慢性肾脏病矿物质骨代谢异常参考课件

慢性肾脏病中的钙化问题DavidA.Bushinsky,MD医学、药理学、生理学JohnJ.Kuiper杰出教授

罗切斯特大学医学院

肾病科主任

罗切斯特大学医学中心

罗切斯特市,纽约州美国DisclosureStatementThecontentandclinicalrecommendationswiththebestevidenceavailablefromallsourceswhichIaminvolvedwillpromotequalityorimprovementsinhealthcareandwillnotpromoteaspecificproprietarybusinessinterestofacommercialinterestinnature.Iwillupholdacademicstandardstoensurebalance,independence,objectivity,andscientificrigorinmyroleintheplanning,development,orpresentationofthisCMEactivity,includinganypresentationoftherapeuticoptions.Thecontentwillbewell-balanced,evidence-based,unbiased.IwillinformlearnerswhenIdiscussorreferenceinvestigationaloroff-labeluseoftherapeuticagentsorproduct.eGFR与死亡率和心血管事件发生率的相关性N=1120295例成年受试者.

*年龄标准化发生率/100病人年;†心血管事件定义为：因冠心病住院、心衰、缺血性卒中和外周动脉疾病/100病人年。GoAS,etal.NEnglJMed.2004,351:1296-1305.eGFR(mL/min/1.73m2)0.761.0802468101214

6045–5930–4415–29<154.7611.3614.14

全因死亡率*32023/12/4eGFR与死亡率和心血管事件发生率的相关性N=1120295例成年受试者.

*年龄标准化发生率/100病人年;†心血管事件定义为：因冠心病住院、心衰、缺血性卒中和外周动脉疾病/100病人年。eGFR(mL/min/1.73m2)0.761.0802468101214

6045–5930–4415–29<154.7611.3614.14

全因死亡率*GoAS,etal.NEnglJMed.2004,351:1296-1305.心血管事件发生率†36.602.113.6511.2921.800510152025303540

6045-5930-4415-29<15eGFR(mL/min/1.73m2)42023/12/4透析患者的心血管疾病死亡率更高普通男性普通女性普通黑种人普通白种人透析男性透析女性透析黑种人透析白种人0.010.111010025-3435-4445-5455-6465-7475-84>85年龄年心血管死亡(%)FoleyRN,etal.AmJKidneyDis.1998;32(suppl3):S112-S119.52023/12/4透析患者的死亡原因Stenvinkeletal.ComprehensiveClinNeph200762023/12/4慢性肾脏病的危险因素Stenvinkeletal.ComprehensiveClinNeph200772023/12/4慢性肾脏病的危险因素Stenvinkeletal.ComprehensiveClinNeph200782023/12/4CKD-MBD的病理生理学磷代谢平衡成人体内含磷总量700g,85%在:食物

1200mg/日1350mg/日粪便排泄400mg/日排泄150mg/日吸收950mg/日骨形成300mg/日骨吸收300mg/日血液<1%磷库尿磷排泄800mg/日102023/12/4iPTH,25(OH)D和1,25(OH)2D水平的进展

早期肾脏病的评估研究（SEEK研究）050100150200250300PTH水平0510153035404550维生素D水平iPTH1,25维生素D25(OH)维生素DN=61N=117N=230N=396N=355N=358N=204N=93>8079-7069-6059-5049-4039-3029-20<20GFR水平2025N=1814LevinA,etal.KidneyInt.2007;71:31-38.112023/12/4CKD各期的血清FGF-23水平ESRD=终末期肾病25,00020,00015,00015001000500012345ESRDFGF-23(RU/mL)CKD分期PandeSetal.NephronPhysiol.2006;104:p23-p32.122023/12/4FGF-23与PTH的对比FGF-23PTH产生部位成骨细胞甲状旁腺主细胞主要刺激因素磷负荷/高磷血症低钙血症主要调节因素磷钙磷对尿磷的作用磷尿磷尿对1,25D合成的作用抑制促进132023/12/4iPTH、25(OH)D和1,25(OH)2D水平的进展

早期肾脏病的评估研究（SEEK研究）前瞻性、观察性、多中心研究(n=355)(n=61)(n=117)(n=230)(n=396)(n=358)(n=204)(n=93)CKD2CKD3CKD4eGFR区间(mL/min/1.73m2)钙和磷水平(mg/dL)LevinA,etal.KidneyInt.2007;71:31-38.142023/12/4血磷水平伴随着肾功能下降而上升KestenbaumB.JAmSocNephrol.2005;16:20.152023/12/4血磷水平伴随着肾功能下降而上升CraverLetal.NephrolDialTransplant.2007;22:1171-1176.N=13

CKD174

CKD2176CKD341

CKD46

CKD5血磷(mg/dL)(i)PTH(pmol/L)140012001000800600400200N=14

CKD175

CKD2180CKD343

CKD47

CKD524小时尿磷

(mg/24hours)磷排泄分数1601401008060402012003.03.54.04.55.05.5N=174CKD1341CKD2856CKD3354CKD4111CKD50102030N=174CKD1341CKD2856CKD3354CKD4111CKD5162023/12/4CKD中磷代谢平衡被打破食物

1200mg/日1350mg/日粪便排泄400mg/日排泄150mg/日吸收950mg/日骨形成100mg/日骨吸收150mg/日血液<1%磷库尿磷排泄750mg/日172023/12/4CKD中磷代谢平衡被打破食物1200mg/日骨形成100mg/日骨吸收150mg/日尿液排泄750mg/日吸收950mg/日排泄150mg/日磷库2001001350mg/日心血管粪便排泄400mg/日血液182023/12/4继发性甲状旁腺功能亢进的病理生理学↓1,25(OH)2D3↑P↓Ca2+↑

PTH慢性肾脏病骨病和系统毒性FGF-23FGF-23和PTH均促进尿磷排泄192023/12/4PTH1,25DPhosFGF-23202023/12/4这些因素并非相互独立而是相互依赖212023/12/4这些因素并非相互独立而是相互依赖因此，不能仅仅关注单一指标222023/12/4慢性肾脏病-矿物质骨疾病

钙化骨病实验室指标异常血管和软组织钙化异常骨骨转换矿化骨量骨线性生长骨强度升高FGF-23PTH磷降低1,25(OH)2D3钙CKD-MBDKidneyDisease:ImprovingGlobalOutcomes(KDIGO)CKD-MBDWorkGroup.KidneyInt.2009;76232023/12/4矿物质代谢异常的严重危害血磷升高，则心血管疾病风险也升高DhingraRetal.ArchInternMed.2007;167:879-885.Framingham后代研究n=33681.61.41.21.00.80.60.402.62.83.03.23.43.63.8血磷水平(mg/dL)心血管疾病的风险（HR）血磷正常范围252023/12/4血磷越高，则肾功能衰退速度越快中位随访时间=337（31-1442）

天肾功能下降(mL/min/month)透析前治疗开始时的血磷水平(mg/dL)基线eGFR13±5.4(mL/min/1.73m2)n=448r=-0.19P<0.0012.04.06.08.010.0-4.0-2.00.02.04.0VoormolenNetal.NephrolDialTransplant.2007;22:2909-2916.262023/12/4透析前CKD患者的血磷与死亡率的关系KestenbaumBetal.JAmSocNephrol.2005;16:520-528.N=34901.001.151.321.341.831.900.001.002.002.5-2.993.0-3.493.5-3.994.0-4.494.5-4.99>5.0血磷水平(mg/dL)校正死亡风险（HR）272023/12/4血磷水平若高于或低于某个水平

死亡风险更高BlockGA,JAmSocNephrol.2004;15:2208FloegeJ,NephrolDialTransplant.2011;26:1948,Kalantar-ZadehK,etal.KidneyInt.2006;70:771282023/12/4FGF-23水平升高，则死亡风险更高.Q=四分位组;R=参照组.KendrickJ,etal.JAmSocNephrol.2011;22:1913GutiérrezOM,etal.NEnglJMed.2008;359:584N=400

*P<0.05N=1,099292023/12/4FGF-23诱导大鼠左心室肥厚

7days 14days7days 14days未治疗心肌内直接注射溶媒心肌内直接注射FGF-23JClinInvest.2011;121:4393302023/12/4钙化人体内的钙分布References:1.HouillierP,FroissartM,MaruaniG,BlanchardA.Whatserumcalciumcantellusandwhatitcan’t.NephrolDialTransplantation.2006;21:29-32.2.NordinBEC,ed.Calcium,PhosphateandMagnesiumMetabolism:Clinical

PhysiologyandDiagnosticProcedures.NewYork,NY:ChurchillLivingstone;1976.3.HoskingDJ,ChamberlainMJ.Calciumbalanceinchronicrenalfailure:astudyusinginvivoneutronactivationanalysis.QJMed.1973;42:467479.4.BushinskyDA.Contributionofintestine,bone,kidney,anddialysistoextracellularfluidcalciumcontent.ClinJAmSocNephrol.2010;5(suppl1):S12-S22.322023/12/4CKD儿童的血管钙负荷ShroffRCetal.Circulation.2008;118:1748-1757.Permissionrequested.血管壁钙负荷(µg/µL)正常n=6透析前n=10透析n=24P=0.000550403020100P=0.02332023/12/4在各种CKD患者人群中，

钙化是疾病的一个常见的持续进展的结果AdaptedfromRussoD,CorraoS,MirandaI,etal.AmJNephrol.2007;27:152-158.SpiegelDM,RaggiP,MehtaR,etal.HemodialysisInt.2004;8:265-272.ChertowGM,BurkeSK,RaggiP;ForTreattoGoalWorkingGroup.KidneyInt.2002;62:245-252.PercentageofCKDpatients

withcoronaryarterycalcification321342023/12/4中国CKD和透析患者中的钙化情况YearStudyPopulationPrevalenceofCalcification2005/201022MHD95.4%CAC200669MHD55.15%CAC200740MHD62.5%CAC200839MHD64.1%AAC200954MHD86.1%AAC201191MHD75.8%CAC2011181MHD51.9%ValveCalcification2012150CKD3-5,HDorPDND35.2%CACPD72.1%CACHD79.3%CAC2005.中华肾脏病杂志.21卷2期.65-682006.中国血液净化.5卷4期.193-1952007.中华肾脏病杂志.23卷3期.167-1712008.中华肾脏病杂志.24卷7期.456-4602009.中华肾脏病杂志.25卷2期.81-852010.中国血液净化.9卷5期.247-2502011.中国血液净化.10卷6期.331-3342011.中华肾脏病杂志.27卷4期.259-2652012.中华肾脏病杂志.28卷5期.355-360352023/12/4钙化的发生不依赖于血钙水平1-5References:1.RussoD,CorraoS,MirandaI,etal.Progressionofcoronaryarterycalcificationinpredialysispatients.AmJNephrol.2007;27:152-158.2.BlockGA,SpiegelDM,EhrlichJ,etal.Effectsofsevelamerandcalciumoncoronaryarterycalcificationinpatientsnewtohemodialysis.KidneyInt.2005;68:1815-1824.3.ChertowGM,BurkeSK,RaggiP;forTreattoGoalWorkingGroup.Sevelamerattenuatestheprogressionofcoronaryandaorticcalcificationinhemodialysispatients.KidneyInt.2002;62:245-252.4.GoodmanWG,GoldinJ,KuizonBD,etal.Coronary-arterycalcificationinyoungadultswithend-stagerenaldiseasewhoareundergoingdialysis.NEnglJMed.2000;342:1478-1483.5.KidneyDisease:ImprovingGlobalOutcomes(KDIGO)CKD-MBDWorkGroup.KDIGOclinicalpracticeguidelineforthediagnosis,evaluation,prevention,andtreatmentofchronickidneydisease-mineralandbonedisorder(CKD-MBD).KidneyInt.2009;76(suppl113):S1-S130.362023/12/4钙/磷诱导血管平滑肌细胞钙化YangH,etal.KidneyInt.2004;66:2293-2299.P/Ca处理浓度mM(mg/dL)mM(mg/dL)250150100500200细胞内钙含量(µg/mgProtein)正常P情况下升高Ca高P情况下升高Ca正常Ca情况下升高P372023/12/4GiachellliCM.JAmSocNephrol.2004;15:2959-2964.Pi

+

Cbfa-1NaPiPiNa磷升高钙磷负荷的基质囊泡AP碱性磷酸酶钙结合蛋白富含胶原的细胞外基质基质矿化CaxP主动脉细胞382023/12/4冠状动脉钙化和死亡率的增加相关BlockGA,etal.KidneyInt.2007;71:438-441.No.atriskCCS=04642423934184CCS<4004241403632141CCS4003937353126154061218241.0030364248546066MonthsCAC=0CAC<

400CAC>

4000.000.250.500.75P=0.002生存分布函数392023/12/4动脉钙化程度越高，则生存几率越低00.250.50.75120406080随访（月）生存几率0处动脉钙化1处动脉钙化2处动脉钙化3处动脉钙化4处动脉钙化N=110稳定ESRD透析患者组间P<.0001AdaptedfromBlacherJetal.Hypertension.2001;38:938-942.402023/12/4CKD中的动脉钙化动脉粥样硬化钙化动脉内膜钙化Mönkeberg动脉钙化动脉中膜钙化412023/12/4动脉钙化对CKD5期、稳定血液透析患者的影响LondonGMetal.NephrolDialTransplant.2003;18:1731-1740.422023/12/4透析患者钙化的危险因素动脉钙化程度随年龄、透析年数和每日钙摄入量而增加1,2References:1.GuérinAP,LondonGM,MarchaisSJ,MetivierF.Arterialstiffeningandvascularcalcificationsinend-stagerenaldisease.NephrolDialTransplantation.2000;15:1014-1021.2.GoodmanWG,GoldinJ,KuizonBD,etal.Coronary-arterycalcificationinyoungadultswithend-stagerenaldiseasewhoareundergoingdialysis.NEnglJMed.2000;342:1478-1483432023/12/4KDIGO指南对CKD患者钙剂用量的立场KDIGO建议：对合并高磷血症的透析CKD患者，若出现以下情况，则限制钙摄入量1Reference:1.KidneyDisease:ImprovingGlobalOutcomes(KDIGO)CKD-MBDWorkGroup.KDIGOclinicalpracticeguidelineforthediagno