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www.uptodate.com2017UpToDate
Overviewofchronickidneydiseasemineralandbonedisorder(CKDMBD)
Authors: WajehYQunibi,MD,WilliamLHenrich,MD,MACP
SectionEditor: JeffreySBerns,MD
DeputyEditor: AliceMSheridan,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Apr2017.|Thistopiclastupdated:Jan19,2017.
INTRODUCTIONANDDEFINITIONSChronickidneydisease(CKD)iscommonlyassociatedwith
disordersofmineralandbonemetabolism,manifestedbyeitheroneoracombinationofthefollowingthree
components:
Abnormalitiesofcalcium,phosphorus,parathyroidhormone(PTH),fibroblastgrowthfactor23(FGF23),
andvitaminDmetabolism
Abnormalitiesinboneturnover,mineralization,volumelineargrowth,orstrength
Extraskeletalcalcification
TheworkgroupoftheKidneyDisease:ImprovingGlobalOutcomes(KDIGO)recommendedin2006theuse
ofthetermchronickidneydiseasemineralandbonedisorder(CKDMBD)todescribeasystemicdisorder
thatincorporatestheseabnormalities[1].Theworkgrouprecommendedthatthetraditionalterm"renal
osteodystrophy"beexclusivelyusedtodefinealterationsinbonemorphologyassociatedwithCKDand
statedthatdefinitivediagnosisofrenalosteodystrophycanonlybemadebybonebiopsy[1,2].Followingthe
introductionofthetermCKDMBD,variousclinicalpracticeguidelineshaverecommendedlaboratorytargets
andtherapeuticapproachesaimedatamelioratingtheconsequencesofthissystemicdisorder.
ThistopicreviewsthepathogenesisofCKDMBD.Thetreatmentofhyperphosphatemiaandofsecondary
hyperparathyroidisminnondialysisCKDpatientsandinendstagerenaldisease(ESRD)patientsis
discussedelsewhere.(See"Treatmentofhyperphosphatemiainchronickidneydisease"and"Management
ofsecondaryhyperparathyroidismandmineralmetabolismabnormalitiesinadultpredialysispatientswith
chronickidneydisease"and"Managementofsecondaryhyperparathyroidismandmineralmetabolism
abnormalitiesindialysispatients"and"Indicationsforparathyroidectomyinendstagerenaldisease".)
Lowturnover(oradynamic)bonediseaseandtheuseofbonebiopsytoestablishaspecificdiagnosisare
discussedelsewhere.(See"Adynamicbonediseaseassociatedwithchronickidneydisease"and"Bone
biopsyandthediagnosisofrenalosteodystrophy".)
Thepathophysiologyofthedisorderiscomplexandinvolvesanumberoffeedbackloopsbetweenthekidney,
bone,intestine,andthevasculature.Themaingoalofthissystemismaintenanceofcalciumandphosphorus
balance,oftenattheexpenseofabnormalitiesinothercomponentsofthesystem.
WhilemostelementsofCKDMBDareusuallypresentwhentheglomerularfiltrationrate(GFR)fallsbelow
40mL/min,somecomponentsmaybeobservedearlierinthecourseofCKDandprecedetheonsetof
clinicallydetectableabnormalitiesinserumphosphorus,calcium,PTH,andvitaminD[37].Theseinclude
decreasedboneformationrates,vascularcalcification,lossofklotho,andincreasedFGF23secretion.
Withprogressivelossoffunctioningnephrons,phosphateexcretionismaintainedbyreducingthetubular
reabsorptionoffilteredphosphateintheremainingnephrons,aneffectmediatedbyFGF23andPTH.Bone
diseasedevelopsasearlyasCKDstage2(ie,estimatedGFR[eGFR]60to89mL/min/1.73m2)and
becomesalmostuniversalinpatientswithCKDstage5(eGFR<15mL/min/1.73m2)[3,8,9].Vascular
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calcificationsalsodevelopearly,andtheirprevalenceincreasesastheGFRdeclinessuchthatapproximately
80percentofincidentdialysispatientshaveevidenceofcoronaryarterycalcification[10,11].
ABNORMALITIESOFPARATHYROIDHORMONE,CALCIUM,PHOSPHORUS,FIBROBLASTGROWTH
FACTOR23,ANDVITAMINDMETABOLISM
OverviewSecondaryhyperparathyroidismisamajorfeatureofCKDMBD.Secondary
hyperparathyroidismbeginsearlyinthecourseofCKD,anditsprevalenceincreasesaskidneyfunction
declines(particularlytoestimatedglomerularfiltrationrate[eGFR]<60mL/min/1.73m2).Secondary
hyperparathyroidismoccursinresponsetoaseriesofabnormalitiesthatinitiateandmaintainincreased
parathyroidhormone(PTH)secretion[12].Themainabnormalitiesthatcontributetothepathogenesisof
secondaryhyperparathyroidismare:
Phosphateretention
Decreasedfreeionizedcalciumconcentration
Decreased1,25dihydroxyvitaminD(calcitriol)concentration
Increasedfibroblastgrowthfactor23(FGF23)concentration
ThereducedexpressionofvitaminDreceptors(VDRs),calciumsensingreceptors(CaSRs),fibroblast
growthfactorreceptors,andklothointheparathyroidglands
TherelativeimportanceoftheseabnormalitiesintriggeringPTHproductioncanbeunderstoodbyexamining
thechangesintheirconcentrationsinrelationtotheincreaseinPTHduringthecourseofCKD.Increased
PTHconcentrationsfirstbecomeevidentwhentheeGFRdropsbelow60mL/min/1.73m2.Atthattime,
serumcalciumandphosphateconcentrationsarenormalandremainwithinnormalrangesuntiltheeGFR
decreasestoapproximately20mL/min/1.73m2[13].Circulatingcalcitriolconcentrationsbegintofallmuch
earlier,whentheGFRis<60mL/min/1.73m2(occasionallyevenathighereGFRs[13]),andaretypically
markedlyreducedinsubjectswithendstagerenaldisease(ESRD)[14].Theprimaryreasonforthedeclinein
calcitriolconcentrationislikelyanincreaseinFGF23concentration,ratherthanthelossoffunctioningrenal
tissue[15].Hyperphosphatemia(arelativelylatephenomenoninCKD)mayalsocontributetothedeclinein
calcitriolsynthesisbysuppressionof1alphahydroxylaseenzyme.
Thus,progressivekidneydysfunctionresultsincalcitrioldeficiencyandhyperphosphatemia,bothofwhich
resultinhypocalcemia.TheseabnormalitiesdirectlyincreasePTHconcentrationsviadifferentmechanisms.
PhosphateretentionandhyperphosphatemiaPhosphateretentionhaslongbeenthoughttobethe
initialtriggerformanyofthecomponentsofCKDMBD,particularlytheincreasedPTHsecretion.Atendency
tophosphateretention,beginningearlyinCKDasthedeclineinGFRdecreasesthefilteredphosphateload,
isthoughttoplayacentralroleinthedevelopmentofsecondaryhyperparathyroidism[1618].Threemajor
andnotmutuallyexclusivetheorieshavebeenproposedtoexplainhowphosphateretentioninitiallypromotes
PTHrelease[1921]:
Theinductionofhypocalcemia
Decreasedformationoractivityofcalcitriol(1,25dihydroxyvitaminD,theactiveformofvitaminDthatis
producedbythekidney)
IncreasedPTHgeneexpression
PhosphateretentioncontributestosecondaryhyperparathyroidisminearlyCKDatleastinpartbydecreasing
serumfreecalciumconcentrationandcalcitriolsynthesis[1921].Ifphosphateretentionispreventedby
restrictingphosphateintakeinproportiontothereductioninGFR,theriseinplasmaPTHconcentrationcan
beprevented[2123].Eveninpatientswhohavemoderaterenalinsufficiencyandalreadyestablished
secondaryhyperparathyroidism,loweringtheplasmaphosphateconcentrationwithoralphosphatebinders
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canpartiallyreversethehypocalcemia,hyperparathyroidism,andcalcitrioldeficiency[24,25].(See
"Treatmentofhyperphosphatemiainchronickidneydisease".)
However,serumphosphatelevelsarenotelevatedinthemajorityofpatientsintheearlystagesofCKD,
probablyduetoareductioninrenaltubularphosphateresorptionmediatedbyincreasedlevelsofPTHand
FGF23[15].TheeffectsofFGF23onphosphateexcretionmaybecomebluntedbyklothodeficiency,which
occursearlyinCKD.Atthispoint,PTHmaybecometheprimaryfactorinmaintainingserumphosphatelevel.
Fromtheviewpointofphosphatehomeostasis,theinitialelevationinPTHsecretionisappropriatesincethe
ensuingincreaseinphosphateexcretionlowerstheplasmaphosphateconcentrationtowardnormal.Among
patientswithseverelyreducedGFR,PTHinhibitsproximaltubulephosphatereabsorptionfromthenormal80
to95percenttoaslowas15percentofthefilteredphosphate[12,26].Hyperparathyroidismalsotendsto
correctboththehypocalcemia(byincreasingboneresorption)andthecalcitrioldeficiency(bystimulatingthe
1hydroxylationofcalcidiol[25hydroxyvitaminD]intheproximaltubule).(See"OverviewofvitaminD",
sectionon'Metabolism'.)
DespitethisseeminglybeneficialadaptiveincreaseinPTHsecretion,hyperparathyroidismbecomes
maladaptiveoverthelongterm[21].Furthermore,theeffectofPTHonphosphatebalancechangesasGFR
declines.InadvancedstagesofCKD,whentheGFRdropsbelow30mL/min,thecompensatoryincreasein
thelevelsofPTHandFGF23becomesinadequate,andhyperphosphatemiadevelops[7,27].Moreover,since
phosphatereabsorptionbytherenaltubulescannotbeloweredbelowaminimumthreshold,continuedPTH
inducedreleaseofphosphatefrombonecanactuallyexacerbatethehyperphosphatemia.
HyperphosphatemiamayalsohaveadirecteffectonPTHsynthesisandsecretionthatisindependentofthe
plasmaconcentrationsofcalciumandcalcitriolinadvancedCKD[2831].Astudyinexperimentalanimals
withESRDdemonstratedthatdietaryphosphaterestrictiontonormalizetheplasmaphosphateconcentration
loweredplasmaPTHconcentrationsfrom130to35pg/mL[29].Thisoccurredwithoutchangesintheplasma
calciumorcalcitriolconcentrations.Parathyroidsizealsodecreasedintheseanimals,suggestingthat
hyperphosphatemiastimulatesparathyroidgrowthinrenalfailure.Thiseffectisapparentlythroughthe
reductionofPTHmessengerRNA(mRNA)concentrationsviaincreasingposttranscriptionalPTHmRNA
messagestability[31].
Theseobservationsappeartobeapplicabletohumans,asillustratedbythefollowingfindings:
Onereportevaluatedtheeffectofaddingphosphatetothedialysateofpatientsonmaintenance
hemodialysis[30].Phosphatewasaddedtothedialysatetoraisetheplasmaphosphateconcentrationby
2.4mg/dL(0.75mmol/L)abovethebaselineof4.7to5.9mg/dL(1.5to1.9mmol/L).At12weeks,7of15
patientsshowedsignificantelevationsinplasmaPTHconcentrationswithoutchangesintheplasma
concentrationsofionizedcalciumorcalcitriol(thelatterwaslowinitiallyandremainedlowthroughoutthe
study).
Onestudyshowedthatinvitroexposureofhyperplasticparathyroidtissueobtainedfrompatientswith
renalfailuretohighphosphateconcentrationsincreasedpreproPTHmRNAandenhancedPTHsecretion
[32].
HyperphosphatemiaalsostimulatesthesecretionofFGF23,whichactstosuppressPTHsecretion[33,34].
(See'Fibroblastgrowthfactor23'below.)
Perhapsthemostimportantconsequenceofhyperphosphatemiaisonthecardiovascularsystemsince
hyperphosphatemiastimulatesosteoblastictransformationofthevascularsmoothmusclecellinthe
vasculatureanddirectlycontributestocardiovascularcalcificationandarterialstiffness[35,36].
DecreasedcalcitriolactivityPlasmacalcitriolconcentrationsgenerallyfallbelownormalwhentheGFR
is<60mL/min/1.73m2,althoughlowconcentrationshavealsobeenfoundinsomepatientswithhighereGFR
(ie,<80mL/min/1.73m2)[13,21,3739].
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Initially,thedeclineincalcitriolconcentrationislikelytobeduetotheincreaseinFGF23concentrationrather
thanthelossoffunctioningrenalmass[15].TheFGF23induceddecreaseincalcitriolbeginsearly,whenthe
GFRdropsto<70mL/min/1.73m2.However,inadvancedCKD,hyperphosphatemiaandlossofrenalmass
inadditiontoincreasedFGF23levelscontributetothedeclineincalcitriolsynthesis.
Phosphateretention(orperhapsincreasedphosphateconcentrationsintheproximaltubule)candirectly
suppresstherenalsynthesisofcalcitriolbyinhibiting1alphahydroxylaseactivity[21].FGF23decreasesthe
synthesisofcalcitriolbysuppressingtheactivityof1alphahydroxylase,whichconverts25hydroxyvitaminD
tocalcitriol,andbystimulatingthe24hydroxylaseenzyme,whichconvertscalcitriol(1,25dihydroxyvitamin
D3)toinactivemetabolitesintheproximaltubule[15,40,41].Increaseddietaryphosphateloadandincreased
calcitriolstimulatethesecretionofFGF23,predominantlybyboneosteocytes,whichactontargettissuesby
bindingtoandactivatingtheFGF23receptorinthepresenceofitscoreceptor,klotho[42].Concentrationsof
FGF23increasesoonafterrenalinjuryandprogressivelyincreaseaskidneyfunctionworsens,possiblyasa
physiologicadaptationtomaintainnormalserumphosphatebyenhancingexcretionintheurine.Thus,the
increaseofFGF23,whileimportantformaintainingphosphatebalanceinearlyCKD,resultsina"tradeoff"of
reducedcalcitriolconcentrations,whichmayactastheinitialtriggerforincreasedPTHproduction.(See
'Fibroblastgrowthfactor23'below.)
LowcalcitriolconcentrationsincreasePTHsecretionbyindirectanddirectmechanisms[4345].Indirect
effectsonPTHareachievedthroughdecreasedintestinalabsorptionofcalciumandcalciumreleasefrom
bone,bothofwhichpromotethedevelopmentofhypocalcemia,whichstimulatesPTHsecretion.
CalcitriolnormallyactsontheVDRintheparathyroidglandtosuppressPTHtranscriptionbutnotPTH
secretion[46].AdecreaseincalcitriolconcentrationsalsolowersthenumberofVDRsintheparathyroidcells
[47].Thelackofcalcitriolandthedecreasednumberofreceptorsmaybothpromoteparathyroidchiefcell
hyperplasiaandnoduleformationthroughpotentialnongenomiceffects.
Evennormalplasmacalcitriolconcentrationsdonotnecessarilyprecludearoleforinitialcalcitrioldeficiency,
sincetheensuingsecondaryhyperparathyroidismwillincreasecalcitriolsynthesis.However,notallPTH
fragmentsstimulatethe1alphahydroxylaseandincreasecalcitriolsynthesis.Inananimalmodel,thePTH
fragment(134)increasedcalcitriolconcentrations,whereasPTH(184)didnot.Moreover,infusionof
carboxyl(C)terminalPTHfragmentsactuallyreducedthesynthesisofcalcitriolbyaposttranscriptional
mechanism[48].
Moreimportantly,lowcalcitriolconcentrationcanincreasePTHsecretionbyremovingtheinhibitoryeffectof
calcitriolontheparathyroidgland[21,49].Theadministrationofcalcitriol,ontheotherhand,canpartially
reversethehyperparathyroidismbothinearly[38]andadvanceddisease[49].CalcitriolandothervitaminD
analogscanreduceparathyroidcellproliferationinvitro,inpartbyblockingtheincreaseinthegrowth
promotingfactortransforminggrowthfactoralpha(TGFalpha)[50,51].
Thereisalsoevidencethatdecreasedresponsivenesstocalcitriolcontributestothedevelopmentof
hyperparathyroidism.Inparticular,physiologicconcentrationsofcalcitriolmaybeunabletonormallysuppress
PTHsecretion,perhapsduetoareductioninthenumberofVDRsintheparathyroidgland[47,52].In
experimentalmodels,thischangecanbedemonstratedrelativelyearlyinthecourseofrenalfailure(ie,when
theplasmacreatinineconcentrationhasonlydoubled)[43].Lowcalcitriolconcentrationsappeartoplayan
importantroleinthedeclineinVDRssincethedefectcanbelargelycorrectedbycalcitriolsupplementation
[47].Atalaterstage,retaineduremictoxinsmayalsocontributebydecreasingbothreceptorsynthesisand
theabilityoftheactivehormonereceptorcomplextobindtovitaminDresponseelementsinthenucleus
[43,53].
Studiesinpatientsonmaintenancedialysisrevealthatthedecreaseinreceptordensityismostprominentin
areasofnodular,ratherthandiffuse,hyperplasia[52].Thus,areducednumberofVDRsmaycontributeboth
totheprogressionofhyperparathyroidismandtotheproliferationofparathyroidcells,leadingtonodule
formation.(See'Tertiaryhyperparathyroidism'below.)
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DisordersofcalciumbalanceStudieshavesuggestedthatdisordersofcalciumbalanceduetoCKD
MBDmayplayaroleinthehighcardiovascularmortalityinpatientswithCKD.Bothhypocalcemiaand
hypercalcemiaareassociatedwithincreasedmortalityinpatientswithCKD[54,55].Hypocalcemiaiscommon
amongCKDpatientsandmaybeassociatedwithincreasedPTHsecretionandabnormalboneremodeling.
Ontheotherhand,hypercalcemiahasbeenimplicatedinthepathogenesisofextraskeletalcalcification.
Moreover,positivecalciumbalancemayalsobeanimportantfactorinprogressionofcalcification.Ananimal
modelofCKDshowedthatcalciumaddedtothedrinkingwaterledtoincreasedthoracicaorta,heart,and
aorticvalvecalcificationregardlessoftheserumcalciumlevel[56].
CalciumisamajorregulatorofPTHsecretion.Minutechangesintheserumionizedcalciumaresensedbya
specificmembranereceptor,theCaSR,whichishighlyexpressedonthesurfaceofthechiefcellsofthe
parathyroidglands[57].ChangesinPTHsecretioninresponsetoserumcalciumaretightlyregulatedbythe
CaSR.
ThefallinserumcalciumconcentrationinCKD,assensedbytheCaSR,isapotentstimulustothereleaseof
PTH[58,59].Thisisbestshowninmouseandhumangeneticstudies,inwhichextracellularcalcium,acting
throughtheCaSR,wasthemajorregulatorofPTHtranscription,secretion,andparathyroidglandhyperplasia
[58,59].AreviewofthefunctionoftheCaSRcanbefoundelsewhere.(See"Disordersofthecalciumsensing
receptor:Familialhypocalciurichypercalcemiaandautosomaldominanthypocalcemia".)
TotalserumcalciumconcentrationdecreasesduringthecourseofCKDduetophosphateretention,
decreasedcalcitriolconcentration,andresistancetothecalcemicactionsofPTHonbone.PTHsecretion
variesinverselywithserumcalciumconcentration[28].Persistentlylowserumcalciumconcentrationsalso
appeartodirectlyincreasePTHmRNAconcentrationsviaposttranscriptionalactionsandstimulatethe
proliferationofparathyroidcellsoverdaysorweeks[28,38].(See"Parathyroidhormonesecretionandaction"
and"Disordersofthecalciumsensingreceptor:Familialhypocalciurichypercalcemiaandautosomal
dominanthypocalcemia".)
InCKD,thenumberofCaSRsmaybereducedinhypertrophiedparathyroidglands,particularlyinareasof
nodularhypertrophy[6062].DecreasedexpressionoftheCaSRappearstoberelatedtotheproliferationof
parathyroidtissue,andbothmayberelatedtoincreasedphosphorus[61,63].Thechangeinreceptornumber
canleadtoinadequatesuppressionofPTHsecretionbycalcium,resultingininappropriatelyhighPTH
concentrationsinthesettingofnormalorevenhighcalciumconcentrations.(See"Parathyroidhormone
secretionandaction".)
TheroleoftheCaSRinregulatingparathyroidglandfunctionhasdirecttherapeuticimplications.The
administrationofacalcimimeticagentincreasesthesensitivityofthereceptortoextracellularcalciumandcan
lowerPTHsecretionfromtheparathyroidgland[57,64].Calcimimeticagentsalsomediatereductionsin
serumPTHconcentrationsbydirectlydecreasingPTHgeneexpression[65]andbyincreasingtheVDR
expressionintheparathyroidglands[66].TheadministrationofcalcimimeticagentsreducesplasmaPTH
concentrationsby>50percentinbothhumansandanimalmodelsofrenalfailureandcansuppress
parathyroidcellhyperplasiainanimals.TheuseofcalcimimeticagentsinpatientswithESRDisdiscussed
elsewhere.(See"Managementofsecondaryhyperparathyroidismandmineralmetabolismabnormalitiesin
dialysispatients",sectionon'Calcimimetics'.)
Fibroblastgrowthfactor23FGF23isacirculatingpeptidethatplaysakeyroleinthecontrolofserum
phosphateconcentrations.[12,67,68].FGF23issecretedbyboneosteocytesandosteoblastsinresponseto
calcitriol,increaseddietaryphosphateload,PTH,andcalcium[6873].AmongCKDpatients,increased
FGF23concentrationsmayalsobeduetodecreasedclearance[15,72,73].Ananimalmodelsuggestedthat
thekidneyitselfplaysakeyroleinFGF23metabolism[74].Inthisstudy,thehalflifeofexogenous
recombinanthumanFGF23wassignificantlyprolongedinanephricrats.Moreover,measurementsofplasma
FGF23intherenalarteryandrenalveinofratsdemonstratedasignificantrenalextractionofFGF23.
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FGF23'sprimaryfunctionistomaintainnormalserumphosphateconcentrationbyreducingrenalphosphate
reabsorptionandbyreducingintestinalphosphateabsorptionthroughdecreasedcalcitriolproduction.Inrenal
proximaltubularcells,FGF23bindstotheFGFreceptor(FGFR)anditscoreceptor,klotho,causing
downregulationoftheluminalmembranesodiumphosphatecotransporterNa/PiIIa(andpossiblyalsothe
Na/PiIIctransporter)[75].Decreasedcotransportersintheproximaltubuleleadtoreducedphosphate
reabsorptionfromurineandincreasedurinaryphosphateexcretion.FGF23alsoinhibitstheproximaltubular
expressionof1alphahydroxylaseenzyme,leadingtodecreasedcalcitriolsynthesisbythekidney[40].
Therefore,FGF23directlyincreasesurinaryexcretionofphosphateandindirectlysuppressesintestinal
phosphateabsorptionbydownregulatingtheproductionofcalcitriol.Theneteffectofbothhormonalactionsis
tolowerserumphosphateconcentration.
IncreasedFGF23levelsmaybeoneoftheearliestdetectablebiomarkersofCKDMBD[7].Inpatientswith
CKD,FGF23levelsincreasepriortochangesintheserumcalcium,phosphorus,orPTHlevels.Treatments
usedtocontrolCKDMBD,suchasvitaminDanalogsandcalciumbasedphosphatebinders,stimulate
FGF23production.
However,amongindividualswitheGFRinanormalrange,thePTHmayincreasebeforeFGF23,whenthe
eGFRdecreasesmodestly[76].Moreover,thestudyfoundthatplasmaFGF23isassociatedwithreduced
plasma1,25dihydroxyvitaminD3andreducedrenalcalciumexcretionbutnotwithincreasedrenal
phosphateexcretion[76].ThesedatasuggestthattheroleofFGF23asa1,25dihydroxyvitaminD3
counterregulatoryhormonemaybemoreimportantthanitsroleasaphosphaturichormone,atleastwhenthe
renalfunctionisnormal.
Anotherstudyfoundthat,inpatientswithCKDandvitaminDdeficiency,PTHlevelsweremarkedlyelevated
relativetothoseofFGF23,suggestingthatFGF23mayhavealowerphosphaturicrolewhenPTHsecretion
isstimulatedinresponsetovitaminDdeficiency[77].
FGF23alsosuppressesPTHsecretionbytheparathyroidgland[78].However,amongCKDpatients,the
presenceofhighPTHconcentrations,despitehighFGF23concentrations,suggeststhattheparathyroid
glandbecomesrelativelyresistanttotheelevatedconcentrationsofFGF23.Thismayberelatedtothe
markedlydecreasedexpressionofFGFR1andklothoproteininthehyperplasticparathyroidgland[79,80].
Klotho,atransmembraneproteinproducedbyosteocytes,isrequiredforFGF23receptoractivation[42].The
klothoextracellulardomaindoesnotdirectlybindtoFGF23butenhancesFGF23bindingtoitsreceptor
complexwithamuchhigheraffinitythantotheFGFRalone[81].
KlothoexpressiondeclinesearlyinthecourseofCKDandthenprogressivelywithdecreasingGFR[82].The
reductioninklothotemporallycoincideswiththeriseinFGF23,suggestingthatthisdeclinemaybepartially
responsiblefortheprogressiveriseinFGF23concentration.Moreover,thedecreaseinklothoexpressionon
hyperplasticparathyroidglandsmaycontributetotheresistanceandimpairedparathyroidsuppressionby
FGF23[3,83].OnestudyshowedthatproteinuriainducedelevationofbothplasmaphosphateandFGF23
concentrationsandimpairedurinaryphosphateexcretion[84].ThedecreasedphosphaturiceffectofFGF23
inthisstudywasrelatedtodecreasedrenalklothoexpressionandincreasedproximaltubuleNa/PiIIa
cotransporterexpression[84].
FGF23levelsareassociatedwithincreasedriskofcardiovasculardiseaseandmortalityinpatientswithCKD
[85,86].ClinicalandexperimentalstudieshaveshownthatFGF23hasadirectpathogeniceffectcausingleft
ventricularhypertrophy[87].FGF23alsoaugmentssodiumandcalciumreabsorptioninthedistaltubuleby
increasingtheapicalmembraneexpressionofthesodiumchloridecotransporterandtheepithelialcalcium
channel,throughaklothodependentactivationofTheserine/threonineproteinkinase,WNK4[88,89].These
effectscouldconceivablyleadtorenalsodiumretention,volumeoverload,hypertension,andcardiac
hypertrophy.However,FGF23doesnotseemtopromotecardiovascularcalcification[90].
SkeletalresistancetoPTHSkeletalresistancetothecalcemicactionofparathyroidhormone(PTH)
appearstocontributetothegenesisofsecondaryhyperparathyroidisminCKD[31].ResistancetoPTHis
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primarilyduetodownregulationofPTHreceptorsinducedbythehighcirculatingPTHconcentrations,
althoughbothcalcitrioldeficiencyandhyperphosphatemiamayplayacontributoryrole[91].Finally,the
potentialantagonisticactionsofPTHfragmentPTH(784)tothoseofPTH(184)maycontributetothe
higherPTHconcentrationsinpatientswithCKD[92].
TertiaryhyperparathyroidismSomepatientswithESRDdevelopmarkedlyelevatedPTHconcentrations,
oftenassociatedwithhypercalcemiathatcannotbeexplainedbytheadministrationofcalciumcarbonateor
calcitriolsupplements.Suchpatientsoftenfailmedicaltherapyandultimatelyrequireparathyroidectomy.This
entity,calledtertiaryhyperparathyroidism,inpartreflectssevereparathyroidhyperplasia,withautonomous
secretionofPTHthatisnolongeradequatelyresponsivetotheplasmacalciumconcentration.Autonomous
functionofparathyroidtissueresultsfromtheincreaseinparathyroidglandmassratherthananalterationin
thesetpointofPTHrelease[93].Setpointabnormalitiesarepresentinfamilialhypocalciurichypercalcemia
(inwhichitistheprimarydefect)andprimaryhyperparathyroidism(inwhichthereisbothasetpointerrorand
increasedglandmass)[93].(See"Disordersofthecalciumsensingreceptor:Familialhypocalciuric
hypercalcemiaandautosomaldominanthypocalcemia".)
Inpatientswithtertiaryhyperparathyroidism,decreasedexpressionofCaSRandVDRsresultsinalackof
suppressionofPTHbyincreasingcalciumorvitaminDanalogs[94].Thestateofprolongedstimulationof
parathyroidcellgrowthinCKDpatientsduetohighphosphate,lowcalcitriol,andhypocalcemiaresultsin
nodularhyperplasia.Nodularparathyroidglandsdonotundergoinvolution,despiteresolutionofsomeofthe
triggeringmechanisms.ThisisbestillustratedbythehighPTHconcentrationsandhypercalcemiathatmay
persistinCKDpatientsafterreceivingrenaltransplant.
Anotherimportantpathogeneticfactorinmanycasesoftertiaryhyperparathyroidismisneoplastic
transformation,leadingtoovergrowthbyamonoclonalparathyroidadenoma[95,96].Themechanisms
responsiblefortheswitchtomonoclonalproliferationarenotwellunderstood[96].OnefactormaybeVDR
density,whichappearstobemarkedlyreducedinareasofnodulartransformation[52].Thischangewould
furtherreducethenormalinhibitoryeffectofcalcitriolonPTHsecretionand,perhaps,parathyroidgrowth[96].
ABNORMALITIESINBONETURNOVER,MINERALIZATION,VOLUMELINEARGROWTH,OR
STRENGTHAsnotedabove,renalosteodystrophyreferstobonepathology,asassessedbybonebiopsy
[97](see'Introductionanddefinitions'above).Thegoldstandardforthediagnosisandclassificationofbone
diseaseinCKDisbonebiopsy.However,becausebonebiopsyisinvasiveandcostly,severalbone
biomarkershavebeenusedforthediagnosisandmonitoringofboneturnover.Unfortunately,allhave
limitationsintheassessmentofrenalbonedisease.
Boneturnovercanbeviewedastheratiobetweenboneformationandboneresorptionandthusisafunction
ofthedegreeofhyperparathyroidism.Althoughparathyroidhormone(PTH)maybeabetterindicatorof
parathyroidglandactivityratherthanofboneturnover,PTHlevelhastraditionallybeenusedasamarkerof
boneturnover.
However,PTHlevelswithintheKidneyDiseaseOutcomesQualityInitiative(KDOQI)orKidneyDisease:
ImprovingGlobalOutcomes(KDIGO)recommendedtherapeutictargetsarenotconsistentlyhelpfulin
predictingthenatureoftheunderlyingboneturnover.Onestudysuggestedthatcombinationofbonespecific
alkalinephosphatase(BSAP)withPTHmayimprovethediagnosticabilityofeithermarkeraloneinpredicting
thetypeofbonediseaseinCKD[98].However,amorerecentstudyshowedthatthiscombinationonly
marginallyimprovedtheabilitytodiscriminatehighfromlowboneturnover,suggestingthat,despiteits
limitations,PTHlevelremainsareasonablemarkerofboneturnover[99].
KDIGOrecommendsthatthreeparametersbeusedtoassessbonepathology[2].Theseparametersinclude
boneturnover,mineralization,andvolume(TMVsystem).Anycombinationofparametersmaybeusedto
describeagivensample.TheTMVsystemofclassificationofrenalosteodystrophyservestoemphasizethe
contributionsofmineralizationandvolume,aswellasturnover,tobonequality[100].
TMVcharacteristicsofthemajorCKDrelatedbonediseasesareasfollows:
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OsteitisfibrosacysticaOsteitisfibrosacysticaischaracterizedbyhighboneturnoverdueto
secondaryhyperparathyroidism.
AdynamicbonediseaseAdynamicbonediseaseischaracterizedbylowboneturnover.Although
aluminumdepositionmaycausethisdisorder,mostcurrentcasesresultfromexcessivesuppressionof
theparathyroidglands.Thisrepresentsthemajorbonelesioninperitonealdialysisandhemodialysis
patients.(See"Adynamicbonediseaseassociatedwithchronickidneydisease".)
OsteomalaciaOsteomalaciaischaracterizedbylowboneturnoverincombinationwithabnormal
mineralization[19,20].Inosteomalacia,themineralizationlagtimeisprolongedto>100daysin
comparisonwith<35daysinnormalsubjectsandthosewithpureosteitisfibrosa.Osteomalacia,whichis
nowuncommon,wasdueprimarilytoaluminumdepositioninboneatatimewhenaluminumcontaining
antacidswereusedasphosphatebinders.Theincidenceofosteomalaciahasdecreasedwiththe
abandonmentofaluminumbasedphosphatebindersandtheintroductionofmoreefficienttechniquesfor
treatmentofwaterusedinpreparingthedialysate[101104].(See"Aluminumtoxicityinchronickidney
disease".)
MixeduremicosteodystrophyMixeduremicosteodystrophyischaracterizedbyeitherhighorlow
boneturnoverandbyabnormalmineralization.
Afifth,butdifferent,typeofuremicbonedisease,withauniquepathogenesis,occursinpatientsonlongterm
dialysisandpresentsasbonecysts,whichresultfrombeta2microglobulinassociatedamyloiddeposits.(See
"Dialysisrelatedamyloidosis".)
Despiteprogressivelesions,symptomsand/orsignsduetothevariousbonedisorders,suchasfracturesand
bonepain,generallydonotoccuruntilthepatientisalreadyonmaintenancedialysis[19].However,
subclinicalchangesinboneremodelingbeginearlyinthecourseofCKD.Alterationsinbonequalityinboth
highturnoverandlowturnoverbonediseasesmaycontributetothediminishedmechanicalcompetenceof
boneinCKD.Bonequalityreferstothestructuralandmaterialparametersthatenablebonetobearloadand
resistfracture[105].Onestudyreportedthatlowturnoverismanifestedbychangesinmicrostructural
parameters,whilebonewithhighturnoverismanifestedbychangesinmaterialcompositionand
nanomechanicalproperties[106].
Theprevalenceofhighturnoverbonedisease(osteitisfibrosacystica)amongdialysispatientshasmarkedly
decreased,whilenonaluminuminducedlowturnoverbonedisease(adynamicbonedisease)hasincreased,
withvariationsbasedinpartupongeographicregionevaluated[102,103,107,108].Asexamples:
Inastudyof56dialysispatientsfromThailandfollowedbetween1996and1998,bonebiopsyin
combinationwithotheranalysesrevealedthatlowturnover(adynamic)bonediseasewaspresentin41
percent,andhighturnover(osteitisfibrosacystica)diseasewaspresentin29percentofpatients[103].
Ina2003trialof98dialysispatientsinEurope,bonebiopsyshowedlowturnoverdisease(definedas
boneformationrate<5percentandosteoclastsurface<20percent)andhighturnoverdiseasein
approximately20percentofpatientseach[102].
Ina2008study,bonebiopsiesrevealedlowturnoverdiseasein59percentof119hemodialysispatients
[109].ThishighprevalencewasobserveddespitetreatingmostpatientsinaccordancewithKDOQI
guidelinesandhavingserummineralparameterswithinrecommendedranges.
Inastudyof97bonebiopsiesfromdialysispatientswithintactPTHlevelsof150to300pg/mL,two
thirdshadlowturnoverbonedisease,andonequarterhadhighturnoverbonedisease[110].
Inastudyof630bonebiopsiesfromadultpatientsondialysis,whiteindividualsexhibitedpredominantly
lowturnover(62percent),whereasblackindividualsshowedmostlynormalorhighturnoverbone
disease(68percent).Moreover,PTHlevelswereapredictorofhighandlowturnoveronlyinwhite
individuals[111].
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Inanotherstudyof492dialysispatientsfromBrazil,Portugal,Turkey,andVenezuela,PTH
concentrationsdifferentiatedhighboneturnoverfromnonhighturnover,butnotlowturnoverfromnon
lowturnover,usingtheintactPTHthresholdssuggestedbyKDIGO[99].
EvenamongCKDpatientsnotyetondialysis,theprevalenceoflowturnoverdiseasehasincreased.Ina
bonebiopsystudyin84unselectedpatientswithstage5CKD,adynamicbonediseasewasthemost
prevalenttypeofrenalosteodystrophy,particularlyindiabeticpatients[112].
Thisincreasedprevalenceoflowturnoverbonediseasemayreflectmultiplefactors,includingchangesin
patients'demographics(olderandincreasednumberofdiabeticpatients)andchangesintherapeutic
strategies,suchastheincreasedandearlieruseofvitaminDanalogsandcalciumcontainingphosphate
binders,anddifferencesindialysistechniques[104].Thisissueisdiscussedelsewhere(see"Adynamicbone
diseaseassociatedwithchronickidneydisease").GiventherecommendationbyKDIGOtotargetPTH
concentrationstwotoninetimestheupperlimitofnormal,theprevalenceofadynamicbonediseaseislikely
todecrease,whilethatofosteitisfibrosamayincrease[113].
EXTRASKELETALCALCIFICATIONExtraskeletalcalcificationiscommoninpatientswithCKD,
particularlythoseondialysis[114116].Vascularcalcificationcontributestomortality.Thepathogenesisand
clinicalimplicationsofvascularandothersofttissuecalcificationisdiscussedelsewhere.(See"Vascular
calcificationinchronickidneydisease".)
CLINICALPRESENTATIONTheclinicalpresentationofpatientswithCKDMBDvariesdependingupon
theprevailingmetabolicabnormalityandthecharacteristicbonedisease.(See"Managementofsecondary
hyperparathyroidismandmineralmetabolismabnormalitiesindialysispatients",sectionon'Clinicalfeatures'
and"Adynamicbonediseaseassociatedwithchronickidneydisease",sectionon'Clinicalfeatures'.)
TREATMENTThetreatmentofpatientswithCKDMBDvariesdependingupontheprevailingmetabolic
abnormality,thecharacteristicbonedisease,andtheseverityofunderlyingkidneydysfunction.(See
"Treatmentofhyperphosphatemiainchronickidneydisease"and"Managementofsecondary
hyperparathyroidismandmineralmetabolismabnormalitiesinadultpredialysispatientswithchronickidney
disease",sectionon'Overviewoftherapy'and"Managementofsecondaryhyperparathyroidismandmineral
metabolismabnormalitiesindialysispatients",sectionon'Treatment'and"Adynamicbonedisease
associatedwithchronickidneydisease",sectionon'Treatment'.)
SUMMARYANDRECOMMENDATIONS
Disordersofmineralandbonemetabolismarecommonsequelaeofchronickidneydisease(CKD).Such
disordersarecollectivelytermedchronickidneydiseasemineralandbonedisorder(CKDMBD).The
term"renalosteodystrophy"isexclusivelyusedtodefinebonepathologyobservedonbiopsy.CKDMBD
ischaracterizedbythefollowing(see'Introductionanddefinitions'above):
Abnormalitiesofcalcium,phosphorus,parathyroidhormone(PTH),orvitaminDmetabolismand/or
Abnormalitiesinboneturnover,mineralization,volumelineargrowth,orstrengthand/or
Extraskeletalcalcification
Secondaryhyperparathyroidismencompassesmostofthebiochemicalabnormalitiesthatcharacterize
CKDMBD.Causesofsecondaryhyperparathyroidismincludephosphateretentiondecreasedfree
calciumconcentrationdecreased1,25dihydroxyvitaminD(calcitriol)concentrationandthereduced
expressionofvitaminDreceptors(VDRs),calciumsensingreceptors(CaSR),fibroblastgrowthfactor
receptors(FGFRs),andklothointheparathyroidglands.(See'Abnormalitiesofparathyroidhormone,
calcium,phosphorus,fibroblastgrowthfactor23,andvitaminDmetabolism'above.)
Threeparametersareusedtoassessbonepathology(ie,renalosteodystrophy):boneturnover,
mineralization,andvolume(TMVsystem).Anycombinationofparametersmaybeusedtodescribea
givensample.TheTMVsystemofclassificationofrenalosteodystrophyemphasizesthecontributionof
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mineralizationandvolume,aswellasturnoverrate,tobonequality.TMVcharacteristicsofthemajor
CKDrelatedbonediseasesareasfollows(see'Abnormalitiesinboneturnover,mineralization,volume
lineargrowth,orstrength'above):
Osteitisfibrosacysticaischaracterizedpredominantlybyhighturnoverduetosecondary
hyperparathyroidism.
Adynamicbonediseaseischaracterizedpredominantlybylowturnover.Mostcasesresultfrom
excessivesuppressionoftheparathyroidglands.ThisisthemostcommonCKDrelatedbonelesion
amongdialysispatients.
Osteomalaciaischaracterizedbylowboneturnoverincombinationwithabnormalmineralization.
Osteomalaciaisuncommonsincethedeclineinuseofaluminumcontainingphosphatebinders.
Mixeduremicosteodystrophyischaracterizedbyeitherhighorlowboneturnoverandbyabnormal
mineralization.
Patientswithanyofthelesionsdefinedaboveareatgreaterriskofbonefracturesthanthegeneral
populationbecauseofchangesinbonequality.However,despiteprogressivelesions,symptomsand/or
signsduetothevariousbonedisorders,suchasfracturesandbonepain,generallydonotoccuruntilthe
patientisalreadyonmaintenancedialysis.(See'Abnormalitiesinboneturnover,mineralization,volume
lineargrowth,orstrength'above.)
Vascularorothersofttissuecalcificationiscausedbycalciumphosphateprecipitationduetopersistent
hyperparathyroidismandassociatedwithincreasedmortality.(See'Extraskeletalcalcification'aboveand
"Vascularcalcificationinchronickidneydisease".)
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