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RevistadelaSociedadEspañoladeNefrología

www . r e v i s t a n e f r o l o g i a . c o m

Original

article

Effect

of

paricalcitol

on

mineral

bone

metabolism

in

kidney

transplant

recipients

with

secondary

hyperparathyroidism

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

e

aServiciodeNefrología,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±1.9␮g/week, 12 months 5.2±2.4␮g/week; 24 months 6.0±2.9␮g/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

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/).

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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±1,9␮g/semana,12meses

5,2±2,4␮g/semana;24 meses6,0±2,9␮g/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

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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

2–3␮gper 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

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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±1.9␮g/week, median 3␮g/week, and

range 1–10␮g/week.Adose lower than 3␮g/week was

pre-scribedin16patients(23.2%);3␮g/weekwasprescribedin30

patients (43.5%);4–6␮g/weekwasprescribed in11 patients

(15.9%); 7␮g/week was prescribed in 11 patients (15.9%);

and 10␮g/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±1.9␮g/week; at6months,

4.4±2.2␮g/week; at 12months, 4.9±2.4␮g/week; at 18

months,5.3±2.3␮g/week;andat24months,5.9±2.8␮g/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.

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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,

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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

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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±1.8␮gparicalcitol/␮gcalcitriol (median,3.4;range,1–8␮gparicalcitol/␮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±1.9␮g/week.Thisdosewassimilarinpatients not taking cinacalcet (3.8±1.9␮g/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

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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 patientsreceived1␮g/dayofparicalcitolfromthe thirdday post-transplant,increasingto2␮g/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 of1␮g/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.

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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 (2␮g/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

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beneficialeffectsofparicalcitolonbonemineralisationwhen PTHlevelsaresuccessfullyreducedtosuitablelevels.

Conflicts

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interest

Theauthorsdeclarenoconflictsofinterest.

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