慢性肾脏病矿物质骨代谢异常培训课件.ppt

1、慢性肾脏病矿物质骨慢性肾脏病矿物质骨代谢异常代谢异常Disclosure StatementThe content and clinical recommendations with the best evidence available from all sources which I am involved will promote quality or improvements in healthcare and will not promote a specific proprietary business interest of a commercial interest in na

2、ture.I will uphold academic standards to ensure balance,independence,objectivity,and scientific rigor in my role in the planning,development,or presentation of this CME activity,including any presentation of therapeutic options.The content will be well-balanced,evidence-based,unbiased.I will inform

3、learners when I discuss or reference investigational or off-label use of therapeutic agents or product.2慢性肾脏病矿物质骨代谢异常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。Go AS,et al.N Engl J Med.2004,351:1296-1305.eGFR(mL/min/1.73 m2)0.761.0802468101214 60455

4、9 3044 1529 154.7611.3614.14 全因死亡率*3慢性肾脏病矿物质骨代谢异常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。eGFR(mL/min/1.73 m2)0.761.0802468101214 60455930441529 154.7611.3614.14 全因死亡率*Go AS,et al.N Engl J Med.2004,351:1296-1305.心血管事件发生率36.602.113.6511.2921.800510

5、152025303540 6045-5930-4415-2985年龄年心血管死亡(%)Foley RN,et al.Am J Kidney Dis.1998;32(suppl 3):S112-S119.5慢性肾脏病矿物质骨代谢异常透析患者的死亡原因Stenvinkel et al.Comprehensive Clin Neph 20076慢性肾脏病矿物质骨代谢异常慢性肾脏病的危险因素Stenvinkel et al.Comprehensive Clin Neph 20077慢性肾脏病矿物质骨代谢异常慢性肾脏病的危险因素Stenvinkel et al.Comprehensive Clin Ne

6、ph 20078慢性肾脏病矿物质骨代谢异常CKD-MBD的病理生理学9慢性肾脏病矿物质骨代谢异常磷代谢平衡成人体内含磷总量成人体内含磷总量700 g,85%700 g,85%在在:食物食物1200 mg/1200 mg/日日1350 mg/1350 mg/日日粪便排泄粪便排泄400 mg/400 mg/日日排泄排泄150 mg/150 mg/日日吸收吸收950 mg/950 mg/日日骨形成骨形成300 300 mg/mg/日日骨吸收骨吸收300 mg/300 mg/日日血液血液 1%8079-7069-6059-5049-4039-3029-2020GFR 水平2025N=1814Levin

7、 A,et al.Kidney Int.2007;71:31-38.11慢性肾脏病矿物质骨代谢异常CKD 各期的血清 FGF-23 水平ESRD=终末期肾病25,00020,00015,000 1500 1000500012345ESRDFGF-23(RU/mL)CKD分期分期Pande S et al.Nephron Physiol.2006;104:p23-p32.12慢性肾脏病矿物质骨代谢异常FGF-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1,25 D合成的作用抑制促进13慢性肾脏

8、病矿物质骨代谢异常iPTH、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)CKD 2CKD 3CKD 4eGFR 区间区间(mL/min/1.73 m2)钙和磷水平钙和磷水平(mg/dL)Levin A,et al.Kidney Int.2007;71:31-38.14慢性肾脏病矿物质骨代谢异常血磷水平伴随着肾功能下降而上升Kestenbaum B.J Am Soc Nephrol.2005;16:2

9、0.15慢性肾脏病矿物质骨代谢异常血磷水平伴随着肾功能下降而上升 Craver L et al.Nephrol Dial Transplant.2007;22:1171-1176.N=13CKD174CKD2176CKD341CKD46CKD5血磷血磷(mg/dL)(i)PTH(pmol/L)140012001000800600400200N=14CKD175CKD2180CKD343CKD47CKD524小时尿磷小时尿磷(mg/24 hours)磷排泄分数磷排泄分数1601401008060402012003.03.54.04.55.05.5N=174CKD1341CKD2856CKD335

10、4CKD4111CKD50102030N=174CKD1341CKD2856CKD3354CKD4111CKD516慢性肾脏病矿物质骨代谢异常CKD中磷代谢平衡被打破食物食物1200 mg/日日1350 mg/日日粪便排泄粪便排泄400 mg/日日排泄排泄150 mg/日日吸收吸收950 mg/日日骨形成骨形成100 mg/日日骨吸收骨吸收150 mg/日日血液血液1%磷库磷库尿磷排泄尿磷排泄750 mg/日日17慢性肾脏病矿物质骨代谢异常CKD中磷代谢平衡被打破食物食物1200 mg/日日骨形成骨形成100 mg/日日骨吸收骨吸收150 mg/日日尿液排泄尿液排泄750 mg/日日吸收吸收9

11、50 mg/日日排泄排泄150 mg/日日磷库磷库2001001350 mg/日日心血管心血管粪便排泄粪便排泄400 mg/日日血液血液18慢性肾脏病矿物质骨代谢异常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19慢性肾脏病矿物质骨代谢异常PTH1,25DPhosFGF-2320慢性肾脏病矿物质骨代谢异常这些因素并非相互独立而是相互依赖21慢性肾脏病矿物质骨代谢异常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22慢性肾脏病矿物质骨代谢异常慢性肾脏病-矿物质骨疾病钙化钙化骨病骨

12、病实验室指标异常实验室指标异常 血管和软组织钙化 异常骨异常骨骨转换骨转换矿化矿化骨量骨量骨线性生长骨线性生长骨强度骨强度 升高升高 FGF-23FGF-23 PTHPTH 磷磷 降低降低-1,25(OH)1,25(OH)2 2D D3 3-钙钙CKD-MBDCKD-MBDKidney Disease:Improving Global Outcomes(KDIGO)CKD-MBD Work Group.Kidney Int.2009;7623慢性肾脏病矿物质骨代谢异常矿物质代谢异常的严重危害24慢性肾脏病矿物质骨代谢异常血磷升高，则心血管疾病风险也升高Dhingra R et al.Arch

13、Intern Med.2007;167:879-885.Framingham 后代研究后代研究n=33681.61.41.21.00.80.60.402.62.83.03.23.43.63.8血磷水平血磷水平(mg/dL)心血管疾病的风险（心血管疾病的风险（HR）血磷正常范围血磷正常范围25慢性肾脏病矿物质骨代谢异常血磷越高，则肾功能衰退速度越快中位随访时间=337（31-1442）天肾功能下降肾功能下降(mL/min/month)透析前治疗开始时的血磷水平透析前治疗开始时的血磷水平(mg/dL)基线基线eGFR135.4(mL/min/1.73m2)n=448r=-0.19P5.0血磷水平血

14、磷水平(mg/dL)校正死亡风险（校正死亡风险（HR）27慢性肾脏病矿物质骨代谢异常血磷水平若高于或低于某个水平死亡风险更高 Block GA,J Am Soc Nephrol.2004;15:2208 Floege J,Nephrol Dial Transplant.2011;26:1948,Kalantar-Zadeh K,et al.Kidney Int.2006;70:77128慢性肾脏病矿物质骨代谢异常FGF-23水平升高，则死亡风险更高.Q=四分位组;R=参照组.Kendrick J,et al.J Am Soc Nephrol.2011;22:1913 Gutirrez OM,e

15、t al.N Engl J Med.2008;359:584N=400*P 0.05N=1,09929慢性肾脏病矿物质骨代谢异常FGF-23 诱导大鼠左心室肥厚 7 days 14 days 7 days 14 days未治疗未治疗心肌内直接注射溶媒心肌内直接注射溶媒心肌内直接注射心肌内直接注射FGF-23FGF-23J Clin Invest.2011;121:439330慢性肾脏病矿物质骨代谢异常钙化31慢性肾脏病矿物质骨代谢异常人体内的钙分布References:1.Houillier P,Froissart M,Maruani G,Blanchard A.What serum calc

16、ium can tell us and what it cant.Nephrol Dial Transplantation.2006;21:29-32.2.Nordin BEC,ed.Calcium,Phosphate and Magnesium Metabolism:Clinical Physiology and Diagnostic Procedures.New York,NY:Churchill Livingstone;1976.3.Hosking DJ,Chamberlain MJ.Calcium balance in chronic renal failure:a study usi

17、ng in vivo neutron activation analysis.Q J Med.1973;42:467 479.4.Bushinsky DA.Contribution of intestine,bone,kidney,and dialysis to extracellular fluid calcium content.Clin J Am Soc Nephrol.2010;5(suppl 1):S12-S22.32慢性肾脏病矿物质骨代谢异常CKD 儿童的血管钙负荷Shroff RC et al.Circulation.2008;118:1748-1757.Permission r

18、equested.血管壁钙负荷(g/L)正常正常n=6透析前透析前n=10透析透析n=24P=0.000550403020100P=0.0233慢性肾脏病矿物质骨代谢异常在各种CKD患者人群中，钙化是疾病的一个常见的持续进展的结果1.Adapted from Russo D,Corrao S,Miranda I,et al.Am J Nephrol.2007;27:152-158.2.Spiegel DM,Raggi P,Mehta R,et al.Hemodialysis Int.2004;8:265-272.3.Chertow GM,Burke SK,Raggi P;For Treat t

19、o Goal Working Group.Kidney Int.2002;62:245-252.Percentage of CKD patientswith coronary artery calcification32134慢性肾脏病矿物质骨代谢异常中国CKD和透析患者中的钙化情况YearStudy PopulationPrevalence of Calcification2005/201022 MHD95.4%CAC200669 MHD55.15%CAC200740 MHD62.5%CAC200839 MHD64.1%AAC200954 MHD86.1%AAC201191 MHD75.8%

20、CAC2011181 MHD51.9%Valve Calcification2012150 CKD 3-5,HD or PDND 35.2%CACPD 72.1%CACHD 79.3%CAC1.2005.中华肾脏病杂志.21卷2期.65-682.2006.中国血液净化.5卷4期.193-1953.2007.中华肾脏病杂志.23卷3期.167-1714.2008.中华肾脏病杂志.24卷7期.456-4605.2009.中华肾脏病杂志.25卷2期.81-856.2010.中国血液净化.9卷5期.247-2507.2011.中国血液净化.10卷6期.331-3348.2011.中华肾脏病杂志.27卷

21、4期.259-2659.2012.中华肾脏病杂志.28卷5期.355-36035慢性肾脏病矿物质骨代谢异常钙化的发生不依赖于血钙水平1-5References:1.Russo D,Corrao S,Miranda I,et al.Progression of coronary artery calcification in predialysis patients.Am J Nephrol.2007;27:152-158.2.Block GA,Spiegel DM,Ehrlich J,et al.Effects of sevelamer and calcium on coronary arte

22、ry calcification in patients new to hemodialysis.Kidney Int.2005;68:1815-1824.3.Chertow GM,Burke SK,Raggi P;for Treat to Goal Working Group.Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.Kidney Int.2002;62:245-252.4.Goodman WG,Goldin J,Kuizon BD,et

23、 al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med.2000;342:1478-1483.5.Kidney Disease:Improving Global Outcomes(KDIGO)CKD-MBD Work Group.KDIGO clinical practice guideline for the diagnosis,evaluation,prevention,and treatment of ch

24、ronic kidney disease-mineral and bone disorder(CKD-MBD).Kidney Int.2009;76(suppl 113):S1-S130.36慢性肾脏病矿物质骨代谢异常钙/磷诱导血管平滑肌细胞钙化Yang H,et al.Kidney Int.2004;66:2293-2299.P/Ca 处理浓度mM(mg/dL)mMmM(mg/dL)(mg/dL)250150100500200细胞内钙含量(g/mg Protein)正常正常P P情况下升高情况下升高CaCa高高P P情况下升高情况下升高CaCa正常正常CaCa情况下升高情况下升高P P37慢

25、性肾脏病矿物质骨代谢异常冠状动脉钙化和死亡率的增加相关Block GA,et al.Kidney Int.2007;71:438-441.No.at riskCCS=04642423934184CCS 4004241403632141CCS 4003937353126154061218241.0030364248546066MonthsCAC =0CAC 4000.000.250.500.75P=0.002生存分布函数39慢性肾脏病矿物质骨代谢异常动脉钙化程度越高，则生存几率越低0 00.250.250.50.50.750.751 12020404060608080随访（月）随访（月）生存几率

26、生存几率0 0 处动脉钙化处动脉钙化1 1处动脉钙化处动脉钙化2 2处动脉钙化处动脉钙化3 3处动脉钙化处动脉钙化4 4处动脉钙化处动脉钙化N=110 稳定ESRD透析患者组间P.0001Adapted from Blacher J et al.Hypertension.2001;38:938-942.40慢性肾脏病矿物质骨代谢异常CKD中的动脉钙化动脉粥样硬化钙化动脉粥样硬化钙化动脉内膜钙化动脉内膜钙化Mnkeberg 动脉钙化动脉钙化动脉中膜钙化动脉中膜钙化41慢性肾脏病矿物质骨代谢异常动脉钙化对CKD5期、稳定血液透析患者的影响London GM et al.Nephrol Dial T

27、ransplant.2003;18:1731-1740.42慢性肾脏病矿物质骨代谢异常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动脉钙化程度随年龄、透析年数和每日钙摄入量而增加1,21,2References:1.Gurin AP,London GM,Marchais SJ,Metivier F.Arterial stiffening and vascular calcifications in end-stage renal disease.Nephrol Dial Transplantation.2000;15:1014-1021.2.Goodman WG,Go

28、ldin J,Kuizon BD,et al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.N Engl J Med.2000;342:1478-148343慢性肾脏病矿物质骨代谢异常KDIGO指南对CKD患者钙剂用量的立场KDIGOKDIGO建议：对合并高磷血症的透析建议：对合并高磷血症的透析CKDCKD患者，若出现以下情况，则限制钙摄患者，若出现以下情况，则限制钙摄入量入量1 1Reference:1.Kidney Disease:

29、Improving Global Outcomes(KDIGO)CKD-MBD Work Group.KDIGO clinical practice guideline for the diagnosis,evaluation,prevention,and treatment of chronic kidney disease-mineral and bone disorder(CKD-MBD).Kidney Int.2009;76(suppl 113):S1-S130.44慢性肾脏病矿物质骨代谢异常骨病45慢性肾脏病矿物质骨代谢异常软组织软组织CKD患者的钙代谢骨骼骨骼肾脏肾脏肠道肠道46慢

30、性肾脏病矿物质骨代谢异常CKD5期患者的骨密度Ott,SM.Nephrology 14:395,2009(age dependent)47慢性肾脏病矿物质骨代谢异常eGFR60ml/min高度预测髋骨骨折风险Nickolas et al;JASN;200648慢性肾脏病矿物质骨代谢异常髋骨骨折风险随透析龄而变化Alem AM,et al.Kidney Int.2000;58:396-399.N=326464*年龄标准化标准化发病率*(95%CI)男性女性透析龄标准化发病率*(95%CI)49慢性肾脏病矿物质骨代谢异常髋骨骨折对透析患者全因死亡率的影响 Mittalhenkle A,et al.

31、Am J Kidney Dis.2004;44:672-679.无骨折(n=22896)骨折(n=7636)1.000.750.500.250.00012345生存率研究历时(年)50慢性肾脏病矿物质骨代谢异常软组织软组织CKD患者的钙代谢骨骼骨骼肾脏肾脏肠道肠道51慢性肾脏病矿物质骨代谢异常CKD患者的钙代谢因此，因此，CKDCKD患者体内钙有分布异常患者体内钙有分布异常:应该存在于骨的钙含量下降不应存在于血管壁的钙含量却增加52慢性肾脏病矿物质骨代谢异常CKD患者的钙代谢状态因此，因此，CKDCKD患者体内钙有分布异常患者体内钙有分布异常:应该存在于骨的钙含量下降不应存在于血管壁的钙含量却增加导致发病率发病率和死亡率的死亡率的增加53慢性肾脏病矿物质骨代谢异常Questions?School of Athens/Scuola di Atene:Raphael/Raffaello Sanzio(1483-1520).Vatican.The School of Athens portrays Plato,Aristotle,and other ancient philosophers engaged in philosophic inquiry.54慢性肾脏病矿物质骨代谢异常Thank you!55慢性肾脏病矿物质骨代谢异常