The pleiotropic effects of paricalcitol: Beyond bone-mineral metabolism

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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

Review

The pleiotropic effects of paricalcitol: Beyond bone-mineral metabolism ^夽

Jesús Egido

^a,^∗

, Alberto Martínez-Castelao

^b

, Jordi Bover

^c

, Manuel Praga

^d

, José Vicente Torregrosa

^e

, Elvira Fernández-Giráldez

^f

, Carlos Solozábal

^g

aServiciodeNefrologíaeHipertensión,FundaciónJiménezDíaz,UniversidadAutonoma,Madrid,CIBERDEM,FRIAT,Spain

bServiciodeNefrología,HospitaldeBellvitge,L’HospitaletdeLlobregat,Barcelona,Spain

cServiciodeNefrología,FundaciónPuigvert,Barcelona,Spain

dServiciodeNefrología,Hospital12deOctubre,Madrid,Spain

eServiciodeNefrología,HospitalClínic,Barcelona,Spain

fServiciodeNefrología,HospitalUniversitarioArnaudeVilanova,Lleida,Spain

gServiciodeNefrología,HospitalVirgendelCamino,Pamplona,Navarra,Spain

a r t i c l e i n f o

Articlehistory:

Received28January2013 Accepted30October2015 Availableonline5April2016

Keywords:

VitaminD

Secondaryhyperparathyroidism Parathyroidhormone

Vascularcalcification Atherosclerosis Proteinuria Dialysis Transplant

a bs t r a c t

Secondaryhyperparathyroidism(SHPT)isacommoncomplicationinpatientswithchronic kidneydisease(CKD)thatischaracterisedbyelevatedparathyroidhormone(PTH)levels andaseriesofbone-mineralmetabolismanomalies.InpatientswithSHPT,treatmentwith paricalcitol,aselectivevitaminDreceptoractivator,hasbeenshowntoreducePTHlevels withminimalserumcalciumandphosphorusvariations.Theclassiceffectofparicalcitolis thatofamediatorinmineralandbonehomeostasis.However,recentstudieshavesuggested thatthebenefitsoftreatmentwithparicalcitolgobeyondPTHreductionand,forinstance, ithasapositiveeffectoncardiovasculardiseaseandsurvival.Theobjectiveofthisstudy istoreviewthemostsignificantstudiesontheso-calledpleiotropiceffectsofparicalcitol treatmentinpatientswithCKD.

夽Pleasecitethisarticleas:EgidoJ,Martínez-CastelaoA,BoverJ,PragaM,TorregrosaJV,Fernández-GiráldezE,etal.Efectospleiotrópicos delparicalcitol,másalládelmetabolismoóseo-mineral.Nefrología.2016;36:10–18.

∗ Correspondingauthor.

E-mailaddress:JEgido@fjd.es(J.Egido).

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Efectospleiotrópicosdelparicalcitol,másalládelmetabolismo óseo-mineral

Palabrasclave:

VitaminaD

Hiperparatiroidismosecundario Hormonaparatiroidea

Calcificaciónvascular Aterosclerosis Proteinuria Diálisis Trasplante

r e s u me n

Elhiperparatiroidismosecundario(HPTS)esunacomplicaciónhabitualenpacientescon enfermedad renal crónica que se caracteriza por unos niveles elevados de hormona paratiroidea(PTH)yunaseriedeanomalíasenelmetabolismomineral-óseo.Enpacientes conHPTS,eltratamientoconparicalcitol,unactivadorselectivodelosreceptoresdelavita- minaD,hademostradoreducirlosnivelesdePTHconmínimasvariacionesdelcalcioydel fósforoséricos.Elefectoclásicodeparicalcitoleseldemediadorenlahomeostasismin- eralyósea.Sinembargo,estudiosrecienteshanindicadoquelosbeneficiosdeltratamiento conparicalcitolvanmásalládelareduccióndePTH,porejemplo,ocasionandoefectos positivosenlaenfermedadcardiovascularyenlasupervivencia.Elobjetivodelpresente trabajoesrevisarlosestudiosmássignificativossobrelosllamadosefectospleiotrópicos deltratamientoconparicalcitolenpacientesconERC.

Introduction

TheclassicphysiologicalroleofthevitaminDhormonalsys- temisintheessentialregulationofbonemineralmetabolism.

1␣,25-dihydroxyvitaminD3bindswithahighaffinitytovita- minDreceptors(VDR)andregulatesserumlevelsofcalcium (Ca) and phosphorus (P) by increasing their absorption in the intestine, increasing calcium reabsorptionin the renal tubules,andsuppressingsecretionofparathyroidhormone (PTH),whichinturnisakeyregulatorofmineralmetabolism.¹ Thedecreasein1␣,25-dihydroxyvitaminD3levelsisattributed totheincreasedproductionofFGF23induced bytheaccu- mulationofphosphate,whichstimulatesFGF23production, even without an evident increase in serum P concentra- tion.Therefore,vitaminDdeficiencyplaysacentralrole in thedevelopmentofsecondaryhyperparathyroidism(SHPT), acommonearlycomplicationinpatientswithchronickid- neydisease(CKD)^2–4 thatprogressesasglomerularfiltration ratedecreases.⁴SHPTischaracterisedbyhighPTHlevelsand thepresenceofboneandmineralabnormalities.^1,2SHPTand abnormalmineralmetabolismleadtoclinicalconsequences at2levels:inthemusculoskeletalsystemandinthecardio- vascularsystem. Theconsequencesinthe musculoskeletal systemareduetoincreasedboneremodelling,themostcom- monconditionbeingosteitisfibrosa.Theconsequencesonthe vascularsystemarerelatedtotheincreasedriskofvascular calcification.²

TheusualtreatmentforSHPTinvolvesdietaryphospho- rus restrictionand drugs suchas phosphate binders, VDR activators(selectiveandnon-selective),and/orcalcimimetics suchascinacalcet.^2,3

ThefirstcommercialVDRactivator(VDRA)wascalcitriol.² Calcitriol is an important drug in the treatment of SHPT in patients with CKD. However, due to its potent effects onintestinalCaandPabsorption,this moleculefrequently induceshypercalcaemia,hyperphosphatemia,andrenalcal- culiformation,andincreasesthelikelihoodofcalcification.

In 1998, paricalcitol was approved for the treatment of SHPT.⁵Thisthird-generationvitaminDanalogueemergedin viewoftheneedfortreatmentsthatcouldinhibithighPTH concentrationsinpatientswithSHPT,withaminimaleffect onserumconcentrationsofCa,P,andthecalcium-phosphorus product(Ca×P),without renaltoxicity.⁴ Recently,paricalci- tolhasbeenreclassifiedbytheWorldHealthOrganisationto H05BX(otherantiparathyroidagents)ratherthanA11CC(vita- minDandanalogues).

ThebeneficialeffectofparicalcitolinreducingPTHlevels inpatientswithCKDiswidelyestablished.⁴ Itstherapeutic efficacy isduetothe tissueselectivityofitsmechanismof action.⁴ Paricalcitolisconsidered aselectiveVDR activator.

Theterm“selective”referstothedifferentialbindingofthe ligandtotheVDR.ThesynthesisofselectivevitaminDrecep- toractivators(sVDRA)suchasparicalcitolandmaxacalcitol cameaboutbecauseoftheclinicalneedtobroadenthethera- peuticwindowoftheclassicvitaminDformsandtotryto reducethe risk ofhypercalcaemia andhyperphosphatemia associated withthe non-selective derivatives calcitriol and alfacalcidol.SelectiveVDRAsallowmoreefficientinhibition ofPTHsynthesisandsecretion,withalessereffectonintesti- nalabsorptionofcalciumand phosphorus.⁶ Theselectivity ofparicalcitolisexplainedatabiochemicallevel bythe C- terminalofthevitaminDreceptor,whichistheregionthat bindsspecificallytotheligand.⁶

AlthoughcurrentclinicalpracticeguidelinesforCKDlimit theuseofVDRAstothetreatmentofSHPT,⁷theVDRhasbeen identifiedinmorethan30differenthumantissues(Table1).⁸ ThissuggeststhedifferentactionsthatvitaminDmayhave, inadditiontothoserelatedtoboneandmineralhomeostasis, givingwhatareknownasthe“non-classical”effectsofvitamin D.Sucheffectsincludeananti-inflammatoryimmunomodu- latoryeffectoncardiomyocyteremodelling,⁹arenalprotective effect,andtoalesserdegree,aneffectontheprogressionof vascularremodelling,particularlyinsomederivatives.

ThewidedisseminationofVDRsinhumantissuesexplains somepotentialeffectsinterms ofimprovedcardiovascular

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Table1–TissuedistributionofvitaminDreceptors.

System Tissue

Endocrine Parathyroid,pancreaticBcells,thyroidC cells

Cardiovascular Arterialsmoothmusclecells,cardiac myocytes

Musculoskeletal Osteoblasts,chondrocytes,striatedmuscle Gastrointestinal Oesophagus,stomach,intestine

Hepatic Liverparenchymalcells

Renal Tubules,juxtaglomerularapparatus(renin), podocytes

Reproductive Testicles,ovaries,uterus

Immune Tcells,Bcells,bonemarrow,thymus Respiratory Alveolarcellsofthelung

Epidermis Keratinocytes,hairfollicles Centralnervous

system

Neurons

structureand function, reducing the risk ofcardiovascular diseaseandmortality,particularlyinpatientswithCKD.⁶

Paricalcitol and survival in haemodialysis patients

SHPTaffectsto,atleast,halfofallpatientswithend-stage renaldisease on dialysis¹⁰ and isassociatedwithdifferent diseases and comorbidities,such asincreasedrisk offrac- ture,vascularcomplications, andinfections.Many ofthese comorbiditiesmayleadtohospitaladmission.Dobrezet al.

observedthatpatientstreatedwithparicalcitolhadalower riskofall-causehospitalisation(–14%;P<.0001),fewerhospi- talisationsperyear(–0.642;P<.001),andfewerhospitaldays peryear(–6.84;P<.001)thanpatientstreatedwithcalcitriol.¹⁰ Furthermore,severalepidemiologicalstudieshaveshown thesignificantsystemiceffectofVDRactivationonsurvival, inpatientswithSHPTonhaemodialysis.^5,11Theresultsofthe firststudydemonstratedthattreatmentwithparicalcitolled toamortalityratethatwas16%lower thanwiththeVDRA calcitriol(95%CI).⁵Inthatretrospectivecohortstudy,thedif- ferenceinsurvivalwassignificantat12monthsoftreatment and increased over time (P<.001) (Figure 1a).⁵ Withinthat study,therewasonesubgroupofpatientsthatchangedfrom treatmentwithcalcitrioltotreatmentwithparicalcitol.At2

years,thatsubgroupofpatientshadahighersurvivalratethan thesubgroupwhochangedfromtreatmentwithparicalcitol totreatmentwithcalcitriol(73%vs64%,P<.04)(Figure1b).⁵ Thesurvivaladvantageforpatientstreatedwithparicalcitol overthosetreatedwithcalcitriolappearstobeindependent ofbaselineserumlevelsofcalcium,phosphorus,andPTH.⁵

Inasecondretrospectivestudy,patientswhoreceivedi.v.

vitaminD(calcitriolorparicalcitol)showedasurvivalrate20%

higherthanthosewhodidnotreceivevitaminD(HR,0.80;95%

CI).¹¹Survivalat2yearswas75.6%inthegroupofpatientswho receivedvitaminD,vs58.7%inthegroupofpatientswhodid notreceivevitaminD(P<.001).¹¹Thesurvivaladvantagefor patientstreatedwithi.v.vitaminDoverwiththosenottreated withvitaminDalsoappearstobeindependentofbaseline calcium,phosphate,andPTHlevels(Figure2).¹¹

AnotherpublishedstudybyKalantar-Zadehetal.alsoasso- ciatedtreatmentwithparicalcitolwithimprovedsurvival,in a cohort ofpatients on maintenancehaemodialysis.¹² The authors observedthat treatmentwiththe vitaminDrecep- tor activator paricalcitol at any dose was associated with improvedsurvivalcomparedwiththosepatientswhowerenot treatedwithparicalcitol.^12,13Subsequently,Leeetal.compiled theresultsofthestudybyKalantar-Zadehetal.andsimilarly demonstrated thattheadministrationofparicalcitolatany dosewasassociatedwithimprovedsurvivalinsubgroupsof patientsonmaintenancehaemodialysis(Figure3).¹³

Possible mechanisms to explain the survival benefit associated with systemic activation of vitamin D receptors

Vascular protection: paricalcitol in vascular calcification, atherosclerosis,andcardiacstructureandfunction.

Patients with stage 5 CKDon dialysis have a high rate ofmortalityduetocardiovascularcomplications.^14–17Several studieshaveshownthatvitaminDdeficitandactivationof the vitaminDreceptorareassociatedwithvascularcalcifi- cationanddysfunctionandcardiovascularmortality,inboth thegeneralpopulationandinpatientswithCKD.¹Calcifica- tion ofvasculartissueiscommoninpatientswithCKD^14,16 andhashaemodynamicconsequences,suchaslossorarterial elasticity,increasedpulsewavevelocity,developmentofleft

100 90 80 70 60 50 40 30 20 10 0

0 5 10 15

a b

20 25 30 Paricalcitol

Calcitriol

Changed to calcitriol

Changed to paricalcitol

n=67.399 n=16.483

P=.001 P<.04

Follow-up (months)

Survival, % Survival, %

Follow-up (months)

35 40 0 5 10 15 20 25 30 35 40

Fig.1–(a)Survivalinpatientsonhaemodialysistreatedwithparicalcitoli.v.orcalcitriol.(b)Survivalofthesubgroupof patientsthatchangedfromtreatmentwithcalcitrioltoparicalcitolorfromtreatmentwithparicalcitoltocalcitriol⁵ Source:AdaptedfromTengetal.,⁵2003.

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1.3 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4

*

1 2 3

R R

a b

c

R

4 5 1 2 3 4 5

1 2

PTH quintiles

Calcium quintiles Phosphorus quintiles

Hazard ratio Hazard ratio

Hazard ratio

3 4 5

* *

*

* *

* * *

* *

* 1.3 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4

1.3 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4

Fig.2–HazardratiosofdeathaccordingtoquintilesofP(a),Ca(b),andPTH(c).Thedarkbarsrepresenttheeffectof receivinginjectablevitaminD,andthelightbarsrepresenttheeffectofnotreceivinginjectablevitaminD.R,reference category.^*P<.05.

Source:AdaptedfromTengetal.,¹¹2005.

ventricularhypertrophy,reduced coronaryarteryperfusion, myocardialischaemia,and heartfailure.¹⁷Thiscalcification occursat2distinctlevelsinthevessel:intheintimallayer, wereitisassociatedwithatherosclerosis,andinthemedial layer,whereitisassociatedwitharteriosclerosisduetofactors suchasage,diabetes,andend-stagerenalfailure.^14,17

Theexactmechanisms responsibleforthe development and progression of vascular calcification in patients with CKD are not completely known.¹⁶ For many years, it has been proposed thatvascular calcification isthe resultof a

1

0.8

0.5

0 1–4.99

Hazard ratio all-cause mortality No paricalcitol (reference)

PTH:

238

PTH:

229

PTH:

277

PTH:

358

PTH:

555 5.00–9.99

Paricalcitol treatment was associated with improved survival

Paricalcitol dose administered (µg/week) 10.00–14.99 ≥15.00

Fig.3–Relationshipbetweenparicalcitoldoseand mortalityrisk.

Source:AdaptedfromLeeetal.,¹³2007.

passive process, due to high phosphate levels and a high Ca×Pproduct.¹⁷However,recentstudieshaveshownarela- tionship betweenvascular calcification and osteogenesis,¹⁷ indicatingthatvascularcalcificationisanactively-regulated process.^17,18

Calcitriol and other vitamin D analogues are used for the treatment of SHPT, but there is some disagreement regarding whether or not these VDR activators directly accelerate thevascularcalcificationprocess.¹⁷ Forexample, in vitro and in vivo studies have demonstrated that calcitriol induces calcification at high doses. However, other VDRAs,such asparicalcitol,are less likely tocause hyper- calcaemia and hyperphosphatemia or to induce vascular calcification.¹⁶

VDRAs can have differential effects on vascular calcification, and these effects are independent of the Ca×P product,^14,16 serum levelsofCa andP,¹⁴ and PTH.¹⁶ Unlike paricalcitol, calcitriol^15,16 and doxercalciferol^14,16 appear to increase aortic calcium content in studies with uraemic post-nephrectomyrats.Evenmoreimportantly,calcitrioland doxercalciferol appeartoincreasethe expressionofCbfa-1 (RunX-2),atranscriptionfactorthatinitiatestheactivemech- anismsofvascularcalcification.¹⁶

It is known that vascular smooth muscle cells (VSMC) haveVDRsandcontaintheenzyme25-hydroxyvitaminD31␣- hydroxylase,indicatingthatvitaminDanditsanaloguesplay animportantroleinthefunctionandphysiologyofthiscell type.¹⁷InastudybyCardúsetal.,highdosesofcalcitriol,but notofparicalcitol,increasedcalcificationinVSMCsofpost- nephrectomyrats.¹⁸Thesamestudyshowedthattreatment

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with hypercalcaemiant doses of calcitriol increased pulse pressure(thedifferencebetweensystolicarterialpressureand diastolicarterialpressure),probablyduetotheextensivearte- rial calcification observed.In contrast,in rats treated with paricalcitol,noincreasewasobservedinaorticcalcification orpulsepressure.¹⁸

Noonanet al.quantified thefunctionalconsequencesof vascularcalcificationand observedthatparicalcitolhadno effectsonpulsewavevelocity,whereashighdosesofdoxer- calciferolincreasedpulsewavevelocityinpost-nephrectomy ratsat6weeksofstudy.

While the activation of VDRs can slow vascular calcification in induced uraemia, recent data also support the role of VDR activation in the prevention or slowing of atherosclerosis.⁸ VDRAs have shown a beneficial effect on thrombosis, inflammation, and vasodilatation, risk factors associatedwithendothelialfunctionandtheatherosclerotic process.¹⁹Accordingtoastudyperformedinprimarycultures ofhumanaorticsmoothmusclecells,VDRsmayplayarolein atherosclerosisbyregulatingplasminogenactivatorinhibitor- 1,thrombospondin-1,andthrombomodulin.Thus,VDRscould contributetothetherapeuticbenefitthatvitaminDanalogues haveinreducingmorbidityandmortalityriskinpatientswith stage5CKD.²⁰

Asubsequentstudyassessedtheprotectoreffectofpar- icalcitol,anangiotensin-convertingenzymeinhibitor(ACEI) (enalapril), and a combination ofboth, on oxidative dam- ageinatheroscleroticmiceaortas.²¹Inthestudy,paricalcitol alone, enalapril alone, and a combination of paricalcitol plus enalapril all prevented atherosclerotic plaque forma- tioninApoE21-deficientmiceandshowedaprotectoreffect against cardiac oxidative stress in uraemia.²² This protection against the inflammation and oxidative damage of atherosclerosis was greater with the combined ther- apy(enalapril+paricalcitol)thanwithmonotherapy.²¹Inthe resultsof the study,it was observedthat both paricalcitol andenalaprilasmonotherapies,aswellasthecombination ofthetwo,reducedtheconcentrationoftheenzymeaortic malondialdehyde(MDA)andincreasedlevelsoftheenzyme glutathioneperoxidase(GSH-Px).²¹BoththereductionofMDA levelsandtheincreaseinGSH-Pxlevelsareindicativeofthe protectoreffectofparicalcitol,enalapril,andthecombination ofboth,inthismodelofatheroscleroticmice.²¹ Inaddition, paricalcitolalsoappearstoimproveendothelialfunctionin uraemicratsinadose-dependentmannerandindependently ofPTHlevelsandbloodpressure.¹⁹

Inaddition,itisthoughtthatparicalcitolisassociatedwith alowercardiovascularmorbidity,possiblyduetomodification ofcardiacstructureandfunction.^23,24ThePRIMOstudydealt withdeterminingtheeffectsofparicalcitolonleftventricular massoveraperiodof48weeksinpatientswithCKDandleft ventricularhypertrophy.^23,24Duringthestudyperiod,parical- citoldidnotreduceleftventricularmassorimprovecertain Dopplermeasurementsofdiastolicfunction,butitdidappear tobeassociatedwithfewerhospitalisationsforcardiovascu- larcauses.²³InaposthocanalysisofthePRIMOstudy,there wasasignificantreductioninleftventricularvolumeindexin thegroupofpatientstreatedwithparicalcitolcomparedwith thoseintheplacebogroup(P=.002).²⁴

Renalprotection:reductionofproteinuriaandrenal fibrosis

Severalstudieshavedemonstratedtherenoprotectiveeffect ofvitaminDanaloguesinexperimentalanimalmodelswith glomerulardisease.²⁵

Diabeticnephropathy,whichischaracterisedbyglomeru- lar lesions, inflammatory infiltration, tubular atrophy, and interstitialfibrosis,²⁶isoneofthemostcomplexrenaldiseases and isoften associated with cardiovascular complications.

TubulointerstitialdamageorfibrosisinCKDleadstoend-stage renalfailure.²⁷Inamousemodelwithinterstitialobstructive nephropathy due to unilateral ureteric ligation,²⁷ paricalcitol reduced interstitialinflammation and the production and accumulation ofinterstitialmatrix components (colla- genandfibronectin).Inthismodel,paricalcitolalsoinhibited the transition of epithelial cells to mesenchymal cells, a processthatispartlyresponsibleforrenalfibrosis.²⁷Inaddi- tion,paricalcitolrestoredthenumberofVDRsinobstructive nephropathy.²⁷ Paricalcitolalsoblockedinvitroandinvivo expressionoftheSnailgene,Snailbeingatranscriptionfactor thatplaysacrucialroleininitiatingepithelialtomesenchy- maltransition.Theseresultsindicatethatthebeneficialeffect of paricalcitol is associated with its capacity to preserve thetubularepithelialphenotypebysuppressingtransition.²⁷ Likewise, paricalcitol has a beneficial inhibitory effect on renal inflammation thanks to signalling-sequestration of nucleartranscriptionfactorssuchasnuclearfactorkappaB (NF-KB).²⁶

Theurinaryprotein/albuminratioisanimportantmarker of renal and cardiovascular disease^28,29 that is associated withCKDprogression.¹ Increasedurinaryproteinreflectsa higherdegreeofglomerulardiseaseorunderlyingrenaltubu- lardysfunction,¹andplaysadirectroleinprogressionofrenal andcardiovasculardisease.^1,28,29

The renin–angiotensin–aldosterone system (RAAS) has been identified as an important mediator of progressive renaldamageindiabeticnephropathy.Thedrugsthataffect the RAAS, such as ACEIs and angiotensin receptor block- ers(ARBs),candelaycardiovascularandrenalmorbidityand mortality.³⁰ However, residual proteinuria may be high in patients thatreceivethese treatments¹; therefore,different treatmentstrategiesareneededtoreducethatresidualrisk.¹ Recent studies haveshown that the selectiveactivation of VDRs could be ofrelevance in the reducing proteinuria in patientswithCKD.²⁹

Inaposthocanalysisofarandomisedtrialthatassessed the efficacy oforalparicalcitolin reducingPTH inpatients with CKD,^3,4 a reduction in proteinuria was observed in more than 50% of the patients treated with paricalcitol.

This reductionwas independentofconcomitant treatment with RAAS inhibitors (P=.004).²⁸ In another randomised double-blindstudy,paricalcitolsignificantlyreducedprotein excretionmeasuredbytheurinaryprotein-creatinineratioat baselineandattheendofthestudyin2groupsofpatients:

one treatedwithparicalcitoland the other withplacebo.²⁹ In oneshortstudy, 24 patientswere randomlyassigned to receive placebo, 1␮g of paricalcitol, or 2␮gof paricalcitol.

Followingevaluation,areductioninproteinuriawasobserved

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A

15

B

10

–15

P=.071

Change in UACR, %

P=.23 P=.053 –25

–35

1µg paricalcitol

Placebo 2µg

paricalcitol Combination

of paricalcitol groups

30 40

20 10

–10 –20 –30 –40 0

Placebo 1µg paricalcitol 2µg paricalcitol

Change in UACR, %

Treatment phase Withdrawal phase

–10

–20

–30 5

–5 0

Fig.4–Changesinurinaryalbumin-creatinineratiofrombaselineleveltoendoftreatment(A)andduringtreatmentandon withdrawal(B).

Source:AdaptedfromZeeuwetal.,²⁸2010.

inpatientsonparicalcitol,independentlyofhaemodynamic changesorreductioninPTHlevels.³¹

TheVITALstudyshowedthattreatmentfor24weekswith 2␮gofparicalcitolreducedresidualalbuminuriainpatients withtype2diabetesmellitusandkidney diseasethatwere beingtreatedwithstabledosesofACEIsorARBs.³⁰Thechange intheurinaryalbumin-creatinineratio(UACR)frombaseline levelto theend oftreatment wasgreater in thegroups of patientstreatedwithparicalcitol(1or2␮g)thanintheplacebo group (P=.071). Fig. 4 shows how the differences in UACR appearedtohaveadose-responserelationshipwiththeuseof paricalcitol,indicatingthatparicalcitolcouldbeanimportant adjuvanttreatmentinthereductionofresidualalbuminuria.³⁰ Arecently-published meta-analysisof9studies (n=832) byChenget al.confirmedthe beneficialeffect ofparicalci- tolinreducingproteinuria(P=.001)withoutincreasedriskof adverseeffects.³²

Paricalcitolasanimmunomodulatoryand anti-inflammatoryagent

Several epidemiological studies have associated vitamin D deficiency with an increased susceptibility to immune- mediated diseases, including chronic infections and autoimmune diseases.³³ Systemic inflammatory processes are common inpatients withCKD and constitute amarker of poorprognosis.¹Itisalsoknownthatimmunecellsexpress vitamin D activator enzymes, allowing local conversion of inactivevitaminDtoitsactiveform1,25(OH)(2)D(3).³³These data indicate that vitamin D plays a role in maintaining immunehomeostasis.³³ Several studies haveevaluatedthe immunomodulatoryeffectofparicalcitolandotherVDRAsin thisarea.^25,30,33

Paricalcitol and calcitriol have been demonstrated to reduce differentiation of immature dendritic cells from monocytes and their activation capacity.²⁵ The prevention of dendritic cell maturation may play an important role in the prevention of autoimmune diseases, including atherosclerosis.²⁵Theimmunomodulatoryactionofvitamin

D also occurs through regulation of the activity of different typesofimmunecells,suchasmacrophages,dendritic cells,andTcells,^33,34andregulationofexpressionofthepro- inflammatorycytokinesRANTESandTNF-␣.³⁴

Tanetal.alsoobservedabeneficialeffectfromparicalcitol on the inhibition of renal inflammation, due to sequestration of NF-KB signalling.³⁴ Another short, randomised double-blind study in patients withCKD showed asignifi- cantreductionofserumconcentrationofC-reactiveprotein (CRP),measuredusingahigh-sensitivitymethod.³¹Likewise, paricalcitol was associated with inflammation modulation in patients on haemodialysis by a reduction in inflammatory biomarkers such as CRPand TNF-␣ and improved IL-6/IL-10andTNF-␣/IL-10ratios.³⁵Theseanti-inflammatory effectsofparicalcitolwereindependentofiPTHconcentration (Figure5).³⁵

InanotherrecentlypublishedstudybySánchez-Ni ˜noetal., ananti-inflammatoryeffectwasobservedforbothparicalci- tolandcalcitriol inanexperimentalmodelusing ratswith streptomycin-induced diabetes. Calcitriol and paricalcitol reducedthe expressionoftheanti-inflammatorymediators fibronectinandreninincultivatedpodocytes.TheseVDRAs reducedglomerularinflammationevenatsub-antiproteinuric doses.³⁶

4 3 2 1 0 –1 –2 –3 –4 –5 –6

P=.05

P=.01

TNFα/IL10 IL/IL10 IL6/IL10 IL18/IL10

Fig.5–Changesintheratioofpro-/anti-inflammatory cytokines.

Source:AdaptedfromNavarro-Gonzálezetal.,2011.

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Importanceofparicalcitolintransplantpatients

Anormal-functioningrenaltransplantcorrectstheendocrine and metabolic imbalances secondary to renal function deterioration.^37,38However,afterrenaltransplant,persistent elevation ofPTH is observed ina considerable percentage of patients. Whilst it usually returns to normal slowly in patientswithnormalgraftfunction,inpatientswithmildor moderatedeteriorationofrenalfunctionitcanpersistindef- initely.ThepersistenceofhighPTHisariskfactorforloss ofbonemassandincreasedriskoffracture.Reduced bone mineraldensityhasalsobeenassociatedwithanincreased riskofatherosclerosis.³⁹Therefore,bettercontrolofPTHmay improvebothaspects.

Furthermore, several studies have shown that at one yearpost-transplant,proteinuriaispresent inupto45%of patients; intwothirdsofthesepatients, thelevel isbelow 500mg/day.^40,41Proteinuriaisoneofthefactorsthatsignifi- cantlypredisposestoreducedrenalgraftsurvival.⁴²

Asthereisacertaindegreeofsimilaritybetweenchronic graftdiseaseandchronickidneydisease,iscanbeassumed, logically,thatantiproteinurictherapeuticapproachescouldbe beneficialinrenaltransplantpatients.^43,44 Ashasbeenseen throughoutthisreview,inpatientswithCKD,paricalcitolhas been shown to be capableof reducing proteinuria in both patientswithSHPTandthosewithnormalPTHlevels.

Experiencewithparicalcitolinrenaltransplantpatientsis limited;however,inthefewstudiesthathavebeenpublished, paricalcitolappearstohavebeeneffectiveinimprovingcon- trolofPTHandproteinuriainthisgroupofpatients.

Inaretrospectivestudythatincluded58renaltransplant patientswithsecondaryhyperparathyroidism,treatmentwith paricalcitolsignificantlyreducedserumiPTHlevelsandpro- teinuria (35% decrease relative to baseline levels). Renal functionremainedstableduringtreatmentwithparicalcitol, with asignificant difference comparedwith the deteriora- tionobservedinthe2yearspriortotreatment.⁴⁵Inanother, prospectivestudyinapopulation of46 transplantpatients thatassessedurinarypeptidome,treatmentwith1␮g/dayof paricalcitolfor3monthseffectivelyreducedPTHlevelsand notably modified the urinary peptide profile.³⁷ In another study, published only as an abstract, that compared the useofdifferentvitaminDanaloguesinpatientswithrenal transplant,treatmentwithparicalcitolwasassociatedwitha greaterreductioninproteinuria.⁴⁶

Toxicity from calcineurin inhibitors is one of the most significantcausesofchronicgraftdisease.Atanexperimen- tal level, it has been observed that paricalcitol attenuates cyclosporine-induced nephropathy, suppressing interstitial inflammationandfibrosisandepithelialtubulecellfibrosis.⁴⁷ This could be, therefore, an additional beneficial effect of paricalcitol in renal transplant patients on calcineurin inhibitors.

Conclusions

Paricalcitol, a third-generation VDRA, provides effective control of SHPT with minimal hypercalcaemic and hyper- phosphatemiceffects.⁴Itstherapeuticefficacyisduetothe

tissueselectivityofitsmechanismofaction,asitdoesnotup- regulatetheintestinalvitaminDreceptorandislessactive thancalcitriolatabonelevel.⁴

Recentstudieshaveindicatedthatthebenefitsofparical- citolgobeyondthereductionofPTHandboneandmineral homeostaticcontrol.Thisreviewshowsthatthepleiotropic effectsofparicalcitolon cardiovascularstructureand function,proteinuria,andimmunefunction,amongstothers,^1,8,9 mayexplaintheincreasedsurvivalrateobservedinpatients withCKDtreatedwithparicalcitol.⁵

Althoughmoreexperienceisneeded,useofparicalcitolin renaltransplantpatientsappearstobeasafeandpromising optionforimprovingcontrolofhighPHTlevelsandprotein- uria.

Conflicts of interest

Theauthorsdeclarethefollowingpotentialconflictsofinter- est:

DrJordiBoverhasgiventalkssponsoredbyAbbott(Abb- vie), Amgen,Genzyme, andShire.He hasalsoparticipated innationalandinternationaladvisorycommitteesforAbbott (Abbvie),Amgen,andGenzyme.

DrAlbertoMartínezhasreceivedresearchgrantsandhas giventalkssponsoredbyAbbott(Abbvie),Amgen,Boëhringer- Ingelheim,Esteve,Janssen-Cilag,Novartis,Roche,andShire.

HehasalsoparticipatedinadvisoryboardsforAbbott(Abbvie), Amgen,Esteve,Roche,andShire.

Dr Egido has performed work as scientific advisor, and hasreceivedresearchfundingandgiventakkssponsoredby Abbott(Abbvie).

DrElviraFernandez-Giraldezhasreceivedresearchfunding andhasgiventalkssponsoredbyAbbott(Abbvie).

DrCarlosSolozabalhasgiventalkssponsoredbyAbbott (Abbvie).

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The pleiotropic effects of paricalcitol: Beyond bone-mineral metabolism

Review