prof. Mohsen el kossi

1. By
Mohsen El Kossi
MBBCh, MSc, MD, FRCPE
Consultant Renal Physician Doncaster Royal Infirmary

2. CKD-MBD
(ChronicKidneyDisease-MineralandBoneDisorder)
 Formerlyknownrenalosteodystrophy(reflectsskeletaleffectsonly).
 In2005:KDGIOhassuggestedthisterm asasystemicsyndromesecondary toCKD
tocoverthewiderimplications:
 Biochemicalchanges(Pi,Ca,PTHandvitaminD).
 Skeletalchanges.
 Softtissueincludingvascularcalcification.
(KDIGO CKD-MBDguidelines, KidneyInt Suppl.2009;(113):S1-130)

3. SoftTissueCalcification
(VascularandValvular)

4. WhyBoneHealthPostKidneyTransplantationIs
Important?
 Bonehealthisamajorcauseofmorbidityandmortalityafterkidney
transplantation.
 Fractureriskis300%higherinkidneytransplantpatientsversushealthy
individualsand30%higher than dialysispatientsinthefirstyearafterkidney
transplantation.
 Interplayofpre-transplantCKD-MBD,immunosuppression andpost
transplantationCKDdeterminesbonehealthpostkidneytransplantation.
ZhangandChouhanWorldJTransplant.2012;1(5):127-133.

5. ImplicationsofBoneDysfunction
 Criticalbonefunctionsaremechanical strengthandmineralmetabolicactivity
 Mechanical strengthisachievedbycorticalboneandisimpairedbyfractures
 Mineralactivityisachievedbycancellousboneandboneturnoverandbothcan
resultindisturbanceincalciumhomeostasisandvascular/softtissuecalcification

6. HighTurnover
(OF)
Abnormal
Mineralisation(OM)
LowTurnover
(AD)
Mixed
SkeletalChanges(TMV)
(1)Turnover (2)Mineralisation (3)Volume

7. PreTransplantCategoriesofOsteodystrophy
1-OstitisFibrosaCystica
 SecondaryortertiaryHPTH.
 Highturnoverbonedisease.
 Corticalboneloss,increasedosteoclastactivity,endo-ostealfibrosis.
 Biochemically:highCa,PTH,Pi,APandosteocalcin.
(Mallucheetal,NatRevNephrol.2010;6:32-40)

8. PreTransplantCategoriesofOsteodystrophy
2-AdynamicBoneDisease
 OversuppressionofPTH.
 Patientsatrisk:elderly,peritonealdialysis,cabasedbinders,over-suppressed PTH.
 Lowcellularactivity(fewosteoblastsandosteoclasts)withthinosteoid.
 Lossofcancellous bone.
 Highcardiovascular andsofttissuecalcificationwithhighmortality.
 Biochemically:HighCa,lowPTHandAP.

9. PreTransplantCategoriesofOsteodystrophy
3-Osteomalacia
 Defectivemineralization.
 Riskfactors:hypophosphataemia,lowvitaminD,andaluminum
intoxication(lackofwaterpurificationinthepast).
 Wideun-menralizedosteoid,absent/fewosteoblastandosteoclasts.
 Biochemically:lowphosphate,Ca,andnormaltohighPTHandAP.

10. PreTransplantCategoriesofOsteodystrophy
4-Osteopenia
 DiagnosedbylowBMDonDEXAscan.
 Riskfactors:females,elderly,malnutrition,immobility,Caucasians,
hypogonadism,metabolicacidosis,longtermuseofsteroids.
 Nospecificbiochemicalabnormality.

12. PreTransplantCategoriesofOsteodystrophy
5-DialysisRelatedAmyloidosis
 B2-microglobulinwithlyticbonelesionsanddestructivearthropathy.
 ArthriticsymptomsimprovepostTransplantation butlyticlesions
persist.
Zhangetal,AmJMedSci;2008.335:120-125

13. Corticosteroids
 Increasedriskofvertebralfracturewithanoraldoseofprednisoloneofas lowas2.5mg/d.
 Maximumreductioninbonevolumeoccursinthefirst6monthpost-transplantation.
 Inhibit osteoblastproliferationandfunction.
 Stimulate osteoblastapoptosis.
 Promoteboneresorptionbystimulatingosteoclastogenesis.
 Negativecalciumbalancethroughreducingintestinalabsorptionandincreasing urinary
excretion.
 Lessmobilitywithmuscleweakness.
 Inducehypogonadotrophichypogonadism.

14. Recommendations
 Theleastpossibleorsteroidavoidanceduetomultiplenegativeeffectsonbonemetabolism.
 Reducesteroidtominimizeriskoffractureforthosewithpre-transplantosteoporosis.
 Reducedriskoffractureandrelatedhospitalizationinsteroidfree kidneytransplantpts(USRDS
data).
 Becautiousinimmunologicallyhighriskrecipientstoavoidrejectionandincreasingsteroid
pulses.

15. CalcinurinInhibitors
Cyclosporine
 NoclearcutevidencetolinkCNIwithfractures.(Pateletal1993).
 Cyclosporineisassociatedwithreducedbonevolumeinratsbutnot
foundinsteroidfreecasesofkidneytransplantrecipients.
 TacrolimusinlivertransplantshowedratherhigherBMDinfemoral
neckcomparedtocyclosporine.

16. Sirolimus
 Sirolimus mayhaveapositiveeffectonBMD.
Markersofboneturnover,osteocalcinandN-telopeptidesarehigherin
cyclosporinetreatedpatientscomparedtosirolimusin115patientsoverayear
after kidneytransplantation.

17. SirolimusVs Cyclosporine

18. MMFandAzathioprine
Nocleareffect ofMMForAzawasdemonstratedonbonehealth after
kidneytransplantation.

19. PostKidneyTransplantationBoneMineralChanges
 Anyofpretransplantformscouldpersist.
 Evolutionintodifferentforms.
 Uniqueforms.
 Bonepainsyndrome
 Osteonecrosis.
 Fractures
 Biochemicalchanges.

20. Post-kidneyTransplantBoneMineralChanges
1-BonePainSyndrome
 10%ofposttransplantationpatientsexperiencedeepseatedpainmorein
thelowerlimbs.
 CNIisproposedtobethecause(?vasoconstriction).
 Cachannelblockersmayhelpprobablyduetovasodilatoreffectofthe
intraosseusvasoconstrictioninducedbyCNI.
(GrotzetalTransplantInt2001.14:16-23.)

21. Post-kidneyTransplantBoneMineralChanges
2-Osteonecrosis
 6-24monthposttransplantationaffectaround15%ofpts.
 Commoninthefemoralheadsbutcanoccurinknees,shouldersor
elbow.
 Jointpainisthepresentingsymptom.
 MRIistheinvestigationofchoice.
 Mainriskfactoriscumulativesteroiddose,DMandLupus.
 Management:rest,decompression,vascularisedbonegraftandjoint
replacement.

22. Avascular Necrosis

23. Post-kidneyTransplantationBoneMineralChanges
3-Fractures
 Kidneytransplantrecipientsareatincreasedriskoffracturecomparedtogeneral
populationordialysispatients(20%experiencefracture).
 Fractureriskissimilartopostmenopausal women.
 Fracturereducesrecipientsurvival(60%mortality).
 Classicpatientsatincreasedrisk:women,withlowbodyweight(<70kilo),White
andAsian.

24. FracturePost-kidneyTransplantation
FRAX(FractureRiskAssessmentTool)
 Predictriskofmajorfractureover10yearsinthegeneralpopulation.
 Majorfracturesareproximalhumorous,forearm,hipandvertebral.
 Variablesareage,sex,alcoholusemorethan3units/day,smoking, glucocorticoid
use,rheumatoidarthritis, BMI,hipBMDandparentalhipfracture.
 Thistoolneedsadjustment toincludetransplantationspecificfactorsand
validationtoworkinkidneytransplantpatients.
 AstudyexploredFRAXintransplantationpatientsandareaunderROC0.62but
thestudypowerwaslow(21 fracturesonly)(Nayloretal2014).

25. 3-Fractures
 Commonsitesarehips,anklesandfeet.
 Systematicreviewdeniedtheclassicriskfactors ageandsexasafracture
riskinrenal transplantation.(Nayloretal2013).
 Alcoholintakewastheonlyconsistentriskfactorinarecentstudy.
(Nayloretal2014)
(Nayloretal,WorldJTransplant.2016;6(2):370-9).

26. DEXAScanandFractureRisk
 Limitations:doesnotassessmicroarcticture,doesnotdifferentiate
trabecular fromcortical andreliesonarealratherthanvolumetric,
nearbyvascularcalcificationcanconfoundtheresult.
 InonestudyreducedBMD,osteopeniaandosteoporosisbyDEXAcarries
higherriskoffracture.(Akaberietal2008)
 It’snotvalidinchildren.(Wesseling-Perry and Bacchetta 2011)
 MicroCTandMRIwitharesolutionof8umareunderinvestigation.
(Leaonard MB2009)

27.  Incidenceofhipfracture afterkidneytransplantationhasdeclinedinthe
intervalbetween1997and2010withhazardratiointheyear2010is0.56
comparedto1997.
 Thereasonofdeclineisprobablylessuseofsteroidswiththeuseofmore
specificimmunosuppression

28. TrendsofHipFractureAfterKidneyTransplantation

29. Post-kidneyTransplantationBoneMineralChanges
4-BiochemicalChanges
 DramaticdropofserumPi,Mg,andPTHearlyposttransplant.
 Initialimprovementof25(OH)and1,25(OH)2vitaminD.
 ThesechangesarefollowedbypersistentlowlevelsofvitaminDduetohighFGF23.
 Subsetofpatientshavepersistenthyperparathyroidismeither duetoautonomous
glandand/orlowvitaminDlevels.
 PersistenthighPTHcaninducehypercalcaemia.

30. Post-kidneyTransplantationBoneMineralChanges
 Serialanalysisofboneparametersin129 CyAandsteroidtreatedkidney
transplants:
 Serumphosphorusremainedatlownormal(0.98mmol/l)12month
aftertransplant.
 BonespecificAPpeakedat5month.
 SerumPTHcorrelatedwithgraftfunction.
 1,25VitaminDwaslownormalfrommonth2althoughwasgradually
improving.
(Reinhardtetal1998)

31. BiochemicalChanges
PTH & Ca
Vit D
P, FGF23,
Klotho
eGFR

32. PTHSerumLevelsAfterKidneyTransplantation
 Sharpdropinthefirst3-6monthfollowedbygradualreduction.
 25%ofpatientswithnormalrenaltransplantfunctionhavepersistentelevationofPTHafter1
year.(variesbetween17-50%)
 RiskfactorsforpersistentPTHelevationaredurationofCKD,elevatedalkalinephosphatase,
highPTHandphosphatelevelspretransplant.
 NocorrelationbetweenserumPTHlevelsandboneturnover.
 LowvitaminDserumlevelsandreceptorsandreducedCasensingreceptorsinducepersistent
PTHelevation.

33. Hypophosphataemia
 Described beforeCNIera‘Hypophosphataemicosteomalacia’followingkidney
transplant.(Moorehead etal1974)
 Oneofthe commonbonemineraldisordersintheearlyposttransplantperiod(2
weeks-3month). (Massarietal1997)
 Commonly transient butcanpersistforyears.
 Possiblemechanisms:
 Hyperparathyroidism (Levi2001),(canoccurwithnormalPTH).
 Persistently elevatedFGF23(Bhanetal2006).
 Renaldenervation (Mannetal1992).
 CNI (LeeandKim2007).

34. 1-Hypercalcaemia
 Usuallyhighestinthefirst3monthposttransplantation.
 5-10%hashypercalcaemia followingfirstyearoftransplantation.
 PersistentelevationofPTHandhypercalcaemia cancausemicrocalcificationinthe
renalgraftwithimpairedfunction.

35. 2-Hypercalcaemia
 Riskfactors,highserumPTHpre-transplantparticularlywithcinacalcet
withdrawal.
 Pre-transplantcinacalcetdoseisapredictorofposttransplant
hypercalcaemia.
 HigherproportionofpatientswithsimilarPTHandcalciumlevelsbut
wasoncinacalcetdevelophypercalcaemia3monthpostTxpcompared
tothosewhowerenot.
 PTHincreasesrenaltubularCaabsorption,stimulatessynthesisof
calcitriolwithincreasedintestinalcaabsorptionandincreasedbone
resorption.

36. 3-Hypercalcaemia
 Impactongraftfunction:
 Vasoconstrictionwithacuteandchronicgraftdysfunction.
 Tubulointerstitial microcalcification.
 Reportedcasesofpancreatitis.
 Softtissueandvascularcalcification.
 Persistenthypercalcaemiareflectsdeterioratingbonedisorders.

37. 4-Hypercalcaemia
 Managementdependson:
 Calevel<(11mg/lor2.75mmol/l)
 Duration<(3-6month).
 Symptoms.
 PTH>120pg/l.
 Watchfulwaitingotherwise options:
 PTHectomy(hungrybone,complications,graftdysfunction?).
 Calaemimetics(graftdysfunction??,cost,recurrence)
 Bisphosphonates.

38. AlgorithmofHypercalcaemiaManagement
(AdoptedfromTorregrosaetal2013)

39. Hypophosphataemia
 Common 40% within 6 month post kidney Txp
 Potential causes:
 Enhanced renal excretion with improved eGFR
 Persistently high FGF23
 Calcitriol deficiency
 Glucocorticoid therapy
 High PTH
 Impaired renal tubular absorption

40. Hypomagnesaemia
 Commoninthefirstfewweekspostkidneytransplantation.
 Morefrequentwithcyclosporineduetoimpairedtubularmagnesium
reabsorption.
 APredictorofdevelopingnewonsetDM.
 RapidrateofgraftlossinchronicCNInephrotoxicity.(Mazzolaetal
2003)
 NointerventiontoknowtheimpactofMgreplacementongraft
function.

41. MineralChangesinChildrenAfterKidneyTransplantation(Bonthuis
etal2015)
 Datafrom1237kidneytransplantchildren (0-17years)from10Europeancountries.
 25%withabnormalserumphosphoruslevels.
 14%hypophosphatemiaand11%hyperphosphatemia.
 30%withabnormalserumcalciumlevels.
 19%hypocalcemia, 11%hypercalcemia.
 41%ofthepatientswithhyperparathyroidism.
 HighserumphosphorusisassociatedwithgraftfailureindependentlyofeGFR.

42. BoneHealthAfterSKPT
 TypeIDMisariskfactorforcorticalosteopenia.
 InSwedishstudyosteoporoticfractureoccurredin40%oftypeIdiabetic
transplantscomparedto11%nondiabetic.
 SimilarresultswerefoundinaDutchsuccessfulSPKT,with45%
experiencednon-vertebralfractureandcorticalosteoporosis58%.
(Smetsetal1998)

43. ValuetoIdentifyUnderlyingBonePathology
 Therapeuticapproachiscompletelydifferent.
 HighturnoverrequiresPTHsuppression.
 Lowturnoveravoidexcessivedosesofcalciumand/orvitaminD.
 LowmineralisationrequiresvitaminD.
 Lowvolumeischallengingasbisphosephonatesareinhibitorsofbone
turnover.

44. PostTransplant
 HighTurnover(OF):
 Chronicallograftnephropathy,hyperparathyroidism.
 LowTurnover(AD):
 Steroids,Bisphosphonates,CNI,mTORinhibitors,PTHectomy.
 Reducescancellousbonevolume.
 Osteomalacia:
 VitaminDdeficiency -Hypophosphataemia.
 Osteoporosis
 Avascularnecrosis

45. BoneChangesAfterKidneyDonation
 Lowered1,25(OH)2Colecalciferolconcentration,andslightriseinPTH.
 NoeffectonserumCa,uncleareffectonFGF23.
 Fractureriskiscomparabletogeneralpopulation.
 2000kidneydonors,43yearsold,medianfollowup6.6yearsosteoporotic
fracturesimilartogeneralpopulation.
 Fracturerisk(16.4vs18.7events/10,000person-years).Gargetal2012.

46. MedicationsForBoneDisordersAfterKidney
Transplantation

47. 1-Calcimimetics
 Clacimimeticsincreasecalciumsensingreceptorsensitivitytocalcium
suppressingPTHsecretion.
 CinacalcetreducesserumPTH,Caandincreaseserumphosphate
withoutaffectinggraftfunctioninarecentRCTof154patients.
 Systematicreviewof nonRCT(21studies)with411kidneytransplant
patients,cinacalcetwassafe.
 Hypercalciuriaisasideeffectofcinacalcettreatmentbut noevidenceof
nephrocalcinosis.

48. CinacalcetreducedserumCalevelwithnonsignificant
reductionineGFRcomparedtocontrols.

49. SerumPTH
RiseofserumPTHfollowingdiscontinuationofCinacalcet.

50. BMD
CinacalcetimprovedBMDatthefemoralneckandlumber
spinebutworseneditatdistalradius

51. Calcimimetics
 Lowserumphosphatelevelwascorrectedbycinacalcet (26%increase)
duetoincreasedurinaryphosphatere-absorption.
 Treatinghypophosphataemiawithphosphatesupplementsinthe
contextofhypercalcaemiamayinducesofttissuecalcification.(Thiemet
al2015)
 Parathyroidectomyversuscinacalcet inpersistenthyperparathyroidism
remainsunclearparticularlywiththeriskof hypoparathyroidismpost
surgery.(Evenepoeletal2007)

52. 2-Bisphosphonates
 SyntheticpyrophosphatesreplacingtheOmoleculewithCarbontogive
highaffinitytohydroxappetitecrystalsandtobedifficulttobreak.
 PyrophosphateP-O-P versus BisphophsophnateP-C-P.
 TwosidechainstothecarbonatomdeterminetypeofBis,potency,
durationofactionandsideeffects.
 PotentoneshaveaOHgroup inthesidechaintojoinCa.

53. Bisphosphonates
 Bioavailability100%afterIVand1-5%afteroral.
 50-80%takenbyboneandtherestexcretedunchangedinurine.
 Boneuptakeincreasewithhighturnover.

54. Bisphosphonates
 Nitrogenous(2ndand3rdgenaspamidronate)bindenzyme farensyl
synthetase.
 NonnitrogenousbindALP(1stgen-clodronate)causingosteoclastapoptosis.
 Strengthofetidronateasareference,pamidronateis100, alendronate1000,
residronate5000,ibandronate10000and zolendronate20000.
(TorregrosaandRamosNefrologia.2010;30(3):288-96.)

55. Bisphosphonates
 SystematicR/Vof17trials (1067kidneyTxppts)significantincreasein%
changeofBMDinvertebralandfemoralnecks.
 Fractureincidence ofvertebralornonwasnotdifferent.
(Kanetal.Medicine2016.95(5):1-11)

56. Bisphosphonates
Challenges
 Bisphosphnate cancauseadynaemicbonediseaseandkidneyfunction
worsening.
(CocoetalJASN.2003.14:2669-76)
 ABisacontroversialwithconflictingresults.
 Highdosesandrapidinfusioncanincreasetheriskofrenaldamage.
 CrCl<30ml/minshouldreducethedosebyhalf.andOralpreparations
aresaferthanIV.

57. 3-Denosumab
 MonoclonalantibodyagainstRANKLwithantiresorptiveeffects.
 Itincreases BMDandreducesfractureriskinfemaleswithosteoporosis.
 X2dosesofDensoumabat2wand6monthin46kidneytransplantation
patients,increasedBMDinthelumbarspineandhipcomparedtocontrols
(4.6%and1.9%).

58. Teriparatide
 NoeffectonBMDoflumbarspine,distalradiusbutstabilisedneckoffemur
comparedtoplacebo.

59. VitaminD
 Thereisnocleardefinitionof25-(OH)vitaminDdeficiencyasthereisnoRCTto
defineavitaminDleveliscorrelatedwithhardendpoint.(Cinacioloetal2016)
 Serumlevel<20ng/mlisdeficientandbetween20-30insufficient.(Holick2007)
 Levels>10ng/mlisadequatetopreventricketsorosteomalaciaand>30toprevent
osteoporosisand2nd HPTH.(ThacherandClarke2011)
 Independentpredictorofmortalitywith25(OH)Dlevelslessthan12ng/mlin
kidneytransplantpatients.(Keyzeretal2015)
 25(OH)Dlevelsat3monthispredictorofgraftfunctionat 1yearandrateofgraft
decline.

60. VitaminD
Epidemiology
 DeficiencyandinsufficiencyofvitaminDiscommonafterkidney
transplantation(30and81%respectively).(BoudvilleandHodsman
2006)
 VitaminDlevelisdeterminedbyinteractionofpersistentlyelevated
PTH,FGF-23,graftfunctionandimmunosuppression.

61. VitaminD
 Recoveryofkidneyfunction,hypophosphataemiaandhighPTH
acceleratesconversionof25(OH)into1,25(2OH)D.
 FGF-23inhibits1-αhydroxylaseandstimulates24-hydrolyxaseinducing
lowactivevitaminDlevels.
 FGF-23inhibitsPTHsecretionthroughcalcinurindependentpathway.

62. VitaminD
 SteroidsdoseinverselycorrelatedwithvitaminDlevelpartlythrough
stimulatingFGF-23.
 CNIdownregulatesVDR.
 mTORinhibitorshavenoeffectonvitaminD.
 VitaminDserumlevelsimproveafterthefirstyearoftransplantation
probablywithreductionofFGF-23serumlevels.

63. VitaminD(Nutritional)
 vitaminDpossesspleotropiceffectsinadditiontoskeletalones.
 ThereisnostrongevidencetosupporttheroutineuseofvitaminDinthe
earlyposttransplantationperiod.
 VitaDtrialdidnotshowanydifferenceinrateofinfectionorrejection
betweenvitaminDarmandplacebo.(Thiem etal2016).
 Resultsof VITALE trial fornutritionalvitaminDsupplementationis
awaited inviewofsomepitfalls ofVITA Dtrial.

64. VitaminD(Active Forms)
 Paricalcitolversusplaceboshowedimprovementofproteinurialeveland
serumPTHbutslightincreaseinserumcreatinine.

65. VitaminD(Active Forms)
Inanothertrialtherewasnosignificantdifference ofproteinuriaafter
oneyearofparicalcitoltreatment.

67. KDIGO(2017)
 BMDinthefirst3monthpostTxpforptswithriskofosteoporosisatany
stageofCKD.
 Inthefirst12monthandLowBMD&eGFR>30totreatwithvitamin
D/Clcitrioloralfacalcidol/orbisphosphonates.
 Noevidenceavailablebeyond12month
 ChoiceoftreatmentdependsonbiochemicalvariablesCa,Pi,AP,PTH
and25(OH)-vitD.
 BisphosphonateuseshouldbewithboneBxtoavoidADB.
 Itisreasonabletoconsiderabonebiopsytoguidetreatment

68. Conclusions
 FactorsaffectingpostkidneytransplantationbonehealthareeGFR,
immunosuppression,pre-existingCKD-MBD.
 BaselineDEXAscanisrecommendedinhighriskpatientsafterkidney
transplantation.
 Bonebiopsyisrecommendedinhighriskpatientsprebisphosphonate
initiation.

69. Conclusions
 Persistenthyperparathyroidismisbettertreatedconservativelyinthe
firstyearwithcinacalcet.
 Fractureriskassessmenttool(FRAX)isnotvalidinkidneytransplant
patientsandneedsvalidationafteraddingtransplantationspecific
variables.
 NoclearevidenceofvitaminDvaluenativeoractiveinkidney
transplantationalthoughrecommendedtocorrectvitaminDdeficiency.

70. Thank You