ChronicKidneyDiseaseandDrugDosing:InformationforProviders

(RevisedJanuary2010)

EstimationofKidneyFunctionforPrescriptionMedicationDosageinAdultsKnowledgeofkidneyfunctionisimportantfordosageofmedicationsthatareexcretedbythekidneys.FoodandDrugAdministration(FDA)approveddruglabelingguidesprovideadjustmentsofdrugdosagesforpatientswithimpairedkidneyfunction.Ontheselabels,serumcreatinine;measuredcreatinineclearance(CrCl);or,mostcommonly,estimatedcreatinineclearanceusingtheCockcroftGaultequation(eCrCl)areusedtoestimatekidneyfunction.Formostdrugs,theselabelsweredevelopedpriortostandardizedcalibrationofcreatinineassaysandreportingestimatedglomerularfiltrationrate(eGFR)calculatedusingtheModificationofDietinRenalDisease(MDRD)Studyequation.1ThisdocumentdescribestheNationalKidneyDiseaseEducationProgram's(NKDEP)suggestionsandrationalesforassessmentofkidneyfunctionfordrugdosingpurposes.NKDEPsSuggestedApproachtoDrugDosingHistorically,therehasbeensubstantialvariabilityinserumcreatininevaluesreportedbydifferentclinicallaboratorycreatininemethods.Consequently,pharmacokinetic(PK)studiesperformedusingnonstandardizedcreatininemethodsobtainedresultsthatweredependentupontheparticularcreatininemethodusedinagivenPKstudy.TheresultsfromthePKstudieswereincorporatedintoFDAdruglabels.Assuch,thePKstudiesrecommendeddrugdosages(i.e.,theFDAdruglabels)wereinconsistentlytranslatedintoclinicalpracticeduetothevariabilityamongcreatininemethodsusedindifferentlaboratories.Useofstandardizedcreatininemethodswillleadtolessvariationinestimatingkidneyfunctionandmoreconsistentdrugdosing.Forsomedrugs,theFDAormanufacturersmaydecidetoperformstudiestoreexpressdruglabelingforstandardizedcreatininevalues.However,itwillnotbepossibletoreexpressallcurrentdrugdosingrecommendationsforusewithstandardizedcreatininevalues.AlargesimulationstudycomparedeGFRandeCrClcalculatedfromstandardizedcreatininevaluestoeachotherandtogoldstandardmeasurementsofGFR.Theresultssuggestedthatforthemajorityofpatientsandformostdrugstested,therewaslittledifferenceinthedrugdosethatwouldbeadministeredusingeitherequationtoestimatekidneyfunction.2Basedontheseandotherconsiderations,wesuggestthefollowing:

Useofasinglekidneyfunctionestimatetoguidedetection,evaluation,andmanagementofchronickidneydisease(CKD)anddrugdosingislikelytofacilitatedeliveryofhighqualityhealthcare.

UtilizeeGFRoreCrClfordrugdosing.

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IfusingeGFRinverylargeorverysmallpatients,multiplythereportedeGFRbytheestimatedbodysurfacearea(BSA)inordertoobtaineGFRinunitsofmL/min:

eGFR/1.73m2xestimatedBSA=eGFRfordrugdosing

Note:BSAcanbeobtainedfromastandardnomogramorcanbecalculatedusingequationssuchas3:

(SeemoreonthisintheMDRDStudyEquationsection.)

ConsiderassessingkidneyfunctionusingalternativemethodssuchasmeasuredCrClormeasuredGFRusingexogenousfiltrationmarkerswhenprescribingdrugswithnarrowtherapeuticindices,orforindividualsinwhomeGFRandeCrClprovidedifferentestimatesofkidneyfunction,orforindividualsinwhomanyestimatesbasedoncreatininearelikelytobeinaccurate.4(SeemoreonthisintheLimitationsofAnySerumCreatininebasedEstimatesection.)

ImpactofIDMSstandardizedCreatinineValuesNationaleffortstostandardizeserumcreatinineassaysbyestablishingcalibrationtraceabilitytoanisotope

dilutionmassspectrometry(IDMS)referencemeasurementprocedurehavebeenunderwaysince2005.AllmajorglobalmanufacturershavecompletedrecalibrationtobetraceabletoanIDMSreference

measurementprocedure,andallinventorywitholdercalibrationisexpectedtobenolongerinusebythefirsthalfof2010.(Individualmanufacturersshouldbecontactedforstatusregardingtheirproducts.)Previously,therewasalargevariabilityinserumcreatinineresultsamongclinicallaboratories,

withanoverallpositivebiasbyapproximately10to20percentamonglaboratoriessurveyed.5WhenstandardizationofallcreatininemethodstoIDMStraceablecalibrationiscomplete,therewillbeless

variabilityincreatinineresultsusedformanagingpatients.Thefollowingitemsdescribetheimpactofstandardizedcreatinineassays:

Standardizationofcreatinineassayswillleadtolessvariationinestimatingkidneyfunctionandmore

consistentdrugdosing.

Therelationshipbetweencreatinineresultsbeforeandafterstandardizationwillbedifferentforeachspecificmethodandinstrumentusedinclinicallaboratories.

Itisnotpossibletohaveasingle,uniformconversionformulaorfactortorelateIDMSstandardizedcreatininevaluesbacktononIDMStraceablevaluesthatcanbeappliedtoalllaboratorieswherethePKstudieswereperformedortoallclinicallaboratories.

Usingstandardizedcreatininevalues,theaccuracyofestimatedkidneyfunctionwilldependuponwhetherornotanequationwasdevelopedusingIDMStraceablecreatininevalues.

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UseofIDMStraceablecreatininevaluesintheIDMStraceableMDRDStudyequationwillresultinamoreaccurateeGFR.1,6

UseofIDMStraceablecreatininevaluesintheCockcroftGaultformulawillhaveavariableimpactoneCrCl,dependinguponthecreatininemethod/instrumentused.However,becausemostnonstandardizedmethodshadapositivebias,useoftheCockcroftGaultformulawithIDMStraceablecreatininevalueswillleadtohighereCrClvaluesthanweredeterminedpriortostandardization.6

MeasuredCrClvaluesbasedonmeasuredserumandurinecreatinineresultsmaychangeforsomemethodsthathaveindependentcalibrationforserumandurinesamples.MostmethodsusethesamecalibrationschemeforbothserumandurineandwillbeminimallyaffectedbystandardizationofcalibrationbecausecreatinineisusedinboththenumeratoranddenominatoroftheCrClcalculation.

MDRDStudyEquation

TheModificationofDietinRenalDisease(MDRD)Studyequationwasderivedfromastudypopulationof1,628menandwomenwithCKD,aged18to70,predominantlyCaucasian,nondiabetic,andwhowerenonkidneytransplantrecipients.7

AlargenumberofstudiesnowshowthattheMDRDStudyequationissuitableforuseacrosspopulationswithCKD,butunderestimatesmeasuredGFRathigherlevels.8,9

TheMDRDStudyequationestimatesGFRadjustedforBSA.Kidneyfunctionisproportionaltokidneysize,whichisproportionaltoBSA.BSAof1.73m2isthenormalmeanvalueforyoungadults.AdjustmentforBSAisnecessarywhencomparingapatientskidneyfunctiontonormalvalues,ortothelevelsdefiningthestagesofCKD.Formostdrugs,adjustingforBSAisnotnecessaryfordeterminingdrugdosing.GFRestimatesadjustedforBSAwillgenerallybeadequateexceptinpatientswhosebodysizeisverydifferentthanaverage.(SeeNKDEPsSuggestedApproachtoDrugDosingsection.)

TheoriginalMDRDStudyequationissuitableforusewithcreatininemethodsthatDONOThavecalibrationtraceabletoIDMS.

eGFR=186x(S )1.154cr x(age)0.203x(0.742iffemale)x(1.212ifAfricanAmerican)

Note:GFRisexpressedinmL/minper1.73m2,Scrisserumcreatinineexpressedinmg/dL,andageisexpressedinyears.

TheMDRDStudyequationhasbeenreexpressedforusewithstandardizedserumcreatininevalues.1,10

eGFR=175x(StandardizedS )1.154cr x(age)0.203x(0.742iffemale)x(1.212ifAfricanAmerican)

Note:GFRisexpressedinmL/minper1.73m2,Scrisserumcreatinineexpressedinmg/dL,andageisexpressedinyears.

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CockcroftGaultEquation

TheCockcroftGault(CG)equationwasderivedfromastudypopulationof249Caucasianmenaged18to92,withandwithoutCKD.Nowomenwereincludedinthedevelopmentpopulation,sothefactorforfemalesexishypothetical.11

eCrCl=[((140age)xweight)/(72xScr)]x0.85iffemale

Note:eCrClisexpressedinmL/min,ageisexpressedinyears,weightisexpressedinkilograms,andScrisexpressedinmg/dL.

TheCGequationcannotbereexpressedforIDMStraceablecreatininevalues.Thecreatininemethodusedinthedevelopmentoftheequationisnolongerinuseandsamplesfromthestudyarenotavailable.

TheCGequationestimatesCrClthatisnotadjustedforBSA.SimilartomeasuredCrCl,eCrClsystematicallyoverestimatesGFRduetotubularsecretionofcreatinine.Additionally,eCrClhasmorevariabilitythaneGFRusingtheMDRDStudyequationasevidencedbyCockcroftGaulteCrClhavingonly50to70percentofresults(vs.83percentforeGFR)within30percentofmeasuredGFR.6

ModificationsoftheCGequation,suchastheuseofidealversusactualbodyweight,weredevelopedinanattempttoovercometheimprecisionwiththeuseofmeasuredbodyweight.However,thereisnoevidencethatthesemodificationsaremoreaccuratepredictorsofGFRorprovidebetterdrugdosingguidelines.

LimitationsofAnySerumCreatininebasedEstimate

TheserumconcentrationofcreatinineisinfluencedbyfactorsotherthantheGFR,inparticular,differencesinrateofgenerationrelatedtomusclemassanddiet,aswellasdifferencesintherateoftubularsecretion.Estimatingequationscapturetheaveragedifferenceinrateofcreatininegenerationbyage,sex,race,orweight,butdonotcaptureallfactors.

NeithereGFRnoreCrClwillbeaccurateinindividualswithextremesofbodysizeormusclemass,orthosewithunusualdietaryhabits.Thelimitationsincreatininebasedestimatingequationsareparticularlyrelevantforpopulationswithreducedmusclemass,includingthefrail,elderly,criticallyill,orcancerpatientswhoarelikelytorequiremedications.12

Useofanyserumcreatininebasedestimaterequiresthatkidneyfunctionbeatasteadystate,soanyestimatemustbeusedcautiouslyinhospitalizedpatientswithrapidlychangingkidneyfunction.

MeasurementofGFRusingexogenousfiltrationmarkersandurineorplasmaclearanceorofCrClusingtimedurinecollections,shouldbeconsideredwhendosingmedicationswithnarrowtherapeuticindicesorwithhightoxicity,orinpatientsforwhomserumcreatininebasedestimatesmaybeinaccurate.4

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1LeveyAS,CoreshJ,GreeneT,etal.Usingstandardizedserumcreatininevaluesinthemodificationofdietinrenaldiseasestudyequationforestimatingglomerularfiltrationrate.AnnInternMed.2006;145:24754.2StevensLA,NolinT,RichardsonM,etal.ComparisonofdrugdosingrecommendationsbasedonmeasuredGFRandkidneyfunctionestimatingequations.AmJKidDis.2009;54(1):3342.3Mosteller,RD.SimplifiedCalculationofBodySurfaceArea.NEnglJMed.1987;317(17):1098.4StevensLA,LeveyAS.MeasuredGFRasaConfirmatorytestforestimatedGFR:indicationsandinterpretation.JAmSocNephrol.2009;20:230513.5MillerWG,MyersGL,AshwoodER,etal.Creatininemeasurement:stateoftheartinaccuracyandinterlaboratoryharmonization.ArchPatholLabMed.2005;129:297304.6StevensLA,ManziJ,LeveyAS,etal.ImpactofcreatininecalibrationonperformanceofGFRestimatingequationsinapooledindividualpatientdatabase.AmJKidneyDis.2007;50:2135.7LeveyAS,BoschJP,LewisJB,etal.Amoreaccuratemethodtoestimateglomerularfiltrationratefromserumcreatinine:Anewpredictionequation.ModificationofDietinRenalDiseaseStudyGroup.AnnInternMed.1999;130:461470.8StevensLA,CoreshJ,GreeneT,etal.Assessingkidneyfunctionmeasuredandestimatedglomerularfiltrationrate.NEnglJMed.2006;354:247383.9StevensLA,CoreshJ,FeldmanHI,etal.Evaluationofthemodificationofdietinrenaldiseasestudyequationinalargediversepopulation.JAmSocNephrol.2007;18:274957.10LeveyAS,CoreshJ,GreeneT,etal.ExpressingtheModificationofDietinRenalDiseaseStudyequationforestimatingglomerularfiltrationratewithstandardizedserumcreatininevalues.ClinChem.2007;53:76672.11CockcroftD,GaultM.Predictionofcreatinineclearancefromserumcreatinine.Nephron.1976;16:3141.12PoggioED,NefPC,WangX,etal.PerformanceoftheCockcroftGaultandmodificationofdietinrenaldiseaseequationsinestimatingGFRinillhospitalizedpatients.AmJKidneyDis.2005;46:24252.

ThisinformationwasoriginallypostedtotheNKDEPwebsiteinSeptember2009.Extracopiesofthisupdatedversioncanbeprintedbyvisiting:http://www.nkdep.nih.gov/professionals/drugdosinginformation.htm.NKDEPisaninitiativeoftheNationalInstituteofDiabetesandDigestiveandKidneyDiseases(NIDDK),NationalInstitutesofHealth(NIH),U.S.DepartmentofHealth&HumanServices(DHHS).

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