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PolyuriaandPolydipsiaSyndrome:isitDiabetesInsipidus?

ProfTriciaTanConsultantinMetabolicMedicine&

EndocrinologyClinicalChemistry

ObjecHvesfortalk

1.  tounderstandthepathophysiologyofDI2.  tounderstandthedifferenHaldiagnosis3.  tounderstandhowwecandifferenHate

betweenthedifferentcauses4.  tounderstandtreatmentstrategies

DefiniHonofPolyuria

•  Aurineoutputexceeding– 3L/dayinadults– 2L/m2bodysurfacearea/dayinchildren.

•  MustbedifferenHatedfrom– FrequencyofurinaHon– Nocturia– Thesearenotassociatedwithanincreaseinthetotalurineoutput.

BasicFirstLineInvesHgaHons

•  U&E,Ca,Glucose–excludediabetesmellitus!•  UrinalysisforglucoseandS.G.– S.G.<1.005issuspicious

•  PairedserumandurineosmolaliHes– Normalserumosmo=275-295mOsm/kg– Urineosmorangesfrom100to1200mOsm/kg– Baselineserumosmoof>295withurineosmo<200isdiagnosHcofDI

•  Bladderdiary

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Osmolality•  ConcentraHonofosmoHcallyacHveparHclesinasoluHon

(expressedperkgsolvent)•  Measureusingfreezingpointdepression(proporHonalto

osmolality)

BladderdiaryTime In Out ‘Wet’ Urgencyra4ng

0700 300ml ✔✔ A=feltnoneedtovoidbutdidsoforotherreasons

0800 Tea1cup B=couldpostponevoidingaslongasnecessarywithoutfearof‘wehng’

0900 C=couldpostponevoidingforashortHmewithoutfearof‘wehng’

1000 300ml D=couldnotpostponevoidingandhadtorushtovoidintoilet

1100 Water1cup

E=leakedbeforegehngtotoilet

…

0400 200ml

0500

0600

OsmoreceptorsvsbaroreceptorsOsmoreceptorsmeasureconcentraHonofplasma

Baroreceptorsmeasurebloodpressureandvolume

ADH=argininevasopressin(AVP)

AVPsecreHonisrelatedto

osmolalityandbloodvolume

↑osmo→↑AVP

↓volume→↑AVP

↓volumemodifiesAVPresponsetoosmolality

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AVPcontrolsaquaporinrecruitmentinthecollecHngductofkidney

RelaHonshipofAVPreleasetoplasmaosmolalityandurineosmolality Whenpolyuriaproven…

•  Excludeuncontrolleddiabetesmellitus•  ThreemajorcausesofpolyuriaintheoutpaHentsehng:– primarypolydipsia– centraldiabetesinsipidus(DI)– nephrogenicDI

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PrimarypolydipsiaØ Aprimaryincreaseinwaterintake.•  Mostoqenseenin– middle-agedwomen–  paHentswithpsychiatricillnesses–  includingthosetakingaphenothiazinewhichcanleadtothesensaHonofadrymouth

•  Primarypolydipsiacanalsobeinducedby–  hypothalamiclesionsthatdirectlyaffectthethirstcenter,e.g.sarcoidosis

–  Xerostomia(lackofsaliva)leadingtoexcessivedrinking

CranialDI

Ø DeficientsecreHonofAVPfromposteriorpituitary

•  Oqenidiopathic– possiblyduetoautoimmuneinjurytotheADH-producingcells

•  Trauma(headinjury)•  Pituitarysurgery•  Hypoxicorischaemicencephalopathy•  Familial:mutaHonsinpro-AVPgene

NephrogenicDI

Ø HighAVPbutkidneysinsensiHvetothis•  Familial– MutaHonsinV2receptororaquaporin

•  Litoxicity•  Hypercalcaemia•  Hypokalaemia•  Renaldisease(e.g.CKD)•  Pregnancy–placentalvasopressinase

Case1

•  40yearoldlady•  BipolardisorderonLithiumcarbonate•  Polyuriaandpolydipsia(upto10litresaday)•  ComplainsofadrymouthalltheHme•  Whatarethepossiblediagnoses?

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Case1

•  NephrogenicDI– DuetochronicLitreatment– Li-inducedhyperparathyroidismandhyperCa?

•  Primarypolydipsia– Duetounderlyingpsychiatricdisorder?

•  CranialDIlesslikely

Tests

•  Baseline– Na145,K4.5,Canormal,glucosenormal– Liundetectable

•  WentontowaterdeprivaHontest

WhatisawaterdeprivaHontest?

•  Firststage–  SerialmeasurementsofserumandurineosmoundercondiHonsofwaterdeprivaHon

– Differen4atesprimarypolydipsia(urineosmo↑)fromDI(urineosmofailsto↑beyondalimit)

•  Secondstage–  IfDIproven,giveDDAVP– Differen4atescranialDI(urineosmo↑toDDAVP)vsnephrogenicDI(urineosmodoesnotrespond)

•  Needstobedoneundersupervisionforsafety

InterpretaHonofwaterdeprivaHon

•  Pre-test–  Serumtopendofnormal–  Urinecan’tcomment

•  Waterdeprived–  Serumtoohigh–  Urineisinappropriatelylow(wouldexpect>750)

•  DDAVPgiven–  SerumissHlltoohigh–  UrineissHllnotconcentratedenough

Ø  NephrogenicDI

Pre-test Waterdeprived(8h) GivenDDAVP

Serum Urine Serum Urine Serum Urine

295 460 305 605 306 598

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NephrogenicDIduetoLithium

•  20-40%takingLihave↑urinevol(2-3L/d)•  12%ofpaHentshavefrankpolyuria(>3L/d)•  DirectinhibitoryeffectofLionaquaporinexpressionandrecruitment

•  Chroniceffect:Li-inducedintersHHalnephriHscancontributetoDI

•  UsuallyreversiblewithdisconHnuaHon,butcanpersistlong-term

•  InthiscasedisconHnuaHonledtosevlingofDI

TreatmentofNephrogenicDI

•  IVfluids(ifpaHentveryhypovolaemic)– Needtousefluidofsimilarosmotourineotherwiseinstabilityof[Na]mayensue

•  Lowprotein/Nadiet– ↓amountofsolutethatneedstobeexcretedandtherefore↓urinevolumeneeded

•  ThiazidediureHcs– CausesmildvolumedepleHon– ↑resorpHonofNaandwaterinproximaltubule

TreatmentofNephrogenicDI

•  NSAIDs(e.g.indomethacin)– ProstaglandinsantagoniseeffectofAVP– ThereforeinhibiHngproducHonofPGcausesincreasedwaterreabsorpHon

•  HighdoseDDAVP– MostpaHentswithnon-familialnephrogenicDIhaveparHaldefectsthatmayrespondtoDDAVP

Case2

•  25yearoldwoman•  “Alwaysdrunklotsandpassedlots”•  Nootherrelevantpasthistory•  Baselines– Na136,K3.6,CaandGlucosenormal– Serumosmo277,urineosmo100

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InterpretaHonofwaterdeprivaHon

•  Pre-test

–  Serumlowendofnormal–  Urineisdilute

•  Waterdeprived–  Serumrisestonormalrange–  Urinerisesto>750–  NotewouldexpectUrineosmotoriseto>1000inayoungperson–  Chronicpolydipsiacauses‘washout’ofmedullaryconcentraHonand

thereforesomereducHoninabilitytoconcentrateurineØ  Primarypolydipsia

Pre-test Waterdeprived(8h)

Serum Urine Serum Urine

275 100 280 850

Treatmentofprimarypolydipsia

•  FluidrestricHon•  ConsiderarHficialsalivaifproblemdrivenbydrynessofbuccalmucosa(e.g.withxerostomia)

Case3

•  24y.o.man,RTAlastyear,polyuric•  Baselines– Na145,K4.0,Canormal,glucosenormal

•  WentontowaterdeprivaHontest

Case3intepretaHon

•  Baseline–  Serumtopendofnormal–  Urinenotinterpretable

•  Waterdeprived–  Serumclearlyhigh–  Urineinappropriatelydilute(shouldbe>750atleastoreven>1000in

youngperson)•  DDAVPgiven

–  Sharpriseinurineosmoseen–  Recoveryofserumosmotonormal

Ø  CranialDI

Pre-test Waterdeprived(8h) GivenDDAVP

Serum Urine Serum Urine Serum Urine

295 300 302 295 285 1154

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CranialDIduetoheadinjury

•  Acutelyaqerheadinjuryin1in5paHents•  Seenchronicallyin1in12paHents•  Associatedwithotherpituitaryproblemsorcanbeisolated

•  DDAVPRx:Tablets Nasalspray

Sublingualmelts

OthercausesofcranialDI•  Pituitarytumours– Notcommoninpituitaryadenoma– Morecommonwithothertypesoftumours(e.g.craniopharyngioma,metastasis)

•  Pituitarysurgery•  InfiltraHvedisease–  Sarcoidosis,hisHocytosisX

•  InfecHon– MeningiHs,encephaliHs

•  Hereditary(rare)

HowtomonitoraPaHentonDDAVP

•  DDAVPhasdifferentdosesdependingonpreparaHon,e.g.–  Tablets:100µgnocteto200µgTDS– Nasalspray:10-20µg(1-2sprays)OD-TDS– Melts:60,120,240µgOD-TDS–  SubcutaneousinjecHon:0.5-1µgOD-BD

•  DifferentduraHonsofacHon–  Tablets~4-6h– NasalSpray~8h–  InjecHon~12h

DDAVPisavitaldrug

Pa4entsmustreceivesteadysuppliesofDDAVP

Pa4entsareen4tledtoexemp4onfromprescrip4oncharges

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HowtomonitoraPaHentonDDAVP

•  Twokeyparametersformonitoring:–  Bodyweight(reflectsbodywater)–  Na+

•  Warningsigns:–  Tiredness–  Confusion–  Ataxia–  NauseaandvomiHng–  Headaches–  Acutechangeof>2kgfrombaselinebodyweight

•  CHECKU&EURGENTLY

SomecommonquesHons

•  BlockageofnasalpassagesinpaHentsusingspray(e.g.URTI)–  ConsiderRxtablets

•  Pregnancy– Mayrequireincreaseddose:placentalvasopressinasebreaksdownAVP/DDAVP

•  Travelling–  PaHentsmayrequirealeverforairportsecuritytocarrymedicaHonthroughscreening

–  PaHentsshouldtakedosesaccordingtolocalHme