ChronicKidneyDiseaseandDrugDosing:InformationforProviders

(RevisedJanuary2010) EstimationofKidneyFunctionforPrescriptionMedicationDosageinAdults Knowledgeofkidneyfunctionisimportantfordosageofmedicationsthatareexcretedbythekidneys.Food andDrugAdministration(FDA)approveddruglabelingguidesprovideadjustmentsofdrugdosagesfor patientswithimpairedkidneyfunction.Ontheselabels,serumcreatinine;measuredcreatinineclearance (CrCl);or,mostcommonly,estimatedcreatinineclearanceusingtheCockcroftGaultequation(eCrCl)are usedtoestimatekidneyfunction.Formostdrugs,theselabelsweredevelopedpriortostandardized calibrationofcreatinineassaysandreportingestimatedglomerularfiltrationrate(eGFR)calculatedusing theModificationofDietinRenalDisease(MDRD)Studyequation.1ThisdocumentdescribestheNational KidneyDiseaseEducationProgram's(NKDEP)suggestionsandrationalesforassessmentofkidneyfunction fordrugdosingpurposes. NKDEPsSuggestedApproachtoDrugDosing Historically,therehasbeensubstantialvariabilityinserumcreatininevaluesreportedbydifferentclinical laboratorycreatininemethods.Consequently,pharmacokinetic(PK)studiesperformedusingnon standardizedcreatininemethodsobtainedresultsthatweredependentupontheparticularcreatinine methodusedinagivenPKstudy.TheresultsfromthePKstudieswereincorporatedintoFDAdruglabels.As such,thePKstudiesrecommendeddrugdosages(i.e.,theFDAdruglabels)wereinconsistentlytranslated intoclinicalpracticeduetothevariabilityamongcreatininemethodsusedindifferentlaboratories. Useofstandardizedcreatininemethodswillleadtolessvariationinestimatingkidneyfunctionandmore consistentdrugdosing.Forsomedrugs,theFDAormanufacturersmaydecidetoperformstudiestore expressdruglabelingforstandardizedcreatininevalues.However,itwillnotbepossibletoreexpressall currentdrugdosingrecommendationsforusewithstandardizedcreatininevalues. AlargesimulationstudycomparedeGFRandeCrClcalculatedfromstandardizedcreatininevaluestoeach otherandtogoldstandardmeasurementsofGFR.Theresultssuggestedthatforthemajorityofpatientsand formostdrugstested,therewaslittledifferenceinthedrugdosethatwouldbeadministeredusingeither equationtoestimatekidneyfunction.2Basedontheseandotherconsiderations,wesuggestthefollowing: Useofasinglekidneyfunctionestimatetoguidedetection,evaluation,andmanagementofchronic kidneydisease(CKD)anddrugdosingislikelytofacilitatedeliveryofhighqualityhealthcare.

UtilizeeGFRoreCrClfordrugdosing.

IfusingeGFRinverylargeorverysmallpatients,multiplythereportedeGFRbytheestimatedbody surfacearea(BSA)inordertoobtaineGFRinunitsofmL/min: eGFR/1.73m2xestimatedBSA=eGFRfordrugdosing Note:BSAcanbeobtainedfromastandardnomogramorcanbecalculatedusingequationssuchas3:

(SeemoreonthisintheMDRDStudyEquationsection.)

ConsiderassessingkidneyfunctionusingalternativemethodssuchasmeasuredCrClormeasured GFRusingexogenousfiltrationmarkerswhenprescribingdrugswithnarrowtherapeuticindices,or forindividualsinwhomeGFRandeCrClprovidedifferentestimatesofkidneyfunction,orfor individualsinwhomanyestimatesbasedoncreatininearelikelytobeinaccurate.4(Seemoreonthis intheLimitationsofAnySerumCreatininebasedEstimatesection.)

ImpactofIDMSstandardizedCreatinineValues Nationaleffortstostandardizeserumcreatinineassaysbyestablishingcalibrationtraceabilitytoanisotope dilutionmassspectrometry(IDMS)referencemeasurementprocedurehavebeenunderwaysince2005. AllmajorglobalmanufacturershavecompletedrecalibrationtobetraceabletoanIDMSreference measurementprocedure,andallinventorywitholdercalibrationisexpectedtobenolongerinuse bythefirsthalfof2010.(Individualmanufacturersshouldbecontactedforstatusregardingtheir products.)Previously,therewasalargevariabilityinserumcreatinineresultsamongclinicallaboratories, withanoverallpositivebiasbyapproximately10to20percentamonglaboratoriessurveyed.5When standardizationofallcreatininemethodstoIDMStraceablecalibrationiscomplete,therewillbeless variabilityincreatinineresultsusedformanagingpatients.Thefollowingitemsdescribetheimpactof standardizedcreatinineassays:

Standardizationofcreatinineassayswillleadtolessvariationinestimatingkidneyfunctionandmore consistentdrugdosing. Therelationshipbetweencreatinineresultsbeforeandafterstandardizationwillbedifferent foreachspecificmethodandinstrumentusedinclinicallaboratories. Itisnotpossibletohaveasingle,uniformconversionformulaorfactortorelateIDMSstandardized creatininevaluesbacktononIDMStraceablevaluesthatcanbeappliedtoalllaboratorieswherethe PKstudieswereperformedortoallclinicallaboratories. Usingstandardizedcreatininevalues,theaccuracyofestimatedkidneyfunctionwilldependupon whetherornotanequationwasdevelopedusingIDMStraceablecreatininevalues.

UseofIDMStraceablecreatininevaluesintheIDMStraceableMDRDStudyequationwillresultina moreaccurateeGFR.1,6 UseofIDMStraceablecreatininevaluesintheCockcroftGaultformulawillhaveavariableimpacton eCrCl,dependinguponthecreatininemethod/instrumentused.However,becausemost nonstandardizedmethodshadapositivebias,useoftheCockcroftGaultformulawithIDMS traceablecreatininevalueswillleadtohighereCrClvaluesthanweredeterminedpriorto standardization.6 MeasuredCrClvaluesbasedonmeasuredserumandurinecreatinineresultsmaychangeforsome methodsthathaveindependentcalibrationforserumandurinesamples.Mostmethodsusethe samecalibrationschemeforbothserumandurineandwillbeminimallyaffectedbystandardization ofcalibrationbecausecreatinineisusedinboththenumeratoranddenominatoroftheCrCl calculation.

MDRDStudyEquation TheModificationofDietinRenalDisease(MDRD)Studyequationwasderivedfromastudy populationof1,628menandwomenwithCKD,aged18to70,predominantlyCaucasian, nondiabetic,andwhowerenonkidneytransplantrecipients.7

AlargenumberofstudiesnowshowthattheMDRDStudyequationissuitableforuseacross populationswithCKD,butunderestimatesmeasuredGFRathigherlevels.8,9 TheMDRDStudyequationestimatesGFRadjustedforBSA.Kidneyfunctionisproportionaltokidney size,whichisproportionaltoBSA.BSAof1.73m2isthenormalmeanvalueforyoungadults. AdjustmentforBSAisnecessarywhencomparingapatientskidneyfunctiontonormalvalues,orto thelevelsdefiningthestagesofCKD.Formostdrugs,adjustingforBSAisnotnecessaryfor determiningdrugdosing.GFRestimatesadjustedforBSAwillgenerallybeadequateexceptin patientswhosebodysizeisverydifferentthanaverage.(SeeNKDEPsSuggestedApproachtoDrug Dosingsection.) TheoriginalMDRDStudyequationissuitableforusewithcreatininemethodsthatDONOThave calibrationtraceabletoIDMS. eGFR=186x(Scr)1.154x(age)0.203x(0.742iffemale)x(1.212ifAfricanAmerican) Note:GFRisexpressedinmL/minper1.73m2,Scrisserumcreatinineexpressedinmg/dL,andageis expressedinyears.

TheMDRDStudyequationhasbeenreexpressedforusewithstandardizedserumcreatinine values.1,10 eGFR=175x(StandardizedScr)1.154x(age)0.203x(0.742iffemale)x(1.212ifAfricanAmerican) Note:GFRisexpressedinmL/minper1.73m2,Scrisserumcreatinineexpressedinmg/dL,andageis expressedinyears.

 CockcroftGaultEquation

TheCockcroftGault(CG)equationwasderivedfromastudypopulationof249Caucasianmenaged 18to92,withandwithoutCKD.Nowomenwereincludedinthedevelopmentpopulation,sothe factorforfemalesexishypothetical.11 eCrCl=[((140age)xweight)/(72xScr)]x0.85iffemale Note:eCrClisexpressedinmL/min,ageisexpressedinyears,weightisexpressedinkilograms,and Scrisexpressedinmg/dL.

TheCGequationcannotbereexpressedforIDMStraceablecreatininevalues.Thecreatinine methodusedinthedevelopmentoftheequationisnolongerinuseandsamplesfromthestudyare notavailable. TheCGequationestimatesCrClthatisnotadjustedforBSA.SimilartomeasuredCrCl,eCrCl systematicallyoverestimatesGFRduetotubularsecretionofcreatinine.Additionally,eCrClhasmore variabilitythaneGFRusingtheMDRDStudyequationasevidencedbyCockcroftGaulteCrClhaving only50to70percentofresults(vs.83percentforeGFR)within30percentofmeasuredGFR.6 ModificationsoftheCGequation,suchastheuseofidealversusactualbodyweight,were developedinanattempttoovercometheimprecisionwiththeuseofmeasuredbodyweight. However,thereisnoevidencethatthesemodificationsaremoreaccuratepredictorsofGFRor providebetterdrugdosingguidelines.

LimitationsofAnySerumCreatininebasedEstimate TheserumconcentrationofcreatinineisinfluencedbyfactorsotherthantheGFR,inparticular, differencesinrateofgenerationrelatedtomusclemassanddiet,aswellasdifferencesintherateof tubularsecretion.Estimatingequationscapturetheaveragedifferenceinrateofcreatinine generationbyage,sex,race,orweight,butdonotcaptureallfactors.

NeithereGFRnoreCrClwillbeaccurateinindividualswithextremesofbodysizeormusclemass,or thosewithunusualdietaryhabits.Thelimitationsincreatininebasedestimatingequationsare particularlyrelevantforpopulationswithreducedmusclemass,includingthefrail,elderly,critically ill,orcancerpatientswhoarelikelytorequiremedications.12 Useofanyserumcreatininebasedestimaterequiresthatkidneyfunctionbeatasteadystate,so anyestimatemustbeusedcautiouslyinhospitalizedpatientswithrapidlychangingkidneyfunction. MeasurementofGFRusingexogenousfiltrationmarkersandurineorplasmaclearanceorofCrCl usingtimedurinecollections,shouldbeconsideredwhendosingmedicationswithnarrow therapeuticindicesorwithhightoxicity,orinpatientsforwhomserumcreatininebasedestimates maybeinaccurate.4

 LeveyAS,CoreshJ,GreeneT,etal.Usingstandardizedserumcreatininevaluesinthemodificationof dietinrenaldiseasestudyequationforestimatingglomerularfiltrationrate.AnnInternMed. 2006;145:24754. 2 StevensLA,NolinT,RichardsonM,etal.Comparisonofdrugdosingrecommendationsbasedon measuredGFRandkidneyfunctionestimatingequations.AmJKidDis.2009;54(1):3342. 3 Mosteller,RD.SimplifiedCalculationofBodySurfaceArea.NEnglJMed.1987;317(17):1098. 4 StevensLA,LeveyAS.MeasuredGFRasaConfirmatorytestforestimatedGFR:indicationsand interpretation.JAmSocNephrol.2009;20:230513. 5 MillerWG,MyersGL,AshwoodER,etal.Creatininemeasurement:stateoftheartinaccuracyand interlaboratoryharmonization.ArchPatholLabMed.2005;129:297304. 6 StevensLA,ManziJ,LeveyAS,etal.ImpactofcreatininecalibrationonperformanceofGFRestimating equationsinapooledindividualpatientdatabase.AmJKidneyDis.2007;50:2135. 7 LeveyAS,BoschJP,LewisJB,etal.Amoreaccuratemethodtoestimateglomerularfiltrationratefrom serumcreatinine:Anewpredictionequation.ModificationofDietinRenalDiseaseStudyGroup.Ann InternMed.1999;130:461470. 8 StevensLA,CoreshJ,GreeneT,etal.Assessingkidneyfunctionmeasuredandestimatedglomerular filtrationrate.NEnglJMed.2006;354:247383. 9 StevensLA,CoreshJ,FeldmanHI,etal.Evaluationofthemodificationofdietinrenaldiseasestudy equationinalargediversepopulation.JAmSocNephrol.2007;18:274957. 10 LeveyAS,CoreshJ,GreeneT,etal.ExpressingtheModificationofDietinRenalDiseaseStudyequation forestimatingglomerularfiltrationratewithstandardizedserumcreatininevalues.ClinChem. 2007;53:76672. 11 CockcroftD,GaultM.Predictionofcreatinineclearancefromserumcreatinine.Nephron.1976;16:31 41. 12 PoggioED,NefPC,WangX,etal.PerformanceoftheCockcroftGaultandmodificationofdietinrenal diseaseequationsinestimatingGFRinillhospitalizedpatients.AmJKidneyDis.2005;46:24252. ThisinformationwasoriginallypostedtotheNKDEPwebsiteinSeptember2009.Extracopiesofthisupdated versioncanbeprintedbyvisiting:http://www.nkdep.nih.gov/professionals/drugdosinginformation.htm. NKDEPisaninitiativeoftheNationalInstituteofDiabetesandDigestiveandKidneyDiseases(NIDDK), NationalInstitutesofHealth(NIH),U.S.DepartmentofHealth&HumanServices(DHHS).
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