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Original
article
Effect
of
paricalcitol
on
mineral
bone
metabolism
in
kidney
transplant
recipients
with
secondary
hyperparathyroidism
夽
Francisco
José
Borrego
Utiel
a,∗,
Juan
Antonio
Bravo
Soto
b,
María
José
Merino
Pérez
c,
Isabel
González
Carmelo
c,
Verónica
López
Jiménez
d,
Teresa
García
Álvarez
e,
Yelenei
Acosta
Martínez
f,
María
Auxiliadora
Mazuecos
Blanca
eaServiciodeNefrología,ComplejoHospitalariodeJaén,Jaén,Spain
bServiciodeNefrología,HospitalUniversitarioVirgendelasNieves,Granada,Spain cServiciodeNefrología,HospitalJuanRamónJiménez,Huelva,Spain
dServiciodeNefrología,HospitalRegionalCarlosHaya,Málaga,Spain eServiciodeNefrología,HospitalPuertadelMar,Cádiz,Spain
fServiciodeNefrología,HospitalUniversitarioVirgendelRocío,Sevilla,Spain
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received10November2014
Accepted16January2015
Availableonline2November2015
Keywords: Secondaryhyperparathyroidism Renaltransplantation Paricalcitol Cinacalcet Calcitriol
a
b
s
t
r
a
c
t
Introduction:Secondaryhyperparathyroidismishighlyprevalentinkidneytransplant
recip-ients, andcommonlyresultsinhypercalcaemia;anassociationtoosteopeniaandbone
fractures hasalso beenobserved.Paricalcitolhasprovedeffectivetocontrol secondary
hyperparathyroidisminchronickidneydiseaseinbothdialysedandnon-dialysedpatients,
withalowhypercalcaemiaincidence.Currentlyavailableexperienceonparicalcitolusein
kidneytransplantrecipientsisscarce.Ourmainaimwastoshowtheeffectofparicalcitol
onmineralbonemetabolisminkidneytransplantrecipientswithsecondary
hyperparathy-roidism.
Materialandmethods:Aretrospectivemulticentrestudyinkidneytransplantrecipientsaged
>18years witha 12-monthorlongerpost-transplantationcourse,stablerenalfunction,
havingreceivedparicalcitolformorethan12months,withavailableclinicalfollow-upfora
24-monthperiod.
Results:A total of 69 patients with a 120±92-month post-transplantation course
were included. Baseline creatinine was 2.2±0.9mg/dL and GFR-MDRD was
36±20mL/min/1.73m2. Paricalcitol doses were gradually increased during the study:
baseline 3.8±1.9g/week, 12 months 5.2±2.4g/week; 24 months 6.0±2.9g/week
(P<.001).Serum PTHlevelsshowed a significant fastdecline:baseline288±152pg/mL;
6 months 226±184pg/mL; 12 months 207±120; 24 months 193±119pg/mL (P<.001).
ReductionfrombaselinePTHwas≥30%in42.4%ofpatientsat12monthsandin65.2%of
patientsat24months.Alkalinephosphataseshowedasignificantdecreaseinfirst6months
夽Pleasecitethisarticleas:BorregoUtielFJ,BravoSotoJA,MerinoPérezMJ,GonzálezCarmeloI,LópezJiménezV,GarcíaÁlvarezT,
etal.Efectodeparicalcitolsobreelmetabolismomineralóseoenpacientestrasplantadosrenalesconhiperparatiroidismosecundario.
Nefrologia.2015;35:363–373.
∗ Correspondingauthor.
E-mailaddress:fborregou@senefro.org(F.J.BorregoUtiel).
2013-2514/©2015SociedadEspa ˜noladeNefrología.PublishedbyElsevierEspaña,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
followedbyaplateau:baseline92±50IU/L;6months85±36IU/L,12months81±39IU/L (P<.001).Overall,nochangeswereobservedinserumcalciumandphosphorus,andinurine calciumexcretion.PTHdeclinewaslargerinpatientswithhigherbaselinelevels.Patients withlowerbaselinecalciumlevelsshowedsignificantlyincreasedlevels(meanincrease was0.5–0.6mg/dL)butstillwithinnormalrange,whereaspatientswithbaselinecalcium >10mg/dLshowedgraduallydecreasinglevels.Fifteen(21.7%)patientshadreceivedprior calcitrioltherapy.Whenshiftedtoparicalcitol,suchpatientsrequiredparicalcitoldoses significantlylargerthanthosenothavingreceivedcalcitriol.Paricalcitolwasused concomi-tantlytocinacalcetin11patientswithsignificantPTHreductionsbeingachieved;clinical coursewassimilartootherpatientsandparicalcitoldoseswerealsosimilar.
Conclusions:Paricalcitolisaneffectivetherapyforsecondaryhyperparathyroidisminkidney transplantrecipients.Overall,nosignificantchangeswereobservedincalciumand phos-phoruslevelsorurinaryexcretion.Patientshavingpreviouslyreceivedcalcitriolrequired higherparicalcitoldoses.Whenusedinpatientsreceivingcinacalcet,paricalcitolresults inasignificantPTHfall,withparicalcitoldosesbeingsimilartothoseusedinpatientsnot receivingcinacalcet.
©2015SociedadEspa ˜noladeNefrología.PublishedbyElsevierEspaña,S.L.U.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Efecto
de
paricalcitol
sobre
el
metabolismo
mineralóseo
en
pacientes
trasplantados
renales
con
hiperparatiroidismo
secundario
Palabrasclave: Hiperparatiroidismosecundario Trasplanterenal Paricalcitol Cinacalcet Calcitriol
r
e
s
u
m
e
n
Introducción:Elhiperparatiroidismosecundarioesmuyprevalenteenpacientes
trasplan-tadosrenales.Cursaconfrecuenciaconhipercalcemiaysehaasociadoaldesarrollode
osteopeniayfracturasóseas.Elparicalcitolhamostradosueficaciaenelcontroldel
hiper-paratiroidismosecundarioenlaenfermedadrenalcrónicaconysindiálisis,conunabaja
incidenciadehipercalcemia.Laexperienciaconparicalcitolentrasplantadosrenalesesmuy
escasa.Elobjetivodeestetrabajofuemostrarelefectosobreelmetabolismomineralóseo
delparicalcitolentrasplantadosrenalesconhiperparatiroidismosecundario.
Materialymétodos:Estudioretrospectivomulticéntricocontrasplantadosrenalesdemásde
18a ˜nosdeedadymásde12mesesdeevoluciónpostrasplante,confunciónrenalestable,
quehayansidotratadosconparicalcitoldurantemásde12meses,conseguimientoclínico
hastalos24mesesdetratamiento.
Resultados: Se incluyó a 69 pacientes, con 120±92 meses postrasplante, con
creatin-ina inicialde2,2±0,9mg/dlyFG-MDRD36±20ml/min/1,73m2.Ladosisde paricalcitol
seincrementóprogresivamenteduranteelestudio:basal3,8±1,9g/semana,12meses
5,2±2,4g/semana;24 meses6,0±2,9g/semana(p<0,001).Los nivelesséricosdePTH
descendierondeformarápidaysignificativa:basal288±152pg/ml;6meses226±184pg/ml;
12meses207±120;24meses193±119pg/ml(p<0,001).Observamosunareducciónsobre
PTHbasal≥30%enel42,4%delospacientesalos12mesesyenel65,2%delospacientesa
los24meses.Lafosfatasaalcalinadescendiótambiénsignificativamenteenlos6primeros
mesesparaluegoestabilizarse:basal92±50UI/l;6meses85±36UI/l,12meses81±39
UI/l(p<0,001).Globalmentenohubomodificacionesenelcalcioofósforoséricosnienla
excreciónurinariadecalcio.LareduccióndePTHfuemásimportanteentrasplantadoscon
nivelesséricosmáselevadosdepartida.Observamosquelospacientesconcalciobasal
másbajomostraronunincrementosignificativodesuscifrasde0,5-0,6mg/dlen
prome-dioaunquemanteniéndoseenrangodenormalidad,mientrasquepacientesconcalcio
basal>10mg/dlmostraronunareducciónprogresivadesuscifras.Quince(21,7%)pacientes
seguíantratamientoprevioconcalcitriolyalcambiarlosaparicalcitolprecisarondosis
signi-ficativamentemayoresquelospacientesquenohabíanrecibidocalcitriol.Elparicalcitolfue
asociadoacinacalceten11pacientes,conreduccionessignificativasdePTH,conevolución
Conclusiones:Paricalcitoleseficazeneltratamientodelhiperparatiroidismosecundario detrasplantadosrenales.Globalmentenoobservamosmodificacionessignificativas delosnivelesdecalcionidefósforo,niensuexcreciónurinaria.Lospacientesen tratamientoprevioconcalcitriolprecisarondosismayoresdeparicalcitol.Cuandoel paricalcitolseadministraapacientestratadosconcinacalcet,seobservaundescenso significativodelaPTHcondosisdeparicalcitolsimilarapacientessincinacalcet.
©2015SociedadEspa ˜noladeNefrología.PublicadoporElsevierEspaña,S.L.U.Estees unartículoOpenAccessbajolalicenciaCCBY-NC-ND(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Introduction
Paricalcitolis a selectivevitamin D receptor activatorthat
has been demonstrated to be effective in the treatment
ofsecondaryhyperparathyroidisminadvancedchronic
kid-neydisease1–3 and indialysis patients.4,5 In haemodialysis
patients, paricalcitol has been shown to reduce serum parathyroidhormone (PTH) levels by morethan 30% from baselinein68–91%ofcases,bymorethan50%frombaseline in45–60%ofpatients,2,4,6 andtoreachlevelsrecommended in guidelines in 30–50% of patients. Some studies have shownparicalcitoltobeaseffectiveormoreeffectivethan cinacalcet.6 Whenparicalcitolwascomparedwithcalcitriol in patients on haemodialysis with resistant hyperparathy-roidism, reductions in PTH were observed, even in those patientstheydid notrespondtocalcitriol.5–7 As compared withcalcitriol,paricalcitolhaslesseffectoncalciumand phos-phorustransporterproteinsatanintestinallevel,thereforethe degreeofincreaseinserumlevelsofcalciumandphosphateis lessafterparicalcitolthancalcitriol.8,9Thisallowssafer man-agementincasesofmoreseverehyperparathyroidism.
Residualhyperparathyroidismiscommoninrenal trans-plant recipients: various series have found that 30–50% of patients have abnormal PTH levels.10,11 It is particularly commontoobservehypercalcaemiaduringthefirstyear post-transplantandinup to10–40%ofpatientsaftermorethan oneyear post-transplant.10,12 Thismaygeneratedifficulties inthetreatmentofresidualhyperparathyroidismwith vita-minDderivatives,suchascalcitriol.Paricalcitolcouldhavea clearindicationinthecontrolofresidualhyperparathyroidism inrenal transplantrecipients,aimingforamoreambitious reductioninPTHlevelsthanwhatisoftenachievedindaily clinicalpractice.
Thereislittleinformationabouttheuseofparicalcitolin renal transplant patients. Inone randomised trial inrenal transplantrecipientsreceivingparicalcitolfromthethirdday post-transplant,prevalenceofresidualhyperparathyroidism attheend ofthefirst yearwas reduced to29%,compared with63%inthecontrolgroup.13 Inoneretrospectivestudy in long-term transplant recipients, paricalcitol was shown toreduceserumPTH levelsandtohavealowincidenceof hypercalcaemia.14
Theaimofthismulti-hospitalstudywastoretrospectively collectinformationontheeffectofparicalcitolonbone min-eralmetabolisminlong-termtransplantrecipients,analysing
thepossiblefactorsaffectingchangesinserumcalciumand PTHlevels.
Patients
and
methods
This was a retrospective multicentre study with a single
cohortofrenaltransplantrecipients.Inclusioncriteriawere:
renaltransplant patients>18yearsold,patientsmorethan
12monthspost-transplant,stablerenalfunction,and
treat-ment withparicalcitol for atleast 12 monthsprior to the
year2012.Wechoseapopulationwithmorethan12months
post-transplant because during the first year, the
progres-siveimprovementinrenalfunctionoritsdeteriorationdue
torejectionorothercausesmaycausechangesinPTHlevels.
Suchchangeswouldadddifficultiestoacorrectinterpretation
tothedirectpotentialeffectofparicalcitolonPTH.Inaddition,
theadministrationofcinacalcettocontrolhypercalcemiais
morecommonduringthefirstyearaftertransplantation;this
treatmentmayalsohaveaffectedtheresults.
Allparticipatingcentreswereaskedtoprovideinformation
onallpatientswhohadreceivedtreatmentwithparicalcitol
andwho mettheinclusioncriteria.Ineachmedicalcentre,
patients receivedtreatment withparicalcitol forsecondary
hyperparathyroidisminaccordancewiththestandardclinical
practiceprotocol,eitherasaprimarymedication,asa
substi-tuteforcalcitrioltreatment,orinconjunctionwithcinacalcet
treatment. Paricalcitolwas prescribed initially ata doseof
2–3gper weekinmostcases,withaprogressiveincrease
inthedosetoachievethedesiredcontrolofPTH.Inpatients
previouslytreatedfromcalcitrioltoparicalcitol,thedose
con-versionratiowaslowerthantherecommended4:1.
Wegatheredanalyticaldataanddoseofparicalcitolused
atbaselineandat6monthintervalsduringa2yearof
follow-upperiod.Informationwascollectedonwhetherpatientshad
receivedprevious treatmentwithparicalcitol,andthe dose
they had been taking. Patients on treatment with
cinacal-cet continued taking it, and the dose used at each stage
wasnoted.ParathyroidhormonewasmeasuredasintactPTH
using Roche® Elecsys electrochemiluminescenceinall
cen-tres,thereforevaluesdidnotrequireconversion(normalrange
15–65pg/mL). Our main objective was to collect and show
the overall changes for all parameters: the increasing and
decreasingtrendsintheirvalues,withmeans,standard
devi-ations,andstandarderrors(ingraphs).Therefore,dataarenot
thesecasesweremanagedatthediscretionofeach nephrol-ogist.Serumcalciumlevels werenotcorrectedforalbumin becauseitwasnotavailableatall assessmenttimes.Renal functionwasrepresentedbyserumcreatininevaluesandby estimatedglomerularfiltrationrateusingtheMDRD4 equa-tion(GFR-MDRD).
Statisticalanalysiswasperformedwiththestatistical pro-gram SPSS11.5.All continuous quantitativevariables were assessed for distribution; if they did not follow a normal distribution,the variablewastransformedusingits natural logarithm.ThisoccurredforPTHandalkalinephosphatase. Quantitativevariablesare expressedasmeanandstandard deviation,exceptinthe graphs,whichshowthe meanand standarderror.Unpairedmeansofquantitativevariablesfrom twogroupswerecomparedusingtheMann–Whitneytestand theFriedmantestwhenthereweremorethan2groups.Paired meansof2variableswerecomparedusingtheWilcoxontest. Pairedmeansofmorethan2timepointswerecomparedusing repeatedmeasuresANOVA,eitherdirectlyorafterlogarithmic transformationiftheydidnotfollowanormaldistribution.For analysisofsubpopulationsofinterest,wedividedthe popu-lationintotertiles,avoidingindividualvaluesthatcouldhave biasedtheresultsandwithequalnumbersineachstratum studied.For multivariate analysis, weusedalinear regres-sionanalysis,checkingiftheremaindersobtainedfolloweda normaldistributioninthemodelconstructed.Forcorrelation analysis,theSpearmancoefficientwaswhenevervariablesdid notfollowanormaldistribution.APvalue<.05wasconsidered statisticallysignificant.
Results
Theepidemiologicalcharacteristicsofthepatientsincludedin
thestudyareshowninTable1.Mostpatientswerelong-term
renaltransplantrecipients:84.1%ofpatientsweremorethan 2yearspost-transplantand63.8%ofpatientsweremorethan 5yearspost-transplant.Thedistribution ofcasesby trans-plantfollow-upcentrewere:Cádiz,3cases;Granada,24cases; Huelva,11cases;Jaen,21cases;Malaga,4cases;andSeville,
Table1–Epidemiologicalcharacteristicsofthestudy
population.
N 69
Age 55±12
Sex,M/F 34/35
Monthspost-transplant 120±92(median100)
Weight,kg 75.2±17.5 BMI,kg/m2 28.6±6.2 SBP,mmHg 134±18 DBP,mmHg 76±11 Diabetesmellitusn(%) 14(20.2) Immunosuppression% CiclosporinA 29.0 Tacrolimus 55.1 Sirolimus 5.8 Everolimus 5.8 MMF/MPS 84.1 Azathioprine 7.2 Prednisone 91.3
6cases.Ageandpost-transplantfollow-uptimeweresimilar
forbothsexes.
Initial PTH levels in the study population were as
fol-lows:PTH<150pg/mL,17.2%ofpatients;PTH150–249pg/mL,
26.6%;PTH250–349pg/mL,31.2%;PTH350–500pg/mL,18.8%;
and PTH>500pg/mL,6.2%. Theprescribed startingdose of
paricalcitol was 3.7±1.9g/week, median 3g/week, and
range 1–10g/week.Adose lower than 3g/week was
pre-scribedin16patients(23.2%);3g/weekwasprescribedin30
patients (43.5%);4–6g/weekwasprescribed in11 patients
(15.9%); 7g/week was prescribed in 11 patients (15.9%);
and 10g/weekwasprescribed in 1patient. ThePTH/dose
ratiowas88±58pg/mL/g/week(median77pg/mL/g/week).
Serum calcium was >10.5mg/dL before starting treatment
with paricalcitol in seven patients (10.1%). Three of those
patientshadhadprevioustreatmentwithcalcitriol,andone
withcinacalcet.
Paricalcitoldosewas increasedprogressivelythroughout
follow-up: dose atbaseline,3.8±1.9g/week; at6months,
4.4±2.2g/week; at 12months, 4.9±2.4g/week; at 18
months,5.3±2.3g/week;andat24months,5.9±2.8g/week
(Wilcoxon P=.002 for 6 months and P<.001 for the other
times).
Effectonbonemineralmetabolism
Changes in parameters of bone mineral metabolism are
summarisedinTable2.PTHandalkalinephosphataselevels
decreasedsignificantlyatsixthmonth.Patientswithhigher initiallevelsofserumPTHlevelshadamoremarkedreduction inPTH,whereaspatientsinthelowesttercilehada moder-atechangePTH(Fig.1).APTHdecreaseof>60%frombaseline valuewasseenin11.9%ofpatientsat12months,andin23.9% ofpatientsat24months.PTHwasreducedby>30%from base-linein42.4%ofpatientsat12monthsandin65.2%ofpatients at24months.
Overall, serum calcium and phosphorus levels did not change significantly, nor did urinary excretion of calcium. Phosphaturia and phosphate clearance decreased signifi-cantlyattheendoffollow-up(availablemeasurements:n=48 patientsatbaselineandn=39at18and24months).
Toanalysetheeffectofinitialcalciumlevelsonchanges inPTH, weclassified patientsbytercilesaccordingtotheir
500 450 400 350 300 250 PTH (pg/mL) 200 150 100 Baseline +6m +12m +18m +24m PTH<227 pg/mL PTH 227-299 pg/mL PTH>299 pg/mL P<.001 P<.001 P=.003 P<.001 P<.001 P=.009 P<.001
Fig.1– ChangesiniPTHbytercilesofinitialiPTH.aP<.001; bP=.003;cP=.009.
Table2–Changesaftertreatmentwithparicalcitolinrenalfunctionandparametersofbonemineralmetabolismin
bloodandurine.
Baseline 6m 12m 18m 24m
Cr(mg/dL) 2.21±0.93 2.29±0.92 2.38±0.97a 2.41±0.95b 2.41±1.05a
GFR-MDRD 36±20 34±18a 35±23 33±20b 33±18a
iPTH(pg/mL) 288±152 226±184c 207±120c 211±140d 193±119c
Reduc.PTH(median)(%) −24.1 −23.7 −29.7 −35.6
Patientswithreduc.>30%frombaselinePTH(%) 39 42.4 48.9 65.2
Alk.Phos.(IU/L) 92±49 85±35b 82±38d 84±44e 87±41f
Ca(mg/dL) 9.7±0.7 9.8±0.6 9.6±0.7 9.6±0.6 9.6±0.6 P(mg/dL) 3.4±0.7 3.4±0.9 3.4±0.8 3.5±0.7 3.6±0.8 Calciuria(mg/day) 122±99 125±99 105±82 120±135 109±91 UrinaryCa/Cr(%mg/mg) 10.5±8.8 11.1±9.1 9.4±8.2 10.1±12.5 9.6±7.3 Frac.Exc.Ca(%) 1.81±1.22 1.96±1.64 1.80±1.30 1.89±1.21 1.95±1.17 Phosphaturia(mg/day) 744±305 704±256 706±316 667±255g 629±245h ClP(mL/min) 16.3±8.5 15.9±7.7 15.4±7.7 13.9±6.7a 12.8±6.7i TRP(%) 64±13 64±13 63±13 64±15 63±19 a P<.05. b P=.005. c P<.001. d P=.001. e P=.004. f P=.007. g P=.014. h P=.006.
i P=.002(comparedwithbaseline).
baseline serum calcium levels. We found that patients in the lowest calcium tercile had higher baseline PTH values and that PTH decreased moremarkedly than in the other groups(Fig.2).Inpatientswhobeganwithbaselinecalcium <9.8mg/dL (lowest tercile),serum calcium levels increased progressively but remained within normal range. In con-trast,inpatientswhobeganwithserum calcium>10mg/dL (highest tercile) calcium levels showed a significant pro-gressivedecrease(Fig.3).Paricalcitoldosewasprogressively increasedinall 3calcium groups.Thisdose wasincreased morerapidlyinthegroupofpatientswiththelowestinitial calciumlevels.At24monthsallgroupswerereceiving sim-ilardosesofparicalcitol(Fig.4).Therewerenon-significant differencesinrenalfunctionbetweenthedifferentcalcium terciles:Ca<9.8mg/dL,Cr2.4±0.9mg/dL;Ca9.8–10mg/dL,Cr 2.1±0.7mg/dL; Ca>10mg/dL, Cr 1.9±1.1mg/dL.Cinacalcet 400 350 300 250 PTH (pg/mL) 200 150 100 Baseline +6m +12m +18m +24m Ca<9.8 mg/dL Ca 9.8-10 mg/dL Ca>10 mg/dL P=.002 P=.001 P=.012 P=.006 P=.011 P=.003 P=.032
Fig.2–ChangesiniPTHbyinitialcalciumlevels.aP=.003; bP=.011;cP=.006;dP=.032;eP=.012;fP=.002;gP=.001. Calcium (mg/dL) 8.5 8.7 8.9 9.1 9.3 9.5 9.7 9.9 10.1 10.3 10.3 Baseline +6m +12m +18m +24m Ca<9.8 mg/dL Ca 9.8-10 mg/dL Ca>10 mg/dL P=.006 P=.002 P=.035 P=.047 P=.026 P<.001 P<.001
Fig.3–MeanPTHvaluesbygroupaccordingtoinitial calciumlevel.aP=.006;bP=.002;cP=.035;dP<.001;e P=.047;fP=.026.
wasgivento6of21patients(28.6%)inthelowestcalcium
tertile,2of24(8.2%)inthemiddletercileand3of24patients
(12.5%)inthehighesttercile;and,thePvaluewasnot
signifi-cant).
Patients were alsoclassified according to their baseline
serum phosphorus levels. Patients from the lowest tercile
(P<3.2mg/dL)showedasignificantandprogressiveincreasein
phosphoruslevels,butlevelsremainedwithinnormallimits
(Fig. 5). In the other tertiles, the changes in serum phos-phoruswerenotsignificant.GFRwasbetterinpatientsfrom thelowesttertileofphosphate:1st(lowest)tercile,serumCr 1.5±0.6mg/dL;2ndtercile,serumCr2.4±1.1mg/dL;3rd ter-cile, serum Cr 2.6±0.6mg/dL (P<.001). Meanbaseline PTH levelsweredifferent.ThereweredifferencesinbaselinePTH levels amongthe different phosphorus tertiles: 1st tercile,
Paricalcitol dose ( μ g/week) 2 3 4 5 6 7 8 Home 6m 12m 18m 24m Ca<9.8 mg/dL Ca 9.8-10 mg/dL Ca>10mg/dL P=.004 P=.007 P=.008 P=.017 P=.003 p=0.04 P=.002 P=.037 3.4 3.8 4.3 4.2 4.9 5.1 6 6.1 5.8 5.7 4.9 5.4 5 3.8 4
Fig.4–Changesinparicalcitoldoseandinitialcalcium levels.aP=.004;bP=.007;cP=.008;dP=.017;eP=.04;f P=.037;gP=.002;hP=.003. p<3.2 mg/dL p 3.2-3.8 mg/dL p>3.8 mg/dL P<.001 P=.015 P=.021 Phosphorus (mg/dL) 2 4.5 2.5 3.5 3 4 Baseline +6m +12m +18m +24m
Fig.5–MeanPTHlevelsbygroupofinitialcalciumlevel.a P=.015;bP=.021;cP=.001.
PTH 238±100pg/mL; 2nd tercile, PTH 252±101pg/mL;3rd
tercile, PTH 362±215pg/mL (P<.001). In the 3phosphorus
groups,PTHdecreasedgraduallyandat24monthsthePTH
valuesweresimilarforallPhosphatetertiles(154±78pg/mL;
186±89pg/mL;189±114pg/mL).
Whenpatientswereclassifiedaccordingtobaselinerenal
function(tercilesofcreatinine),amoresignificantdecrease
inPTHwasobservedinpatients withworserenal function
(Fig.6).Therewerenosignificantchangesincalciumor phos-phoruslevelsinanygroupduringthestudy.
ThepercentchangeinPTH frombaselinetosixmonths correlatedwithbaselinePTHlevel(r=−0.31;P=.016)andwith changes incalcium from baseline tosixmonths (r=−0.33; P=.011).Thiswasobservedevenwhenpatientswithout pre-vious calcitrioltreatment were analysedseparately (Fig. 7). ThepercentchangeinPTHat12monthsshoweda correla-tionwithbaselinePTHvalue(r=−0.47;P<.001)andwiththe startingdoseofparicalcitol(r=−0.27;P=.035),butnotwith paricalcitoldoseat6or12monthsorwithchangesinserum calciumat6or12months.Paricalcitoldoseat12monthsand at18monthsshowedacorrelationwithbaselinePTHvalues (r=0.41andP=.003,andr=0.31andP=.030,respectively).
PTH (pg/mL) 100 150 200 250 300 350 Baseline +6m +12m +18m +24m Cr<1.8 mg/dL Cr 1.8-2.4 mg/dL Cr>2.4 mg/dL P<.001 P<.005 P=.002 P=.011 P=0.03 P<.001 P=.024
Fig.6–ChangesiniPTHbyinitialcreatininelevel.a P<.001;bP=.03;cP=.005;dP=.024;eP=.011;fP=.002. ln(6m PTH) – ln(Baseline PTH) –2.5 –1.5 –.5 0.0 .5 1.0 –1.0 –2.0 –2 –1 0 1 2 3 Rho=–0.33 P=.011 With calcitriol
6 m calcium – baseline calcium No calcitriol
Fig.7–ChangesinPTHlevelsafterparicalcitolat6months comparedwithbaseline,inrelationtochangesincalcium.
Factors predictive of PTH response (percentage change
from baseline) were analysed using linear regression. The
followingfactorswereintroducedasindependentvariables:
paricalcitoldoseateachtimepoint,treatmentwithcinacalcet,
previous treatment with calcitriol, age, sex, months
post-transplant, baseline weight, calcium, phosphorus, baseline
PTH, and baselinecreatinine/GFR-MDMR. At 6months the
predictive factors were initial paricalcitol dose and prior
treatmentwithcalcitriol(r=0.37;P=.018).At12monthsthe
predictive factorswere baselinePTHand initialparicalcitol
dose(r=0.63;P<.001).At18monthstheonlypredictive
fac-tor wasbaseline PTHlevel (r=0.57;P<.001). Welookedfor
predictorsofparicalcitoldoseateachtimepoint,using
lin-earregression,andfoundonlybaselineparicalcitoldoseand
baselinePTH.
Whenchangesincalciumat6monthswereanalysedusing
linearregression,thepredictivevariableswerebaseline
thepredictorswerebaselinecalciumandparicalcitoldoseat 12months(r=0.55;P<.001).At18months,theonlypredictor wasbaselinecalciumlevel.
Changesinalkalinephosphataselevelsmaintaineda cor-relationwithPTHlevelsat6months(r=0.29;P=.046),at12 months(r=0.41;P=.003),at18months(r=0.29;P=.048)and at24months(r=0.48;P=.003).Therewasnocorrelationwith paricalcitoldoseorwithchangesincalciumorphosphorus levels.
Onlinear regressionanalysis, changes inalkaline phos-phatase values between baseline and six months were significantly related (r=0.77; P<.001) with baseline alka-linephosphatasevalues(beta=−.73;P<.001), withprevious calcitriol treatment (beta=.32; P<.001), and with baseline creatinine (beta=−.19; P=.0321). Between baseline and 12 months, the predictors of change in alkaline phosphatase (r=0.74;P<.001) were baseline alkalinephosphatase value (beta=−.67; P<.001), baseline calcium (beta=.25; P=.008), previous treatment with calcitriol (beta=.25; P=.027), and baselinecreatinine(beta=−.19;P=.042),withnoassociation withchangesinPTH.
Comparison of patients treated with cyclosporine with those treated with tacrolimus did notshow differences in changesinPTH,alkalinephosphatase,calcium,phosphorus, excretionofcalcium or phosphorus,or dose ofparicalcitol used. Likewise, there were no differences in these vari-ableswhencomparingpatientswhoreceivedanticalcineurin therapy or m-TOR inhibitors as immunosuppression. Sex, age,timepost-transplant,anddiabeticstatusdidnotaffect immunosuppressionchoice.
Patientspreviouslytreatedwithcalcitriol
Fifteenpatients(21.7%)hadbeenreceivingprevioustreatment withcalcitriol, which was changedtoparicalcitol. The ini-tialdoseconversionwas3.5±1.8gparicalcitol/gcalcitriol (median,3.4;range,1–8gparicalcitol/gcalcitriol).
Paricalcitoldosewas progressivelyincreasedinpatients treated with calcitriol, and these patients received higher dosesthanotherpatients,ascanbeseeninFig.8(Friedman P<.001forpatientswithoutcalcitriolandP=.002forpatients withcalcitriol).Themoststrikingdifferenceswere between
2 3 4 5 6 7 8 Baseline +6m +12m +18m +24m Cinacalcet Calcitriol None 3.5 3.7 4.1 5 4.2 4.2 4.6 4.9 5.5 5.7 6.7 4.9 5.8 6.4 5.4 Paricalcitol dose ( μ g/week)
Fig.8–Changesinparicalcitoldosebytreatmentwith calcitriolorcinacalcet. PTH (pg/mL) 100 200 300 350 250 150 50 0 P=.01 P<.001 P<.001 P<.001 P=.016 P=.006 With calcitriol No calcitriol Baseline +6m +12m +18m +24m
Fig.9–ChangesiniPTHaccordingtoprevioustreatment withcalcitriol.aP<.001;bP=.016;cP=.01;dP=.006.
thesegroups at12 months(Mann–WhitneyP=.076)and 18
months(Mann–WhitneyP=.019).
ChangesinPTH,alkalinephosphatase,calcium,and
phos-phorusweresimilar,withsimilarfinallevelsinbothgroupsof
patients(Fig.9).Therewerenodifferencesinurinaryexcretion
ofcalciumorphosphorus.
Patientsontreatmentwithcinacalcet
Eleven patients (15.9%) were on treatment with cinacal-cet when paricalcitol was introduced. The initial dose of paricalcitol usedin patients thatwere oncinacalcet treat-mentwas3.5±1.9g/week.Thisdosewassimilarinpatients not taking cinacalcet (3.8±1.9g/week). The dose of pari-calcitol was increased to the same extent in both groups (Fig. 8). Thedose of cinacalcet did notchange throughout follow-up:baseline,53±36mg/day;6months,60±40mg/day; 12 months, 60±47mg/day; 18 months, 71±41mg/day; 24 months,71±48mg/day.In7patientstherewasnochangein cinacalcetdoseatanypoint.Inonepatientitwasstoppedat 12months.Inonepatientthedailydoseincreasedby30mg at6months.Intheother2patientsthedailydoseincreased by30mgfrom12monthstoavoidfurtherchanges.
Changesinlevelsofcalcium,phosphorus,PTH,and alka-linephosphatase,andchangesintheexcretionofcalciumand phosphorus wereparallel betweenpatientswith and with-outcinacalcet(Fig.10).Baselinelevelsofcalcium,PTH, and alkalinephosphataseweresimilarinbothgroups,aswasthe dose ofparicalcitolusedatthe6-month intervals.Patients withcinacalcetinitiallyhadslightlylowerlevelsof phospho-rus, althoughnotsignificantly, andhad parallelchangesto patientswithoutcinacalcet.Urinaryexcretionofcalciumwas higherinpatientswithcinacalcet,withnosignificant differ-encesinitschangesoverthestudyperiod(Fig.11).
Discussion
Residual secondary hyperparathyroidism is common in
renal transplant recipients. The factors associatedwith its
With calcitriol No calcitriol P=.037 P<.001 P<.001 P=.004 P=.042 P=.002 P=.055 P=.001 PTH (pg/mL) 100 200 300 350 250 150 50 0 Baseline +6m +12m +18m +24m
Fig.10–ChangesiniPTHaccordingtoprevioustreatment withcinacalcet.aP<.001;bP=.004;cP=.042;dP=.037; eP=.055;fP=.002. With cinacalcet No cinacalcet .088 .093 .0895 .069 .082 .175 0.22 .153 .189 .164 P=.004 P=.004 P=.013 Baseline 6m 12m 18m 24m
Urinary calcium (mg Ca/mg Cr)
0 0.05 0.1 0.2 0.3 0.25 0.15
Fig.11–Changesinurinarycalciumwithorwithout cinacalcettreatment.aP=.013;bP=.004.
secondaryhyperparathyroidismpriortotransplant,needfor
cinacalcetwhilstondialysis,degreeofrenalfunctionachieved
bythegraft,vitaminDreceptorgenotype,andpost-transplant
circulating levels of vitamin D metabolites. Although
sec-ondary hyperparathyroidism has been associated with a
higherincidenceofpost-transplantbonefractures18andwith
lossofbonemass,19–21 thereare noclearguidelinesonthe treatmentofresidual post-transplant hyperparathyroidism. The recommendations are general and are directed more towardspreventionandtreatmentofpost-transplant osteope-nia than specific goals of secondary hyperparathyroidism treatment.Often,levelsofPTHaremaintainedrelativelyhigh forthedegreeofrenalfunctionachieved,ifcomparedwith therecommendedlevelsforpatientswithchronicrenalfailure whodonotreceiveatransplant.Maintainingrelativelyhigh levelsofPTHcouldbeadvisabletoobtainagooddegreeofbone remodelling,counterbalancingtheslowingeffectofsteroids andanticalcineurintherapyonboneremodelling.22However, themaintenanceofpost-transplantsecondary hyperparathy-roidismevenwithhypercalcaemiadoesnotguaranteeahighly remodelledbone; often a low degree of boneremodelling, oreven anadynamicbone,is seen.23 Theapproach ofnot startingactivetreatmentunlesstherearecomplicationscould explainwhyparicalcitolwasstartedinourseriesin29.1%of patientswithPTHof250–349pg/mLandin23.6%ofpatients
withPTH>350pg/mL.Thesamecanbeobservedintheseries presentedbyGonzález,14inwhichtheaveragePTHlevelwas 333pg/mLatthetimeofstartingparicalcitol.
Treatment of residual post-transplant hyperparathy-roidism is based on the use of vitamin D derivatives and cinacalcet.TheuseofCinacalcetiswidespreadandrecognised in renal transplant patientswith post-transplant hypercal-caemia,especiallyduringthe firstpost-transplant year.24,25 Often, when cinacalcetis stopped, newincreases are seen in PTH and calcium, requiring continued treatment foran indefinitetimeperiod.17,26Insomeseriesofrenaltransplant patients,27,28 supplementation with vitamin D derivatives reduced PTH, althoughthe reductionsobtainedwere mod-erate when initial PTH levels were very high. Increases in serumcalciumwerealsoobserved.27,28Theideallevelsof 25-OHvitaminDarenotwell-established.Avalueof>30ng/mL, as innon-transplantpatients, isrecommended,27 although levels above20ng/mLare probablysufficient. Calcitriolhas beenusedinrenaltransplantpatients,directedparticularly atthetreatmentofbonemassloss,withsignificant reduc-tionsinPTH.19,29,30Often,thereisanassociatedincreasein calciuria9andinserumcalcium.31Alfacalcidolalsoachieves PTH reduction, but with an associated increase in serum calcium and reductionofbonemassloss inthespine and femur.32
Paricalcitol isa synthetic analogueof calcitriol. Parical-citol has theadvantagea reducing intestinalabsorptionof calciumandphosphorus,33,34whichexplainsthelower inci-denceofhypercalcaemiaandhyperphosphataemia.35 There is little experience with paricalcitol in renal transplants. Amer13studiedparicalcitolasatreatmentforpost-transplant secondary hyperparathyroidism: in a randomised trial, 51 patientsreceived1g/dayofparicalcitolfromthe thirdday post-transplant,increasingto2g/dayfrom2weeksuntilthe study end. With this dose, theprevalence ofpatientswith PTH >65pg/mLwasreduced to29%,comparedwith63%in theplacebogroup.González14performedaretrospectivestudy on 58 patients who were prescribed paricalcitol at a dose of1g/dayonalternatedays,andobservedanaveragePTH decreaseof30–40%.PTHlevelsdecreasedby≥30%in55–76% ofpatients.Inourstudy,thepopulationachievingaPTH reduc-tion ≥30% at12 monthswas33.9%.Aswell asthis milder responseinourseries,wealsoobservedaprogressiveincrease inparicalcitoldoseusedduringthestudy,reachingdoublethe finaldosethatwasusedinthestudybyGonzález.14The pop-ulationofthestudybyAmer13isnotcomparabletothatof ourstudy asthepatientshad ashortperiodofdialysis(11 months),lowerinitialPTHlevels,andhalfofthepatientshad apre-emptivetransplant.
In our study, the induced changes in PTH correlated inversely withthe changesinserum calcium at6months; thereafter this correlation was lost. The mainpredictor of reductioninPTHwasthestartingvalueofPTH. Therewas noeffectfromthedegreeofrenalfunction,initialphosphorus level,ordoseofparicalcitolused.Thisrelationshipwastobe expected,giventhatpatientswhostartwithhigherPTH lev-elswillhavequantitativelygreaterreductionstomeetthefinal targetPTHlevel,comparedwiththosewithlowerPTHlevels, inwhomaslightreductionwillbringthemintothedesired PTHrange.
Somestudieshaveobservedarelationshipbetween par-icalcitol dose and degree of PTH reduction.1 In our study, paricalcitoldosewasdirectlyrelatedtotheinitialPTHlevelbut nottothefinalPTHlevel,andwasinverselyrelatedtocalcium levels.Thiswasprobablybecausetheparicalcitoldosesused ateachpointwereadjustedbythenephrologistaccordingto initialPTH levels and serum calcium levels, inmost cases aimingforamoderatePTHtargetratherthantryingto nor-maliseitcompletely.Thiswasdifferenttootherprospective controlledstudies,whichhad stricter,moreuniform proto-colswithincreasingdosesandmoreambitiousPTHgoalsthan thosedecidedbytheindividualnephrologistsinthisstudy.
Patientsthatwerepreviouslyontreatmentwithcalcitriol showedchangesinPTHsimilartopatientswithoutcalcitriol, butrequiredhigherparicalcitoldoses.Patientsontreatment with cinacalcet experienced progressive decreases in PTH, withdosesofparicalcitolsimilartothoseofpatientswithout cinacalcet.Combinedtreatmentwithparicalcitoland cinacal-cetwasappealingfrom a pathophysiologicalpoint ofview inthesepatients.Intransplantpatients,cinacalcethasbeen showntobecapableofresettingthesetpointofcalcium36,37 and increasing vitamin D receptors in parathyroid cells.38 Inpatientsonhaemodialysis,cinacalcethasbeenshownto reduceparathyroidglandsizeindependentlyoftheinitialsize. Thiswouldsuggestthatitcouldbeeffectiveincasesofnodular hyperplasia.39 In theremoved parathyroid glandsof trans-plantpatientswithhypercalcaemia,thereisreduceddensity ofcalcium sensingreceptors and VDR onlyinglands with nodularhyperplasia,whereasthisisalmostnormalincases ofdiffusehyperplasia.40Therateofparathyroidcell apopto-sisismuchhigheringlandswithdiffusehyperplasiathanin nodularhyperplasia,theseratesbeingevenhigherthanthose inpatients on haemodialysis.40 This apoptosis,along with lowerproliferation,couldexplainthepost-transplant reduc-tionseeninthesizeofparathyroidglands.41,42
ThenumberofvitaminDreceptorsandcalciumsensing receptorsinparathyroidcellsisreducedinrenalfailure40,43 andalsoimmediatelyfollowingrenaltransplant,43with sub-sequentnormalisationifthereisnonodularhyperplasia.16,40 Paricalcitol, unlike other vitamin D analogues, stimulates the expressionofcalcium-sensing receptors and exerts an antiproliferativeeffectonparathyroidcells.44Paricalcitolcan potentiatetheeffectofcinacalcetonparathyroidcellsand pro-moteafurtherdecreaseinPTH.Inourshortseriesofpatients wedidnotobserveanydifferencesincalciumlevelinpatients withcinacalcetcomparedtothosewithout.Iftherewasan increaseincalcaemia,cinacalcetprobablyhelpedtocontrol thisincrease;thusallowingtheuseofhigherparicalcitoldoses incasesofseverehyperparathyroidismtoslowglandular pro-ductionofPTH.Thedoseofcinacalcetuseddidnotchangein mostpatientsandinonepatientcinacalcetwasstopped.Itis notyetknowniftheaddedreductioninPTHlevelswith par-icalcitolcouldfacilitatethegradualwithdrawalofcinacalcet insomepatients.
Aswasfoundintheother2series,13,14overall,weobserved noincreaseincalciumlevels.Thiscouldbedueinparttothe nephrologists’cautionwithregardtoincreasingparicalcitol doses,increasing them graduallyaccording to the calcium levelsateachpoint(Fig.3).IntheseriesbyAmer,the inci-denceofhypercalcaemiawas20%.Thisforcedthemtostop
paricalcitol in 10% of patients. This hypercalcaemia could probablybeexplainedbythehigherdosesofparicalcitolused (2g/day), the concurrent administration of calcium sup-plementsalongwithparicalcitol,andthetendencytowards hypercalcaemiathatisseeninthefirstyearpost-transplant inasignificantproportionofpatients.
Weobservedthatchangesinserumcalciumdependedon thebaselinecalciumlevel:patientsthatbeganwithlower lev-els(Ca<9.6mg/dL)experiencedasmallincreaseintheirlevels, but theyremained within normallimits, whereas patients with Ca>9.9mg/dLhad nochanges in their levelsor even showedmilddecreases.Inaddition,abaselinecalciumlevel of<9.6mg/dLwasassociatedwithhigherbaselinePTHlevels andamoresignificantPTHreductionthaninpatientswith ahighercalciumlevel.Patientswithlowerbaselinecalcium hadslightlyworserenalfunction,higherbaselinePTHlevels, andhigherparicalcitoldoses,whichcouldexplainthe increas-ingtrendsinserumcalcium.Patientsbelongingtothehighest tercileofcalciumshowedareductionincalciumlevels.This was a consequence of reduced renal tubular reabsorption andreducedboneresorptionofcalciumduetoadecreasein PTH.
Levels of alkaline phosphatase decreased progressively, accompanyingthePTHdecrease,withapartialrelationship betweenchangesinPTHandchangesinalkalinephosphatase values. The VITAL study also foundthis relationship, sug-gesting that the decrease in alkaline phosphatase was a consequenceofnotonlyPTHreduction,butalsoadirect sup-pressiveeffectofparicalcitolonosteoblasts.1Inpatientswho hadhad previouscalcitrioltreatment,alkalinephosphatase levelswerehigheranddecreasedwithparicalcitolina par-allelwaytothatofpatientswhohadnotpreviouslyreceived calcitriol.Thesedecreaseswerenotobservedtoberelatedto anyfactor,andotherauthorshavefoundsimilarly.1 Immuno-suppressortypedidnotshowaneffectonchangesinalkaline phosphatase,althoughthesamplesizeofpatientswith m-TOR inhibitors was too small to be able to compare with patientsonanticalcineurintherapyanddrawdefinitive con-clusions.
Insummary,inthisstudywedescribethechangesinPTH in different subpopulations of long-term renal transplant patients withsecondary hyperparathyroidism treated with paricalcitol,withasignificantreductioninPTHlevelsforall PTH ranges.TheinitialPTHreductionwaspartiallyrelated toanincreaseinserumcalciumlevels,especiallyinpatients withlowerinitiallevels,althoughlaterthisrelationshipwas lost.Theresponsedidnotappeartodependonrenalfunction orinitialcalciumlevel.Patientswhohadpreviouslyreceived calcitrioltreatmentrequiredhigherdosesofparicalcitolthan thosewhohadnot.Patientsoncinacalcettreatmentshowed a good response on paricalcitol doses similar to those of patientswithout cinacalcet.Theuseofparicalcitolappears promising in renal transplant patients. A more ambitious treatmentofresidualsecondaryhyperparathyroidismcould be established, tosee what effects it would have on bone mineralisation, especially inlong-term transplant patients. In patientson cinacalcettreatment, acombined treatment withparicalcitolcouldbeused,directedatbettercontrolof PTH, and potentially evenallowing subsequentwithdrawal of cinacalcet. There remains to be studied the potential
beneficialeffectsofparicalcitolonbonemineralisationwhen PTHlevelsaresuccessfullyreducedtosuitablelevels.
Conflicts
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