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Azotemia

Azotemia
Author:MoroOSalifu,MD,MPH,FACPChiefEditor:VecihiBatuman,MD,FACP,FASNmore...
Updated:Jan6,2015

Background
Azotemiaisanelevationofbloodureanitrogen(BUN)andserumcreatininelevels.ThereferencerangeforBUNis
820mg/dL,andthenormalrangeforserumcreatinineis0.71.4mg/dL.
Eachhumankidneycontainsapproximately1millionfunctionalunitsknownasnephrons,whichareprimarily
involvedinurineformation.Urineformationensuresthatthebodyeliminatesthefinalproductsofmetabolic
activitiesandexcesswaterinanattempttomaintainaconstantinternalenvironment(homeostasis).Urine
formationbyeachnephroninvolves3mainprocesses,asfollows:
Filtrationattheglomerularlevel
Selectivereabsorptionfromthefiltratepassingalongtherenaltubules
Secretionbythecellsofthetubulesintothisfiltrate
Perturbationofanyoftheseprocessesimpairsthekidneysexcretoryfunction,resultinginazotemia.
Thequantityofglomerularfiltrateproducedeachminutebyallnephronsinbothkidneysisreferredtoasthe
glomerularfiltrationrate(GFR).Onaverage,theGFRisabout125mL/min(10%lessforwomen),or180L/day.
About99%ofthefiltrate(178L/day)isreabsorbed,andtherest(2L/day)isexcreted.

Measurementofrenalfunction
RadionuclideassessmentoftheGFRisthebestavailabletestformeasuringkidneyfunction.However,thistestis
expensiveandnotwidelyavailable,andasaresult,serumcreatinineconcentrationandcreatinineclearance(CrCl)
morecommonlyareusedtoestimateGFR.
AninverserelationbetweenserumcreatinineandtheGFRexistshowever,serumcreatinineandCrClarenot
sensitivemeasuresofkidneydamage,for2reasons.First,substantialrenaldamagecantakeplacebeforeany
decreaseintheGFRoccurs.Second,asubstantialdeclineintheGFRmayleadtoonlyaslightelevationinserum
creatinine(seetheimagebelow).Becauseofcompensatoryhypertrophyandhyperfiltrationoftheremaininghealthy
nephrons,anelevationinserumcreatinineisapparentonlywhentheGFRfallstoabout6070mL/min.

Graphshowsrelationofglomerularfiltrationrate(GFR)tosteadystateserumcreatinineandbloodureanitrogen(BUN)levels.In
earlyrenaldisease,substantialdeclineinGFRmayleadtoonlyslightelevationinserumcreatinine.Elevationinserumcreatinineis
apparentonlywhenGFRfallstoabout70mL/min.

Becausecreatininenormallyisfilteredaswellassecretedintotherenaltubules,CrClmaycausetheGFRtobe
substantiallyoverestimated,especiallyaskidneyfailureprogressesbecauseofmaximaltubularexcretion.More
accuratedeterminationsofGFRrequiretheuseofinulinclearanceoraradiolabeledcompound(eg,iothalamate).In
practice,preciseknowledgeoftheGFRisnotrequired,andthediseaseprocessusuallycanbeadequately
monitoredbyusingtheestimatedGFR(eGFR),whichmaybeobtainedwithanumberofdifferentmethods.
CrClisbestcalculatedbyobtaininga24hourcollectionforcreatinineandvolumeandthenusingthefollowing
formula:
CrCl(mL/min)=U/PV
whereUistheurinecreatinineinmg/dL,Pistheserumcreatinineinmg/dL,andVisthe24hourvolumedivided
by1440(thenumberofminutesin24hours).Anadequate24hourcollectionusuallyreflectsacreatininegeneration
of1520mg/kginwomenand2025mg/kginmen.When24hourcreatinineismeasured,theadequacyofthe
collectionmustbeestablishedpriortocalculationofthecreatinineclearance.
Alternatively,theGFRcanbeestimatedbymeansoftheCockcroftandGaultformula,abedsideformulathatuses
thepatientsserumcreatinine(mg/dL),age(y),andleanweight(kg),asfollows:
CrCl(mL/min)=[(140age)weight]/(72serumcreatinine)
Forwomen,theresultoftheequationismultipliedby0.85.
AnotherformulawasderivedfromdatacollectedintheModificationofDietinRenalDisease(MDRD)study.The
MDRDformula,alsocalledtheLeveyformula,isnowwidelyacceptedasmoreaccuratethantheCockcroftand
Gaultformulaandisconsideredanalternativetoradioisotopeclearance.
Becauseserumcreatininelevelsalonecannotdetectearlierstagesofchronickidneydisease(CKD),theMDRD
formulaalsotakesintoaccountthepatientsageandrace.Althoughthisformulaismoreaccurate,itismuchmore
difficulttocalculatemanually.However,softwareforestimatingtheGFRbymeansoftheMDRDformulais

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availableformostpersonaldigitalassistantsandcanbefoundontheInternet.
DelanayeetalhavearguedthattheMDRDformulaisinapplicabletosomeindividuals,suchashealthyindividuals
andpatientswhoareanorecticorobese. [1]Ithasthereforebeenproposedthattheformulashouldbeappliedwith
caution.

Pathophysiology
Therearethreepathophysiologicstatesinazotemia,asfollows:
Prerenalazotemia
Intrarenalazotemia
Postrenalazotemia

Prerenalazotemia
PrerenalazotemiareferstoelevationsinBUNandcreatininelevelsresultingfromproblemsinthesystemic
circulationthatdecreaseflowtothekidneys.Inprerenalazotemia,decreasedrenalflowstimulatessaltandwater
retentiontorestorevolumeandpressure.Whenvolumeorpressureisdecreased,thebaroreceptorreflexeslocated
intheaorticarchandcarotidsinusesareactivated.Thisleadstosympatheticnerveactivation,resultinginrenal
afferentarteriolarvasoconstrictionandreninsecretionthrough1receptors.
Constrictionoftheafferentarteriolescausesadecreaseinintraglomerularpressure,whichreducestheGFR
proportionally.ReninconvertsangiotensinItoangiotensinII,which,inturn,stimulatesaldosteronerelease.
Increasedaldosteronelevelsresultsinsaltandwaterabsorptioninthedistalcollectingtubule.
Adecreaseinvolumeorpressureisanonosmoticstimulusforhypothalamicproductionofantidiuretichormone,
whichexertsitseffectinthemedullarycollectingductforwaterreabsorption.Throughunknownmechanisms,
activationofthesympatheticnervoussystemleadstoenhancedproximaltubularreabsorptionofsaltandwater,as
wellasBUN,creatinine,calcium,uricacid,andbicarbonate.Thenetresultofthese4mechanismsofsaltandwater
retentionisdecreasedoutputanddecreasedurinaryexcretionofsodium(<20mEq/L).

Intrarenalazotemia
Intrarenalazotemia,alsoknownasacuterenalfailure(ARF),renalrenalazotemia,andacutekidneyinjury(AKI),
referstoelevationsinBUNandcreatinineresultingfromproblemsinthekidneyitself.Thereareseveraldefinitions,
includingariseinserumcreatininelevelsofabout30%frombaselineorasuddendeclineinoutputbelow500
mL/day.Ifoutputispreserved,AKIisnonoliguricifoutputfallsbelow500mL/day,ARFisoliguric.AnyformofAKI
maybesoseverethatitvirtuallystopsformationthisconditioniscalledanuria(<100mL/day).
ThemostcommoncausesofnonoliguricAKIareacutetubularnecrosis(ATN),aminoglycosidenephrotoxicity,
lithiumtoxicity,andcisplatinnephrotoxicity.TubulardamageislessseverethanitisinoliguricAKI.Normaloutput
innonoliguricAKIdoesnotreflectanormalGFR.Patientsmaystillmake1440mL/dayofurineevenwhenthe
GFRfallstoabout1mL/minbecauseofdecreasedtubularreabsorption.
SomestudiesindicatethatnonoliguricformsofAKIareassociatedwithlessmorbidityandmortalitythanisoliguric
AKI.Uncontrolledstudiesalsosuggestthatvolumeexpansion,potentdiureticagents,andrenalvasodilatorscan
convertoliguricAKItononoliguricAKIifadministeredearly.
ThepathophysiologyofacuteoliguricornonoliguricAKIdependsontheanatomiclocationoftheinjury.InATN,
epithelialdamageleadstofunctionaldeclineintheabilityofthetubulestoreabsorbsalt,water,andother
electrolytes.Excretionofacidandpotassiumisalsoimpaired.InmoresevereATN,thetubularlumenisfilledwith
epithelialcasts,causingintraluminalobstructionandresultinginadecliningGFR.
Acuteinterstitialnephritisischaracterizedbyinflammationandedema,whichresultinazotemia,hematuria,sterile
pyuria,whitebloodcell(WBC)castswithvariableeosinophiluria,proteinuria,andhyalinecasts.Theneteffectisa
lossofurinaryconcentratingability,withlowosmolality(<500mOsm/L),lowspecificgravity(<1.015),highurinary
sodium(>40mEq/L),and,occasionally,hyperkalemiaandrenaltubularacidosis.However,ifthereissuperimposed
prerenalazotemia,thespecificgravity,osmolality,andsodiummaybemisleading.
Glomerulonephritisorvasculitisissuggestedbythepresenceofhematuria,redbloodcells(RBCs),WBCs,granular
andcellularcasts,andavariabledegreeofproteinuria.Nephroticsyndromeusuallyisnotassociatedwithactive
inflammationandoftenpresentsasproteinuriagreaterthan3.5g/24h.
GlomerulardiseasesmayreduceGFRbychangingbasementmembranepermeabilityandstimulatingtherenin
aldosteroneaxis.Suchdiseasesareoftenmanifestedasnephroticornephricsyndrome.Innephroticsyndrome,the
urinarysedimentisinactive,andthereisgrossproteinuria(>3.5g/day),hypoalbuminemia,hyperlipidemia,and
edema.Azotemiaandhypertensionareuncommoninitially,buttheirpresencemayindicateadvanceddisease.
SomepatientswithnephroticsyndromemaypresentwithARF.Impairmentofcapillarycirculationinthekidneydue
toedema(nephrosarca)andtubularobstructionfromproteincasts,aswellasdecreasedeffectivecirculating
volume,havebeenproposedaspotentialmechanismsforthedevelopmentofARFinpatientswithnephrotic
syndrome.
Innephriticsyndrome,theurinarysedimentisactivewithWBCorRBCcasts,granularcasts,andazotemia.
Proteinuriaislessobvious,butincreasedsaltandwaterretentioninglomerulonephritiscanleadtohypertension,
edemaformation,decreasedoutput,lowurinaryexcretionofsodium,andincreasedspecificgravity.
Acutevasculardiseasesincludevasculitissyndromes,malignanthypertension,sclerodermarenalcrisis,and
thromboembolicdisease,allofwhichcauserenalhypoperfusionandischemialeadingtoazotemia.Chronicvascular
diseasesareduetohypertensivebenignnephrosclerosis,whichhasnotbeenconclusivelyassociatedwithendstage
renaldisease(ESRD)andischemicrenaldiseasefrombilateralrenalarterystenosis. [2]
Inbilateralrenalarterystenosis,maintenanceofadequateintraglomerularpressureforfiltrationgreatlydependson
efferentarteriolarvasoconstriction.Azotemiasetsinwhenangiotensinconvertingenzyme(ACE)inhibitorsor
angiotensinIIreceptorblockers(ARBs)causeefferentarteriolardilatation,therebydecreasingintraglomerular
pressureandfiltration.Therefore,ACEinhibitorsandARBsarecontraindicatedinbilateralrenalarterystenosis.

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Inadditiontoaccumulationofureacreatinineandotherwasteproducts,asubstantialreductioninGFRinCKD
resultsinthefollowing:
Decreasedproductionoferythropoietin(causinganemia)andvitaminD3(causinghypocalcemia,secondary
hyperparathyroidism,hyperphosphatemia,andrenalosteodystrophy)
Reductioninacid,potassium,salt,andwaterexcretion(causingacidosis,hyperkalemia,hypertension,and
edema)
Plateletdysfunction(leadingtoincreasedbleedingtendencies)
Thesyndromeassociatedwiththesignsandsymptomsofaccumulationoftoxicwasteproducts(uremictoxins)is
termeduremiaandoftenoccursataGFRofabout10mL/min.Someoftheuremictoxins(eg,urea,creatinine,
phenols,andguanidines)havebeenidentified,butnonehavebeenfoundresponsibleforallthemanifestationsof
uremia.

Postrenalazotemia
PostrenalazotemiareferstoelevationsinBUNandcreatininelevelsresultingfromobstructioninthecollecting
system.ObstructiontoflowleadstoreversaloftheStarlingforcesresponsibleforglomerularfiltration.Progressive
bilateralobstructioncauseshydronephrosiswithanincreaseintheBowmancapsularhydrostaticpressureand
tubularblockagethatleadstoprogressivedeclineinandultimatecessationofglomerularfiltration,azotemia,
acidosis,fluidoverload,andhyperkalemia.
Unilateralobstructionrarelycausesazotemia.Thereisevidencethatifcompleteureteralobstructionisrelieved
within48hoursofonset,relativelycompleterecoveryofGFRcanbeachievedwithinaweeklittleornofurther
recoveryoccursafter12weeks.Completeorprolongedpartialobstructioncanleadtotubularatrophyand
irreversiblerenalfibrosis.Hydronephrosismaybeabsentifobstructionismildoracuteorifthecollectingsystemis
encasedbyretroperitonealtumororfibrosis.

Etiology
Prerenalazotemiaoccursasaconsequenceofimpairedrenalbloodflowordecreasedperfusionresultingfrom
decreasedbloodvolume,decreasedcardiacoutput(congestiveheartfailure),decreasedsystemicvascular
resistance,decreasedeffectivearterialvolumefromsepsisorhepatorenalsyndrome, [3]orrenalarteryabnormalities.
Itmaybesuperimposedonabackgroundofchronicrenalfailure.Iatrogenicfactors,suchasexcessivediuresisand
treatmentwithACEinhibitors,shouldberuledout.
Intrarenalazotemiaoccursasaresultofinjurytotheglomeruli,tubules,interstitium,orsmallvessels.Itmaybe
acuteoliguric,acutenonoliguric,orchronic.Systemicdisease,nocturia,proteinuria,lossofurinaryconcentrating
ability(lowurinespecificgravity),anemia,andhypocalcemiaaresuggestiveofchronicintrarenalazotemia.
Postrenalazotemiaoccurswhenanobstructiontourineflowispresent.Itisobservedinbilateralureteral
obstructionfromtumorsorstones,retroperitonealfibrosis,neurogenicbladder,andbladderneckobstructionfrom
prostatichypertrophyorcarcinomaandposteriorurethralvalves.Itmaybesuperimposedonabackgroundof
chronicrenalfailure.

Epidemiology
UnitedStatesstatistics
ThereportedincidenceofhospitalorcommunityacquiredARFvariesconsiderably.Inonereport,community
acquiredARFoccurredinabout1%ofallhospitaladmissions.Overall,ARFoccursinabout5%ofallhospital
admissions.However,differencesexistbetweentheincidenceofARFoccurringintheintensivecareunit(ICU
about15%)andthatinthecoronarycareunit(CCUabout4%).
InCKD,progressiveazotemialeadingtoESRDnecessitatingdialysisorkidneytransplantationoccursinanumber
ofchronicdiseases,includingdiabetes(36%),hypertension(24%),glomerulonephritis(15%),cystickidneydisease
(4%),andallotherknownmiscellaneousrenaldisorders(15%).

Internationalstatistics
InareportfromMadridthatevaluated748casesofARFat13tertiaryhospitalcenters,themostfrequentcauses
wereATN(45%)prerenal(21%)acuteorchronicrenalfailure,mostlyduetoATNandprerenaldisease(13%)
urinarytractobstruction(10%)glomerulonephritisorvasculitis(4%)acuteinterstitialnephritis(2%)and
atheroemboli(1%).EtiologiesofCKDdifferaroundtheworld.DiabeticnephropathyasacauseofCKDisonthe
riseindevelopedanddevelopingcountries.

Age,sex,andracerelateddemographics
Amongthepatientsreportedinthe2008annualreportoftheUnitedStatesRenalDataSystem(USRDS),the
frequencyofazotemiawas1.5%forpatientsaged019years,19.1%forthoseaged2044years,44.0%forthose
aged4564years,19.6%forthoseaged6574years,and15.7%forthoseolderthan75years.Themalefrequency
was56.0%,andthefemalefrequencywas44.0%.
[#Clinical]Inthe2010annualreportoftheUSRDS,morethan500,000patientswithESRDwerereceivingdialysis
orakidneytransplantintheUnitedStates.RacialdistributionwasreportedasAsian/PacificIslander(4.7%),black
(32.0%),white(61.0%),AmericanIndian(1.3%),andother/unknown(0.6%).

Prognosis
TheprognosisofARF/AKIgenerallyispooranddependsontheseverityoftheunderlyingdiseaseandthenumber
offailedorgans.WhereasmortalityinpatientswithsimpleARF/AKIwithoutotherunderlyingdiseaseis723%,that
inICUpatientsonmechanicalventilationisashighas80%.
TheprognosisofCKDdependsontheetiology.Patientswithdiabetickidneydisease,hypertensivenephrosclerosis,
andischemicnephropathy(ie,largevesselarterialocclusivedisease)tendtohaveprogressiveazotemiaresultingin

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ESRD.Differenttypesofglomerulonephritishavemajordifferencesinprognosis:somearequitebenignandrarely
progresstoESRD,whereasothersprogresstoESRDwithinmonths.About50%ofpatientswithpolycystickidney
diseaseprogresstoESRDbythefifthorsixthdecadeoflife.

ContributorInformationandDisclosures
Author
MoroOSalifu,MD,MPH,FACPAssociateProfessor,DepartmentofInternalMedicine,Chief,Divisionof
Nephrology,DirectorofNephrologyFellowshipProgramandTransplantNephrology,StateUniversityofNew
YorkDownstateMedicalCenter
MoroOSalifu,MD,MPH,FACPisamemberofthefollowingmedicalsocieties:AmericanCollegeof
PhysiciansAmericanSocietyofInternalMedicine,AmericanMedicalAssociation,AmericanSocietyforArtificial
InternalOrgans,AmericanSocietyofDiagnosticandInterventionalNephrology,AmericanSocietyofNephrology,
AmericanSocietyofTransplantation,andNationalKidneyFoundation
Disclosure:Nothingtodisclose.
Coauthor(s)
OnyekachiIfudu,MDDirectorofInpatientDialysisServices,AssociateProfessor,DepartmentofInternal
Medicine,StateUniversityofNewYorkHealthScienceCenteratBrooklyn
Disclosure:Nothingtodisclose.
ChiefEditor
VecihiBatuman,MD,FACP,FASNHuberwaldProfessorofMedicine,SectionofNephrologyHypertension,
TulaneUniversitySchoolofMedicineChief,RenalSection,SoutheastLouisianaVeteransHealthCareSystem
VecihiBatuman,MD,FACP,FASN,isamemberofthefollowingmedicalsocieties:AmericanCollegeof
Physicians,AmericanSocietyofHypertension,AmericanSocietyofNephrology,andInternationalSocietyof
Nephrology
Disclosure:Nothingtodisclose.
AdditionalContributors
GeorgeRAronoff,MDDirector,Professor,DepartmentsofInternalMedicineandPharmacology,Sectionof
Nephrology,KidneyDiseaseProgram,UniversityofLouisvilleSchoolofMedicine
GeorgeRAronoff,MDisamemberofthefollowingmedicalsocieties:AmericanFederationforMedical
Research,AmericanSocietyofNephrology,KentuckyMedicalAssociation,andNationalKidneyFoundation
Disclosure:Nothingtodisclose.
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollege
ofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:MedscapeReferenceSalaryEmployment

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