingtendency,wehavenotexperiencedthis,andrecommendpromptLP

whenindicated.

NerveconductionstudiesandElectromyographyUraemicneuropathyispredominantlyaxonal,althoughsensoryandmotor

conductionvelocitiesareoftenreduced.WithchronicrenalfailureaGuillain-

Barretypeofneuropathycanbeobservedwithconductionblock,conduction

slowingandprolongedFwavelatencies.Electromyographywithuraemic

myopathyisusuallynormal.

Conclusion

Numerousneurologicalcomplicationsareinducedbydialysisandrenal

transplantation.Neurologicalmanifestationsoccurinboththecentraland

peripheralnervoussystemsresultinginmorbidityandmortality.Itislikelythat

dialysis-specificcomplicationsareunderreportedcomparedtotransplant

relatedcomplications.Thisismostlikelyduetotheclosermonitoringof

transplantrecipientsbyphysicians.Cliniciansshouldrecognisethatsymptoms

thatmaybeperceivedtobelessalarming,suchasheadacheordizziness

commonlyreportedbyhaemodialysispatients,maybeanearlywarningsignof

moreseriouscomplications.Nephrologistswillappreciatethedifficultyand

frustrationofpatientsonhaemodialysisreporting‘aches,painsandheadaches’

andinidentifyingwhichpatientstoexaminemorethoroughly.

Followingtransplantationamajorityofneurologicalcomplicationsarerelatedto

immunosuppressivetherapy.Itisimportanttobeawarethatagentsevenat

therapeuticlevelsresultinneurotoxicity.

Acloserelationshipbetweennephrologistsandneurologistsiscriticalto

effectivelydealwithneurologicalcomplicationsinthesevulnerableand

susceptiblegroupsofpatients.Earlyidentificationofthediseaseprocessand

rapidtreatmentiscrucialtoensureagoodlong-termoutcome.

Learningpoints

1. Immunosuppressivemedicationsoftenhaveanarrowtherapeuticindex.

Druglevelsmaynotalwaysberaisedevenwithevidenceofclinical

toxicity.

2. Neurologicalpresentationsinrenalreplacementtherapypatientsare

oftenmultifactorial,andmorethanoneproblemmayneedtobe

addressed.

3. Unlesscontraindicatedmagneticresonanceimagingisthepreferred

modalityofneuroimagingforthesegroupsofpatients.

4. Ahealthyworkingrelationshipbetweenneurologistsandnephrologistsis

crucialtodiagnoseandeffectivelymanagethesepatients.

LEGENDS

LegendtoFigure1aCTvenogramfroma53-year-oldmanwithanABOincompatiblerenaltransplantpresentedwithasuddenonsetoccipitalheadache.PlainCTdidnotshowanyclearabnormality,butCSFopeningpressurewas47cmCSF.Thereisthrombusatthejunctionofthelefttransverseandsigmoidsinuses

LegendtoFigure1bThrombusintheinferiorsuperiorsagittalsinus(inthesamepatient)

LegendtoFigure2AbnormalEEG(Predominantlyanteriorspikeandwave)inanencephalopathictransplantpatientontacrolimus(therapeuticlevels).Othercausesofencephalopathywereruledoutandsherecoveredaftertacrolimuswasreplacedwithsirolimus.

LegendtoFigure3Repetitivenervestimulationwithrecordingfromabductordigitiminimiina65yearoldpatientwithfatiguableocularandlimbweaknesswhichdeveloped12monthsafterrenaltransplantwhichwascarriedwithalemtuzumabinduction.Acetylcholinereceptorantibodieswerenegative.Thereisacleardecrementofresponsestorepeatedstimulationat2Hz(PanelA)and3Hz(PanelB).StimulationsinglefibreEMGofOrbicularisoculishowedincreasedmeanjitter(MCD36usec)and10%blocking..Thepatientrespondedwelltopyridostigmine.AlemtuzumabisassociatedwithautoimmunecomplicationsandmyastheniahaspreviouslybeenreportedoneyearfollowingrenaltransplantwithAlemtuzumabinduction(50).

.

LegendtoTable2CNS,centralnervoussystem

LegendtoTable4PRES,posteriorreversibleencephalopathysyndrome

LegendtoTable5CNS,centralnervoussystem;

CONTRIBUTORSHIP

KKwrotethefirstdraft.DT,RPandNKcontributedinthewritingofthepaper.PMcontributedtowritingandfinalapprovalofthepaper.

ACKNOWLEDGEMENTS

ThisworkissupportedbytheNationalInstituteforHealthResearch(NIHR)ImperialBiomedicalResearchCentre.ThankstoDrGemmaDaweforherhelpwiththeFigures.

CONFLICTSOFINTEREST

None

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