European Journal of Endocrinology 10.1530/EJE-16-0430 Finally, theeffects ofparathyroidsurgeryandmedicaltreatmentonkidneyinvolvementPHPTarereviewed. these featuresmighthaveclinicalrelevanceandshouldbeconsideredbothduringdiagnosticworkoutfollow-up. likely tobeaffected byvariantsofgenescodingthekeymoleculesregulatingcalciumandionsrenalhandling; criteria forparathyroidsurgeryincludingasymptomatickidneydisease.Moreover, kidneyinvolvementinPHPTis Fourth Workshop recommendationsofamoreextensivediagnosticworkout aboutkidneyfeaturesandofwider function isassociatedwithincreasedriskofcardiovasculardisease.Theseconsiderationsprovidedthebasisfor the Disease: ImprovingGlobalOutcomes(KDIGO)panelofexpertshighlightedthatevenmildreductionkidney glomerular filtrationrate,andrelatedincreasedmorbiditymortality. Inthelastdecade,effort oftheKidney the pathogenesisisfarfrombeingelucidated,PHPTassociatedwithreducedrenalfunction,intermsofestimated of asymptomatickidneystones,hypercalciuriaandreducedfunctioninPHPTpatients.Though Nonetheless, theroutineuseofimagingandbiochemicaldeterminationshaverevealedfrequentoccurrence have becomerareandthePHPTcurrentpresentationisasymptomaticwithuncertainlong-lastingprogression. elevated PTHandcalciuminPHPT. TheclassicPHPTcomplicationsofsymptomatickidneystonesandnephrocalcinosis Primary hyperparathyroidism(PHPT)isthethirdmostcommonendocrinedisease.Kidneyatargetofbothchronic Abstract Milan, Italy Service, DepartmentofBiomedicalSciencesforHealth,UniversityMilan,IRCCSIstitutoOrtopedicoGaleazzi, 1 C Verdelli and molecularaspects hyperparathyroidism: anupdateonclinical Kidney involvementinpatientswithprimary MECHANISMS INENDOCRINOLOGY Laboratory ofExperimentalEndocrinology, IRCCSIstitutoOrtopedicoGaleazzi,Milan,Italyand DOI: 10.1530/EJE-16-0430 www.eje-online.orgwww.eje-online.org Diseases (SIOMMMS)andofthe boardoftheItalianSocietyEndocrinology. a memberofthescientificcommittee oftheItalianSocietyOsteoporosis,MineralMetabolism andSkeletal hyperparathyroidism.Sheis Endocrinology Guidelinesforthe diagnosisandmanagementofthemildprimary She haspublishedover100papers. In2014,shecollaboratedonthedevelopmentof Italian Societyof hyperparathyroidismfocusing onkidneyinvolvement,andintheparathyroidtumorigenesis. aspects ofprimary Society ofEndocrinologyfrom2007.Overthelast15years,shehas developedherscientificinterestintheclinical Experimental EndocrinologyatIRCCSIstitutoOrtopedicoGaleazzi inMilan.SheisamemberoftheEuropean of andoftheLaboratory professor ofEndocrinologyattheUniversityMilan,head theEndocrineService Prof SabrinaCorbetta Invited Author’s profile Review 1 and
S Corbetta graduatedinMedicineandobtainedaPhDatUniversityofMilan inItaly. Sheisa 1 , 2 © 2017EuropeanSociety ofEndocrinology © 2017EuropeanSociety ofEndocrinology C Verdelli andSCorbetta Printed inGreatBritain hyperparathyroidism Kidney diseaseinprimary Published byBioscientifica Ltd. 2 Endocrinology Downloaded fromBioscientifica.com at09/30/202109:13:15PM
(2017) Endocrinology European Journal of [email protected] Email to SCorbetta should beaddressed Correspondence 176 176 : 1 176
:1 , R39–R52
R39
–R52 via freeaccess European Journal of Endocrinology www.eje-online.org stones’, or‘kidneydisease’, or ‘CKD’,‘nephrolithiasis’ hyperparathyroidism’and‘kidney as keywords:‘primary evidence wasavailable.Search strategiesusedthefollowing case reportswerereportedonly whenanyotherconsistent Original studiesandmeta-analysiswereincluded,while from 2005untilnow, werescreeneduntilApril 30th,2016. search strategies.Paperspublishedinthelast10years, The mainsource ofdataacquisitionincludedPubMed involvement in the current asymptomatic PHPT patients. revision oftheclinicalandmolecularaspectskidney modulate theclinicalpresentationofPHPT. accumulated andsomeofthemhavebeenshown to of calcium,phosphateandotherelectrolyteshavebeen panel of experts, molecular insight about renal handling ofkidneyfunctionpromotedbytheKDIGO mild injury glomerular filtration rate ( detected byimagingandofaslightlyreducedestimated biochemical urine,ofasymptomatickidneystones to theoccurrenceofhypercalciuria and/orlithogenic extend therecommendationsforparathyroidsurgery of the Forth Workshop on asymptomatic PHPT to is importantandshouldbepursuedinat-riskpopulations. associated withreducedkidneyfunction,earlydiagnosis healthy ( highlighted thatmildkidneyfunctionimpairmentaffects produced guidelinesonkidneydiseasessince2008, kidney diseaseguidelinedevelopmententity, thathas Improving GlobalOutcomes(KDIGO),aninternational and milddecreasesinkidneyfunction. renal microlithiasisdetectedbyultrasoundexamination proportion experienceshypercalciuria, asymptomatic with asymptomaticPHPTrevealedthataconsistent of PHPT. Nonetheless,extensivescreeningofpatients in thecurrentlyprevalentasymptomaticpresentation era ofsymptomaticPHPT, whiletheyhavebecomerare failure, wereconsideredexpectedcomplicationsinthe tractinfections,hydronephrosisandkidney as urinary kidney stonesandstone-relatedcomplications,such and phosphate handling. Clinical kidney injuries, namely PTH biologicalactivity, whichregulatesrenalcalcium coupled receptorPTHR1.Kidneycellsaretargetsofthe mainly actsthroughtheactivationofG-protein (PTH) release from tumour parathyroid glands. PTH endocrine disorderduetoinappropriateparathormone hyperparathyroidism(PHPT)isacommon Primary Introduction Review The aimofthepresentreviewwastoprovidea This burdenofconsiderationspushedthePanel In therecentpast,effortofKidneyDisease: 1 ). Becauseofthemorbidityandmortality 2 ). Besides the attention to C Verdelli andSCorbetta Symptomatic kidneystonesoccurredinPHPTseriesfrom Kidney stonesinPHPTpatients Clinical aspects evaluated foranyadditionalappropriatecitation. addition, thebibliographiesofrelevantcitationswere only reported in conference abstracts were excluded. In consensus. NonEnglishlanguagepapersandstudies Discrepancies indataextractionwereresolvedby and selected full-text manuscripts for eligibility. working independently and reviewed all abstracts records relatedtothemolecularaspects.Bothauthors 50 records related to the clinical setting and 13 used for the molecular aspects. The search retrieved and ‘calcium gene’, or‘phosphate gene’, or‘VDR’were for theclinicalsetting,while‘calciumsensingreceptor’ increased renal calcium excretion and increased urine ( in calciumphosphatestone formation,havebeenfound deposits,common formation, andintratubular crystal which arecommoninidiopathiccalciumoxalatestone interstitial apatite plaques, also known as Randall plaques, key factor. InPHPTpatients with kidneystones,both retentionisa modulate thestoneformation.Crystals interactions betweenpromotersandinhibitorsfurther inorganic andorganicconstituentsinurine, Thepresence ofmultiple and agglomerationofcrystals. mainly intheearlystagesofnucleation,aggregation formation, is unknown:itlikelyrelatedtocrystal in the general population, and also in PHPT patients, in anotherseries( PHPT patients( creatinine excretionrateinaseriesofsurgicallyproven nephrocalcinosis) wereassociatedwithhighercalcium/ PHPT patients( in normocalcaemic (15%) and hypercalcaemic (19%) Moreover, kidneystonesoccurwithasimilarprevalence with stonesbeingbilateralin16.4%ofPHPTpatients( ranging from25%to55%indifferentseries( PHPT patients, stones are common with a prevalence kidney stonesoccurmorefrequently. Inasymptomatic Indeed, imaging screening revealed that asymptomatic dramatically droppedto10–20%ofPHPTpatients. last twodecades,symptomatickidneystonesdiagnosis 1970s and1980sin40–60%ofPHPTpatients.Inthe hyperparathyroidism Kidney diseaseinprimary 7 ). Several factors may promote precipitation of crystals: ). Severalfactorsmaypromote precipitationofcrystals: The precise pathogenesis of urinary stoneformation The precisepathogenesisofurinary 6 4 ). Renalcalcifications(kidneystonesand ), whileanydifferencecouldbedetected 5 ). Downloaded fromBioscientifica.com at09/30/202109:13:15PM 176 :1 3 , R40 4 , 5 5 via freeaccess ). ),
European Journal of Endocrinology also hypocalciuria( variable, fromhypercalciuria, tonormocalciuriaand Renal calcium handling in PHPT patients isextremely Calcium renal handlinginPHPTpatients with aprevalenceof20%stoneformation( (1.5–3.5%) wasreportedinaseriesof332PHPTpatients Similarly, significantreductioninkidneystonesrecurrence about 5years,ofwhom10%hadstoneformation( of 640surgicallytreatedPHPTpatientsfollowedupfor stones, diagnosedonthebasisofsymptoms,inacohort zation isassociatedwithreducedrecurrenceofkidney patients. SuccessfulPTXwithserumcalciumnormali ectomy (PTX) reduces kidney stones recurrence in PHPT Recent studiesconfirmedthatsuccessfulparathyroid stones recurrence Effects ofparathyroidectomy(PTX)onkidney > kidney stonesinPHPTpatientswith24-hurinecalcium recent guidelines( and potassiumhasnotbeenestablished( while theroleofurinephosphate,magnesium,sodium levels contributetokidneystoneriskinPHPTpatients( relative highurineoxalateexcretionandlowcitrate not confirmedbyotherstudies,alsosuggestedthat kidney stonedevelopmentinPHPTpatients( proteinuria. Hypercalciuria isthemainriskfactorfor sodium, decreasedurinecitrateconcentrationsand phosphate, increasedurineoxalate, 400 Review mg by evaluating the urinary stoneriskprofile. mg byevaluatingtheurinary 9 , 10 Fig. 1 ) suggesteddetermining the riskof ). Oversaturationsofurine C Verdelli andSCorbetta 8 8 ). Therefore, ). Evidence,
12 ). 11 3 ), ).
for nephrocalcinosisarenotclearlydefined( known riskfactorsfornephrolithiasis,while with calciumphosphateandoxalateare for familialhypocalciurichypercalcaemia (FHH). calcium excretioninpatientswithPHPTraisedconcern treated withthiazideareexcluded.True low24-hurine proportion reducestolessthan1%whenPHPTpatients might occurinabout5%ofPHPTpatients( calcium hypocalciuria, defined asurinary of kidneystoneswassimilarinthetwogroups.Finally, hypercalcaemic PHPTpatients( calcium excretionthanthatinage-andsex-matched PHPT patientshavesignificantlylowermean24-hrenal kidney stonesinPHPTpatients( has beenindicated as a risk factor for hypercalciuria and quarters ofPHPTpatientsinrecentseries( kidney function,occurredinabouttwo-thirdstothree- > Hypercalciuria, definedasurinecalciumexcretion femoral neck. Therefore, it would be expected that about femoral neck.Therefore,itwouldbeexpectedthatabout improved bonemineraldensityatthespine,totalfemurand patients withpersistentrenalcalciumleakdidnotexperience in PHPTpatientswithoutrenalcalciumleak).Moreover, surgically diagnosedparathyroidhyperplasia(50%vs22% ( inabout40%ofhypercalciuric after surgery PHPTpatients Indeed, Palmieri contributing toreducetheriskofkidneystonesrecurrence. Hypercalciuria isexpected toresolveaftersuccessfulPTX, Effects ofparathyroidectomy (PTX)onhypercalciuria hyperparathyroidism Kidney diseaseinprimary 13 4 mg/kg bodyweight/24 ). Persistent renal calcium leak was associated with ). Persistentrenalcalciumleakwasassociatedwith et al calcium leakarereported.*( conditions abletomodifytheentity of patients. Intheboxesatbottom, factors poorlyinvestigatedinPHPT stones development.Dashlines indicate calcium oxalateandphosphate might providefurtherriskfactorsfor hyperoxaluria andhyperphosphaturia patients arerepresented;relative handling alterationsoccurringinPHPT patients. Thespectrumofcalcium and phosphatehandlingsinPHPT Alterations oftherenalcalcium,oxalate Figure . reportedthathypercalciuria persisted Downloaded fromBioscientifica.com at09/30/202109:13:15PM 1 h in the presence of conserved h inthepresenceofconserved 6 ), thoughtheprevalence 14 176 ). Normocalcaemic www.eje-online.org :1 15 3 < , ), thoughthe 100 mg/24h, 3 13 ). ). Obesity Fig. 1 R41 via freeaccess ). ).
European Journal of Endocrinology www.eje-online.org daily doseofcholecalciferol (600–1000 calcium excretionhasbeendetected( in urinary (2800 study evaluatedtheeffectof vitaminD ( PTH withoutcausinghypercalcaemia andhypercalciuria serum 25-hydroxyvitaminDlevelsandreduces deficiency showedthatvitaminDreplacementincreases study inPHPTpatientswithcoexistentvitamin D stones development ( has beenreported,thoughwithnoevidenceofkidney calcium excretion in PHPTpatients;increaseurinary Few data are available on the effect of vitamin D repletion on hypercalciuria Effects ofcholecalciferol supplementation understood ( as onurineoutputandacidification,remainstobefully effect ofcinacalcetonurinecalciumexcretion,aswell reabsorption. Nonetheless,thisunexpectedlackof that mightovercome the reductionofcalciumtubular by theintestinalcalciumabsorption,acomponent Calcium excretionin24-hurineispartdetermined cinacalcet ontheCASRinthickascendingloop( on tubularcalciumreabsorptionorbyadirecteffectof ofPTH be mediatedbyashiftinthedose–responsecurve as fastingcalcium–creatinineratio)hasbeensupposedto of cinacalcetoncalciumtubularreabsorption(evaluated effect hormones toextracellularcalcium.Theinhibitory setting thesensitivitythresholdforseveralcAMP-coupled derive fromsodium,pHandmineralionmetabolism, acts to fine tune and integrate multiple stimuli that calciumexcretion.Inotherregions,theCASR urinary of Henle,whereitfunctionsasamajordeterminant CASR ismainlyexpressedinthethickascendingloop throughout thedifferentsegmentsofnephron( are unaffected( calcium excretionthough24-hurinelevels normalizes serumcalcium,andreducesfastingurine of disease severity, reduces circulating PTH levels, hypercalcaemia inPHPTpatientswithawiderange receptor (CASR)currentlyavailableforthecontrolof Cinacalcet HCl,theagonistofcalcium-sensing Effects ofcinacalcetonhypercalciuria expected gaininbonemineraldensity( after PTX,andthiscondition,ifnotcorrected,affectsthe 30% of PHPT patients experience persistent hypercalciuria 23 Review ). Arandomized,placebo-controlled, double-blind IU daily for 26 weeks) in PHPT patients: no increase 18 ). 16 , 17 20 ). CASRmoleculesareexpressed , 21 , 22 ). A recent interventional ). A recent interventional C Verdelli andSCorbetta 13 3 supplementation IU) isconsidered ).
24 18 19 ). A ): ): ). ). thiazides ( PHPT based on continued hypercalcaemia after stopping thiazide-associated hypercalcaemia mayhaveunderlying that Griebeler rule outfamilialHHC.Besides,itshouldbeconsidered creatinine clearanceratiocalculationtopreoperatively discontinuing thiazides is crucial for a correct calcium/ influence PTHlevelsinpatientswithPHPT( calcium excretion, yet neither increase serum Ca nor PTH levels.Thiazidessignificantlydecrease24-hurine calcium concentrationsareincreasedindependentlyof resulting inreducedurinecalciumexcretion;serum Thiazides increaserenaltubularreabsorptionofcalcium Effects ofthiazidediureticsonhypercalciuria 25OHD concentration as sufficientinmostcasestoreachthetargetofserum diagnosis is predictive of mortality at a 3-year term, the PHPT patientsand7120controls,serumcreatinineat impairment, inthePEARScohortof1424asymptomatic Supporting theconnectionbetweenPHPTandrenal rate wascommoninadvanced severe PHPT( kidney function,andareducedglomerularfiltration Prolonged hypercalcaemia wasconsideredtoimpair PHPT and this condition is not completely understood. renal function,thoughthespecificrelationshipbetween PHPT hasbeenrecognizedasariskfactorforimpaired Kidney functioninPHPTpatients PHPT patientsareillustrated. and systemicconditionsknown toaffect kidneyfunctionin CKD anditsrelatedriskfactors inPHPTpatients.Specificlocal Figure hyperparathyroidism Kidney diseaseinprimary 2 26 ). t al et . estimate that 71% of patients with > Downloaded fromBioscientifica.com at09/30/202109:13:15PM gm (50 nmol/L). 20 ng/mL ⇑ , increased; 176 ⇓ :1 , decreased. 25 ). Therefore, 27 , R42 28 via freeaccess ). European Journal of Endocrinology Decreased GFR Marker ofkidneydamage(oneormore) Duration Definition Table 1 8. 7. 6. 5. 4. 3. 2. 1. kidney functionimpairment( with hazardratesof13.8and5.1respectively( risks ofkidneyfailureandstonesareincreased Review population and to the age-, sex- and BMI-matched population andtotheage-,sex-BMI-matched in PHPTpatientscomparedwiththegeneralNewJersey heartdiseasehas beenreported mellitus andcoronary obesity, hypertension,hyperlipidaemia,type 2diabetes bloodhypertension Arterial post-operative PTH,andgreatersymptoms( parathyroid tumourweight,higherpre-and Obesity insulin resistance( Insulin resistance cells ( glomerular endothelialcellsandinproximaltubular subsequent organfibrosis,andPTHR1isexpressedin and that increasedPTHacceleratesendothelialinjury Chronic elevatedPTHlevels: patients ( patients withPHPToccurringinaboutone-fifthof Kidney cysts PHPT patients( nephropathy( crystal is responsibleforthelossofkidneyfunctioninoxalate prolonged activationoftheintrarenalinflammosome kidney disease(CKD).Recentstudiesdemonstratedthat kidney diseasedeterminingtubulointerstitialchronic Kidney stones serum creatinelevels; osmotic agentsorconcomitantmorbidities,increased diuresis inducedbymassivehypercalciuria orother Dehydration age from20to90years( as reflectingadeteriorationofkidneyfunctionatany experts recommends to consider an eGFR physiologically declineswithage,theKDIGOpanelof aged 50–70years( Age PHPT patientsdisplayanumberofriskfactorsfor : TheincidenceofPHPTpeaksisinwomen 37 KDIGO definitionanddiagnosticcriteriaofCKD( : SeverelyobesePHPTpatientshavelarger ); 36 : Dehydration secondary toosmotic : Dehydrationsecondary ); : Multiplekidneycystsarefrequentin : Stones are considered the cause of primary : Stonesareconsideredthecauseofprimary 3 : PHPTisassociatedwithincreased , 35 38 32 ); ); 34 , 33 ), whichfrequentlyoccursin 1 ); ). Thoughkidneyfunction : A higher prevalence of : Ahigherprevalenceof Fig. 2 Emergingevidenceshows C Verdelli andSCorbetta ): GFR History ofkidneytransplantation Structural abnormalitiesdetected byimaging Abnormalities detectedbyhistology Electrolyte andotherabnormalities duetotubulardisorders Urine sedimentabnormalities Albuminuria (AER > Abnormalities ofkidneystructureorfunctionwithimplications forhealth < 3 months 29 60 mL/min 39 , < ); 30 60 mL/min/1.73m , 31 1 ). ).
( measured, estimated GFR (eGFRcr) should be calculated on toassesskidneyfunction.Whenserumcreatinineis prognosis. Serumcreatininebyitselfshouldnotberelied measures, with more severe stages corresponding to poorer is stagedbycause and severityofabnormal kidney abnormalities detectedbyhistologyorimaging.CKD abnormalities relatedtotubulardisorders,orstructural albuminuria, urine sediment abnormalities, electrolyte kidney damage( decreased glomerular filtration rate(GFR) or evidence of on serumcreatininelevels( Epidemiology Collaboration(CKD-EPI)equationbased moderately decreasedforadultsofanyage. the mostevidentdeterminantofcirculating cystatinC tool toassessGFRthanserumcreatinine,showedthat proximal tubule,whichisconsideredamorereliable at renal glomerular level and then metabolized by the weight proteinsecretedbynearlyallcells,freelyfiltered patients bymeasurementofcystatinC,alow-molecular- PHPT ( indices ofPHPT, areassociatedwithlowereGFRinmild Traditional riskfactors,ratherthanclinicalorbiochemical to behypertensivethanthosewithoutCKD( 1,25-dihydroxyvitamin Dlevels,andweremorelikely older, hadhigher25-hydroxyvitaminDlevelsandlower 25-hydroxyvitamin D( antihypertensive medicationuse,fastingglucoseand Estimated GFRwasassociatedwithage,hypertension, eGFRcr lowerthan30 a stage3,andonly1–2%ofPHPTpatientshadan Most PHPTpatientswithCKDwerediagnosed from 13%to19%inthedifferentseries( proportion ofPHPTpatientsaged30–80yearsranging an eGFRcr hyperparathyroidism Kidney diseaseinprimary ≥ 1 ; ACR 30 mg/24h; ). AGFRoflessthan60 confirmed inanItalianPHPTseries( goitre patients( Assessing GFR with the Chronic Kidney Disease CKD isdefinedashavingmorethan3monthsof 2 42 , 43 < ). EvaluationofkidneyfunctioninPHPT 60 mL/min/1.73m ≥ 1 gg ( 30 mg/g ). Markersofkidneydamageinclude 40 ). However, suchfindingswerenot Downloaded fromBioscientifica.com at09/30/202109:13:15PM mL/min/1.73 42 ≥ mL/min/1.73 3 mg/mmol)) ). PatientswithCKDwere Table 1 2 , wasdiagnosedina 176 ), CKD,definedas m 41 www.eje-online.org :1 m 2 ). isconsideredas 2 (G4stage). Table 2 42 R43 , 43 via freeaccess ). ). ). European Journal of Endocrinology www.eje-online.org confirmed impairedeGFR among surgicalcriteria, Guidelines onthemanagement ofasymptomaticPHPT Effects ofparathyroidectomy(PTX)onkidneyfunction symptoms ( hypercalcaemia, whichinducedneurologicandcardiologic and efflux,metabolicacidosismightdramaticallyworsen cardiovascular accidents. Due to bone calcium mobilization by concomitantacuteevents,suchasinfections or complications duetometabolicacidosisoftenprecipitated an increasedriskofexperiencinglife-threatening existing renalfailure( elevation occursinPHPT. Besides,PHPTmayworsen < convincing evidencesupportthethresholdofeGFR eGFR PTH levelsweresignificantlyhigherinpatientswith serum from astudyof294patientswithPHPT, where established. Currently, themostconvincingdatacome a significantstimuluselevatesPTHlevels,hasnotbeen PHPT ( between PTHlevelsanddegreeofrenalimpairmentin 47 expression ofPHPThasbeenwelldocumented( cardiovascular andnon-cardiovascularoutcomes. established CKDandwithincreasedriskofmortality, was associatedwithincreasedriskfordevelopmentof population ( blood hypertensionanddyslipidaemia.Inthegeneral characterized byhigherBMI,insulinresistance,arterial showed an unfavourable cardiometabolic profile, disease inaboutone-sixthofPHPTpatients,which Cystatin Cmeasurementdiagnosespreclinicalkidney PHPT might contribute to kidney function impairment. levels wasionizedcalcium,suggestingthatseverityof G1 norG2fulfilthecriteriaforCKD. In theabsenceofevidencekidneydamage,neitherGFRcategory CKD, chronickidneydisease;GFR,glomerularfiltrationrate. G5 G4 G3b G3a G2 G1 category GFR Table 2 60 mL/min/1.73m Review ,
48 PHPT patients with reduced kidney function have PHPT patientswithreducedkidneyfunctionhave The impactofrenalfunctiononthebiochemical , < 50 49 30 mL/min/1.73m GFR categories. ), buttheeGFRthresholdinPHPT, belowwhich (mL/min/1.73 m GFR ). Severalstudiesclearlyidentifyacorrelation 51 44
15–29 30–44 45–59 60–89 ). < ≥ ), thepreclinicalormildkidneydisease 15 90 2 (CKDstage3)belowwhichPTH 2 ) 50 Kidney failure Severely decreased Moderately toseverelydecreased Mildly tomoderatelydecreased Mildly decreased Normal orhigh Terms ). 2 . Therefore, upto now no C Verdelli andSCorbetta 45 ,
46 , successful PTX( eGFR levels,wasreducedday1andatfollow-upafter where renalfunction,evaluatedasserumcreatinineand contrast, inaprospectivestudyon62PHPTpatients, associated withthevariationineGFRafterPTX.By systolic bloodpressurearesignificantlyandindependently 60 mL/min/1.73m baseline eGFR,estimatedbytheCKD-EPIequation,above impairment ( renal functioninPHPTpatientswithacoexisting PTX hasbeenshowntopreventfurtherdeteriorationof at thefollow-upofabout5years( ( PHPT patients showed no effect of PTX on renal function controlled trialsconductedprimarilyinmildasymptomatic renal disease are still lacking ( definite dataaboutabeneficialeffectofPTXonexisting indicating thethresholdof60 phonates incontrolling severe hypercalcaemia as Denosumab mightrepresent analternativetobisphos is notrecommendedwhen eGFRisbelow30 option foracutesymptomatic hypercalcaemic crisis, mind thatintravenouszoledronic acid,atherapeutic the kidneyfunction.Nonetheless,itshouldbekept in been reportedtobeassociatedwithimpairment of ( treatment forosteopenia/osteoporosisinPHPTpatients with PHPT( Alendronate hasbeenshowntoincreaseBMDinpatients Effects ofbisphosphonatesonkidneyfunction studiesarelacking. intervention excretion couldbedetected( stones, thoughanysignificantdifferenceinrenalcalcium 25OHD levelswerehigherinthepatientswithkidney effect of25OHDonkidneyfunction.Moreover, serum of concomitantmetabolicalterationsratherthanadirect correlated witheGFR( 25-hydroxyvitamin D (25OHD) levels were inversely In female patients with PHPT, circulating kidney function Effects ofcolecalciferolsupplementation on PHPT patients( Cinacalcet does not affect creatinine and eGFR levels in Effects ofcinacalcetonkidney function hyperparathyroidism Kidney diseaseinprimary 52 10 , ). The use of alendronateinPHPT patients has not 53 , 54 ). No changes ineGFR were detected after PTX 58 55 , 16 56 ). Thisisnotthecaseinpatientswitha 59 , 2 ). 17 . In this study, presurgical eGFR and , 60 ). 57 ) andthereforeitissuggestedas Downloaded fromBioscientifica.com at09/30/202109:13:15PM ), morelikelyreflectingtheeffect 50 42 mL/min/1.73 ). Previous randomized ). However, datafrom 176 11 ). Morerecently, :1
m 2 . Indeed, mL/min. R44 via freeaccess
European Journal of Endocrinology involved in the renal calcium, phosphate and electrolytes Variations ofthebiologicalactivitykey molecules Molecular aspects 3. 2. 1. Kidney involvementinparticularformsofPHPT and osteoporosis( vascular calcificationinpatientswithstage1–2CKD treatment canimprovebothbonemineraldensityand aggravating hyperparathyroidism. Bisphosphonates uraemic osteodystrophyandadynamicbone,even low boneturnoverdisorderssuchasosteomalacia,mixed requires cautionbecauseoftheincreasedpossibility but prescribingbisphosphonatesinadvancedCKD with aglomerularfiltrationrateof30 Bisphosphonates canbesafeandbeneficialforpatients reported incasesofparathyroidcarcinomas ( Review kidney stoneswerereportedin12%ofpatients( women aged20–40yearswhoexperiencedpregnancy, reported ( crisis withacuteneurologicaldisturbanceshavebeen with renal function deterioration and hypercalcaemic among maternalcomplicationsofPHPT, kidneystones PHPT duringpregnancy 26.8% ofpatients( kidney stones,nephrocalcinosis)couldbedetectedin min/1.73 m serum creatinine levels of PHPTpatientswithparathyroidcarcinoma had with benignparathyroidtumours( parathyroid carcinomas compared withPHPTpatients excretion didnotdifferinPHPTpatientswith calciumtumours; nonetheless, median 24-h urinary than thosedetectedinPHPTwithbenignparathyroid serum calciumandPTHlevelssignificantlyhigher patients withparathyroidcarcinoma experience incidence of1.25per10 carcinoma is an extremely rare tumour with an Parathyroid carcinoma-related PHPT patients ( were reportedin19.4%ofMEN1-relatedPHPT patients ( similar frequencycomparedwithsporadicPHPT occurred inMEN1-relatedPHPTpatientswith ( kidney stonesbefore30yearsofage(upto86.2%) PHPT experiencedhighfrequencyofearly-onset MEN1-related PHPT 64 ), whileinanItalianserieskidneystones 65 66 69 2 ). Different degrees of renalinsufficiency ). ), whilerenalsymptoms(kidneycolics, ). Inarecentseriesof74mildPHPT 63 ). 68 : patientswithMEN1-related ). : PHPTisrareduringpregnancy; 000 > gd (eGFR 1.1 mg/dL 000 peryear. MostPHPT C Verdelli andSCorbetta mL/min orhigher, 67 : parathyroid ). About46% < 61 60 mL/ , 70 62 ). ). ).
receptor-1; NCX1,sodium/calciumexchangerprotein; tubules levels.CASR,calcium-sensingreceptor;PTHR1,PTH handlings atthedistalconvolute(DCT)andconnecting Molecules involvedinthecalcium,oxalateandphosphate Figure 3 PMCA1b, ATPase plasmamembraneCa receptor potentialcationchannelsubfamilyVmember5. dependent phosphatetransportprotein2A;TRPV5,transient SLC26A6, solublecarrierfamily26member6;NaPT2,sodium- might modulateitsclinicalpresentation( handling mightcontributetopathogenesisofPHPTor enhanced bythemagnitude ofthecalciuminflux transport proteins.ThePTH-induced stimulationis coordinated expressionof renaltranscellularcalcium PTH stimulatesrenalcalcium reabsorptionthroughthe TRPV5 not available. Data abouttheroleof PTH receptor(PTHR1) detected ( correlation withkidneystonesorfunctionwas transcriptional activity;nonetheless,anysignificant PHPT ItalianpatientsandtodisplayGCM2enhanced to belinkedPHPTinacombinedcohortof510 The 282Dpolymorphicvarianthasbeendemonstrated familial isolatedhypoparathyroidism(OMIM#146200). factor, whoseinactivatingmutationsareassociatedwith transcriptionGCM2 isaparathyroid-specificembryonic Glial cellmissing2(GCM2) hyperparathyroidism Kidney diseaseinprimary 71 ). PTHR1 Downloaded fromBioscientifica.com at09/30/202109:13:15PM genevariantsinPHPTare 2+ 176 transporting1; www.eje-online.org :1 Fig. 3 ). R45 via freeaccess European Journal of Endocrinology www.eje-online.org NCCR (intron1) NCRR (5’-UTR) Q1011E Ermetici 2015 Tassone 2015 Tassone 2009 Walker 2014 Walker 2014 Walker 2012 R990G A986S CASR SNP PHPT patients.nd,notdetermined; Table 4 calcium excretion was significantly higher inurinary hyperparathyroidism (NSHPT, OMIM#239200).Fasting (HHC1, OMIN#145980)andneonatalsevereprimary in the type 1 familial hypocalciuric hypercalcaemia associated withhypocalciuria(calciumclearance Inactivating mutationsofthe Calcium-sensing receptor(CASR) variant inPHPTpatients. of interesttoinvestigatetheeffect idiopathic calciumstoneformation( multiplicity ofcalciumnephrolithiasisinpatientswith tobeassociatedwithstone(rs4236480) wasobserved with hypercalciuria ( TRPV5 pathogenesis ofPTH-relateddisorders( proteins, includingTRPV5,couldcontributetothe proteins. Therefore, the renaltranscellular transport the expressionofdownstreamcalciumtransport through thegatekeeperTRPV5,whichinturnfacilitates # Table 3 MDRD equation( Review developseverehyperparathyroidismassociated Effects ofsinglenucleotidepolymorphisms(SNPs)thecalcium-sensingreceptor( Prevalence ofreducedkidneyfunctioninPHPTpatients. 103 ); *CKD-EPIcreatinineequation2009( Patients rs1501899 rs7652589 rs1801726 rs1042636 rs1801725 Number Accession 190 109 294 114 114 138 ( n) 73 2005–2010 1995–2012 1993–2007 2005–2013 2005–2013 1984–1991 ). Period TRPV5 ⇓ C Verdelli andSCorbetta CASR , reduced; Substitution G G A C G geneareusually > > > > > polymorphism 74 Italian Italian Italian USA USA USA Origin 72 G A A G T ). Itwouldbe ). Micelacking ⇑ TRPV5 , increased. 104 ); **CKD-EPIcreatinine–cystatinCequation2012( Type < Kidney stones A A G E S gene 0.01) (%) 54 10 10 16 nr nr Activity nd nd ⇓ ⇓ ⇑ Minor Allele in patientswithPHPT( with HHCwereinthesamerangeasthosemeasured most oftheindividualvaluesmeasuredinpatients patients withPHPTthaninthoseHHC,though CASR proteinisexpressedandactiveinkidneycells, protein, hypercalciuria hasbeendiagnosed( gene, locatedinthecytoplasmictailofreceptor harbouring germline inactivating mutations of the while the990GcausesagainoffunctionCASR likely determinesareductionoftheCASRexpression, stones occurrenceinPHPTpatients( rs7652589 andrs1501899,areassociatedwithkidney regionoftheCASRgene,(SNPs), locatedintheregulatory ( increased renalcalciumexcretioninPHPTItalianpatients tail ofthereceptorprotein,hasbeenassociatedwith ( PTH-related hypercalcaemia onrenalcalciumhandling variants ofthe PTH-induced calciumreabsorption.Therefore,common where itsactivationbyextracellularcalciuminhibitsthe hyperparathyroidism Kidney diseaseinprimary 78 Table 4 , CKD-EPI** CKD-EPI* MDRD# CKD-EPI* MDRD# MDRD# Equation 79 ). Two furthersinglenucleotidepolymorphisms 32.1% vs31.5% 32.2% vs33.4% 12.0% vs6.5% 40.0% vs28.0% 26.4% vs19.6% 38.0% vs34.0% 40.0% vs30.0% ). The990Gallele,locatedinthecytoplasmic 2.0% vs5.5% 3.0% vs3.5% 5.0% vs10.0% 5.8% vs8.8% 8.0% vs13.7% 4.0% vs5.0% 14% vs9.0% Frequency CASR 47% 52% > 90 87% 81% 85% 84% CASR genemodulatetheeffectof eGFR Downloaded fromBioscientifica.com at09/30/202109:13:15PM Kidney stones Kidney stones None Kidney stones Kidney stones None kidney phenotype Associated PHPT-related 89–60 75 39% 31% 105 ) geneonkidneydiseasein ). Indeed,insomepatients (mL/min/1.73 m ); nr, notreported. 30–59 13% 15% 19% 15% 15% 176 80 13% ). Thers1501899 :1 2 ) 1% 0% 0% 2% 1% < 30 76 , ( ( ( ( R46 Refs CASR ( ( ( ( ( ( ( ( ( ( ( ( ( ( Ref. 100 101 101 102 ( ( 80 80 98 97 79 78 98 97 79 78 97 79 78 92 43 99 77 ) ) ) ) ) ) ) ) ) ) ) ) ) ) via freeaccess ) ) ) ) ) ) ). ).
European Journal of Endocrinology HHC1 andHHC3patients ( calciumconcentrationsweresimilarinand urinary signalling ( such asCASRandG mediated endocytosisof plasma membraneproteins (OMIM#145981). AP2 mutations ofthe the causeofHHC3(OMIM#600740),whileinactivating mutations ofthe complex 2, andG encoding the loss-of-function mutationsof The FHH/HHCphenotypecanalsobeassociatedwith AP2S1 andGNA11 cytokineIL-1 the proinflammatory multiprotein inflammasomesresultinginmaturationof that stimulatesassemblyofmyeloidcellcytosolic acting viatheCASRcanfunctionasadangersignal D andcalciumlevels.Besides,elevatedlevelsof results indecreasedserumPTH,1,25-dihydroxyvitamin response elementsintheCASRgenepromoters.This parathyroid andkidneydothisthroughdefined and interleukin-6upregulateCASRexpressionin cytokinesinterleukin-1 cells. Proinflammatory regulating theexpressionlevelsofCASRonkidney cytokine like IL-1 proinflammatory cinacalcet ( the 990Galleledidnotinfluenceefficacyprofile of cohort ofMEN1-relatedPHPTpatients,thepresence calcium stone formation ( sensitivity tocinacalcetandexhibitedahigherriskof 990G alleleoftheCASRgenerespondedwithhigher hyperparathyroidism, wherepatientsharbouringthe vivo Similar increasedsensitivityhasbeenreported calcium oscillationsandp44/42-ERKphosphorylation. of theeffectCASRactivationonbothintracellular to thecalcimimeticcompoundR-568( that the990Galleleisassociatedwithhighsensitivity wild-type CASRandthe990Gvariantdemonstrated vitro for thewild-typealleleatbothSNPs( kidney stones,comparedwithpatientshomozygous and 990Gdisplayeda8-foldincreasedriskofexperience one ortwocopiesoftheminoralleleatbothrs1501899 been investigatedinPHPTpatients:patientscarrying effectofthesetwoSNPshaveprotein. Thecombinatory Review inasmallcohortofpatientswithCKD-related Lastly, recentdatahighlightedtheroleof studyinHEK293cellsstablytransfectedwiththe 86 84 , σ ). -2 subunitof the adaptor-relatedprotein 87 ). Estimatedglomerularfiltration rate α AP2S1 11 proteins respectively. Inactivating GNA11 α σ 11 2 isinvolvedintheclathrin- couplesCASRtointracellular genehavebeenidentifiedas 83 genedetermineHHC2 75 ). By contrast, in a small ), thoughpatientswith C Verdelli andSCorbetta AP2S1 β bycaspase-1( β 81 and and IL-6 in ) ( 82 Table 3 ), interms GNA11 85 ). ). In In in in β ,
regulation ofparacellularpermeabilityiontransport The Claudin 14 (OMIN#601678) ( implicated inantenataltype1Barttersyndrome chloride cotransporter-2(NKCC2),whichwaspreviously the a familyharbouringtwoheterozygousmutationsin in theneonatalperiodhasbeenrecentlydescribed Hypercalciuria associatedwithkidneystonesandPHPT SLC12A1 HHC3 thaninHHC1patients. tubular absorption of filtered calcium washigher in patients withHHC1,indicatingthattherateofrenal HHC3 havehigherplasmacalciumconcentrationthan phataemia withoutevidence ofsaltwasting;chronic Patients withPHPTshowed persistenthypophos Phosphate handling in PHPTpatients( SCL26A6 ascontributorinkidneystonedevelopment patients withstoneformation,suggestingarole of be associatedwithlessseverehypercalciuria inPHPT stones inPHPTpatients,thoughithasbeenshownto exhibits reducedactivity, isnotassociated with kidney variant ofthe dependent NaClabsorption. The 206Mpolymorphic of theproximaltubuleswhereitmediatesoxalate- transporter, isexpressedinthehumandistalsegments absorption. urine oxalateexcretionisduetoincreasedintestinal of the rare genetically determined conditions, increased kidney stonesinPHPTpatients( Urine oxalatehasbeenindicatedasariskfactorfor SCL26A6 found ( the genotypegroupsinPHPTpatientscouldbe difference inthefrequencyofkidneystonesbetween bone mineraldensityinhealthywomen;however, no with kidneystones,highlevelsofPTHandlow of the rs219780 SNP of at epithelialtightjunctionsinthenephron.TheCallele hyperparathyroidism Kidney diseaseinprimary SLC12A1 CLDN14 89 ). SLC26A6 geneencodesaproteininvolvedinthe gene,encodingthesodium–potassium– SLC26A6 88 35 ). ). , thegenecodingforasulphate Downloaded fromBioscientifica.com at09/30/202109:13:15PM gene,whoseencodedprotein CLDN14 3 ). With theexception has been associated 176 www.eje-online.org :1 R47 via freeaccess
European Journal of Endocrinology www.eje-online.org 3. 2. 1. Surgical management PHPT patients the clinicalmanagementofkidneydiseasein Specific itemsthatshouldbeconsidered for 3. 2. 1. should considerthat: presentation indifferentcohorts( are notassociatedwithPHPTandclinical kidney stones in the general population ( Though Vitamin Dreceptor(VDR) in PHPTpatients. interest toinvestigatetheroleof and apersistentregulationbyPTH( role indeterminationofrenalphosphatehandling unchanged, suggestingthat control mice,while and proteinexpressionwasreducedby50%relativeto under the control of PTH promoter, parathyroid-specific overexpressionofcyclinD1gene hyperparathyroidisminducedbymodel ofprimary hyperparathyroidism inPTH-D1transgenicmice,a Review 60 mL/min/1.73m Asymptomatic PHPTpatients witheGFRbelow define kidneyinvolvement ( receive anextensivediagnostic workoutaimedto Asymptomatic PHPTpatients arerecommendedto treatment ofPHPT( not experiencedelayinthediagnosisandsurgical Symptomatic PHPTpatientsforkidneystonesshould to distinguishFHHfromPHPT( creatinine clearanceratiolessthan0.02,asitcanhelp the At present,geneticanalysisisrecommendedonlyfor controlled studyarenotyetavailable; stones developmentinPHPTpatients,datafrom calcium handlingmightdefinetheriskofkidney Though genetic analysis of the genes involved in renal often needsmorethanoneevaluation; careful clinical,biochemicalandhormoneworkout great variabilityinclinicalpresentation;therefore, involved inrenalcalciumhandlingdeterminesthe variants orraremutationsoftheircodinggenes, The highnumberofmolecules,withthecommon From aclinicalpracticepointofview, clinicians CASR VDR genemutationsinallpatientswithcalcium– polymorphicvariantsareassociatedwith Slc9a3r1/NHERF-1 2 should be subject to surgery as should be subject to surgery 2 ); Slc34a1 2 ); C Verdelli andSCorbetta 92 9 Slc34a1 ). , hasapredominant 93 90 , 91 and ). Itwouldbeof 94 Slc34a1 ), genevariants ). VDR Pthr1
variants mRNA were 2. 1. Medical management 4. 4. 3. hyperparathyroidism Kidney diseaseinprimary concentration isassociatedwithhigherserum been demonstratedthathigherserumaldosterone a largemulti-ethnic,community-basedcohort,ithas should beconsideredinthePHPTmanagement.In Therefore, hypertensionmonitorandtreatment in PHPT patients as well as in generalpopulation. eGFR isassociatedwitharterialbloodhypertension and previouskidneydamages. age, hypertension,obesity, diabetes/insulinresistance factors ofCKDshouldbeconsideredinPHPTpatients: Diagnosis andtreatmentofalltheconcomitantrisk patients withCKD. shouldbeconsideredforPHPT parathyroid surgery Careful monitoringofthekidneyperformanceafter factors associatedwiththefurtherdeclineineGFR; part ofthetherapeuticgoalaimedtoremoveall (bisphosphonates). recommended drugsforthe controlofhypercalcaemia bone disease) and the indication for the currently bone mineral density by concomitant CKD-related PTH, multiglandularinvolvement andimpaired of hypophosphataemia, further increasedlevelsof classic clinicalpresentationofPHPT(namely, lack related biochemicalandclinicalalterationsalterthe with established CKD can be a challenge as CKD- Monitoring andmanagementofPHPTpatients PHPT patients. population, whilestudieshavenotbeenperformedin kidney stones are derived from studies in the general the urinelithogenicprofileoronrisktodevelop on efficacy ofnutritionalormedicalinterventions patients arelacking.Moreover, evidenceaboutthe profile topredictthekidneystonesriskinPHPT demonstrating thecapacityofabiochemicalurine Panels of the last Consensus Conference ( profile inPHPTpatientshavebeenraisedbythe controversies about the diagnosis of urinelithogenic Modification oflithogenicprofilePHPTurine: pressure ( patients, thoughitwaseffectiveincontrollingblood of aldosterone,failedinreducingPTHlevelsPHPT contrast, treatment with eplerenone, an antagonist control ofhypertensioninPHPTpatientsalso.By inhibitors mightbeconsideredandtestedforthe associated withlowerPTHconcentration( angiotensin–aldosterone system(RAAS)inhibitorsis PTH concentration,andthattheuseofrenin– 96 ). Downloaded fromBioscientifica.com at09/30/202109:13:15PM 176 :1 2 ), as studies 95 ). RAAS R48 via freeaccess European Journal of Endocrinology References of theIRCCSIstitutoOrtopedicoGaleazzi. This research was partially supported by the Ricerca Corrente L4080 grant Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest disease aswellestablishedCKD. patients withcarefulattentiononmildpreclinicalkidney highlights theneedtoapproachkidneydiseaseinPHPT studies inPHPTpatients.Nonetheless,availableevidence evidence derivedfromthegeneralpopulationthan kidney disease in asymptomatic PHPT are largely based on elucidated andtheguidelinesformanagementof the progressionofkidneydiseasearefarfrombeing on thehealthconditionsofPHPTpatientsaswell frequently occurs in current PHPT patients. The impact Kidney involvement, though mainly asymptomatic, Conclusions Review 8 7 6 5 4 3 2 1 calcifications in primary hyperparathyroidism. calcifications inprimary 147–160. for humankidneystoneformation. 0673-3) Mineral Metabolism those ofhypercalcemic hyperparathyroidism. hyperparathyroidism isassociatedwithcomplicationssimilarto Ozbek M, Berker D,Delibasi T&Guler S.Normocalcemic 2015 imaging technology. hyperparathyroidism using stones andvertebralfracturesinprimary Pepe J, Piemonte S,Scillitani A,Minisola S (doi:10.1530/EJE-12-0032) variables. hyperparathyroidism:associationswithbiochemical primary Vestergaard P. Renalstonesandcalcificationsinpatientswith (doi:10.1007/BF03345354) ofEndocrinologicalInvestigation Journal hyperparathyroidism. factors associatedtokidneystonesinprimary Eller-Vainichier C, Ponticelli C,Beck-Peccoz P&Spada A.Risk 3570–3579. Workshop. hyperparathyroidism: proceedingsoftheFourthInternational & Thakker RV. Diagnosisofasymptomaticprimary (doi:10.1038/kisup.2012.76) of chronickidneydisease. 2012 clinicalpracticeguidelinefortheevaluationandmanagement Rejnmark L, Vestergaard P &Mosekilde L.Nephrolithiasisand renal Coe FL, Evan AP, Worcester EM &Lingeman JE.Threepathways Tuna MM, Caliskan M,Unal M,Demirci T, Dogan BA,Kucukler K, Cipriani C, Biamonte F, Costa AG,Zhang C,Biondi P, Diacinti D, Starup-Linde J, Waldhauer E, Rolighed L,Mosekilde L & Corbetta S, Baccarelli A,Aroldi A,Vicentini L, Fogazzi GB, Eastell R, Brandi ML,Costa AG,D’Amour P, Shoback DM Kidney Disease:ImprovingGlobalOutcomes(KDIGO).KDIGO 100 1309–1315. (doi:10.1007/s00240-010-0271-8) European Journal ofEndocrinology European Journal Journal ofClinicalEndocrinologyMetabolism Journal (doi:10.1210/jc.2014-1414) 2016 Journal ofClinicalEndocrinologyandMetabolism Journal (doi:10.1210/jc.2014-3708) 34 Kidney International 331–335. Urological Research C Verdelli andSCorbetta 2005 (doi:10.1007/s00774-015- 2012 et al. 28
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