1、慢性肾脏病中的钙化问题David A.Bushinsky,MD医学、药理学、生理学 John J.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
2、specific proprietary business interest of a commercial interest in nature.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
3、 content will be well-balanced,evidence-based,unbiased.I will inform learners when I discuss or reference investigational or off-label use of therapeutic agents or product.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:
4、1296-1305.eGFR(mL/min/1.73 m2)0.761.0802468101214 604559 3044 1529 154.7611.3614.14 全因死亡率*32022-12-7eGFR 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.200
5、4,351:1296-1305.心血管事件发生率36.602.113.6511.2921.800510152025303540 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-S119.52022-12-7透析患者的死亡原因Stenvinkel et al.Comprehensive Clin Neph 200762022-12-7慢性肾脏病的危险因素Stenvinkel et al.Comprehensive Clin Neph 200772022-12-7慢性肾脏病的危险因
6、素Stenvinkel et al.Comprehensive Clin Neph 200782022-12-7CKD-MBD的病理生理学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%8079-7069-6059-5049-4039-3029-2020
7、GFR 水平2025N=1814Levin A,et al.Kidney Int.2007;71:31-38.112022-12-7CKD 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-p32.122022-12-7FGF-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
8、的作用抑制促进132022-12-7iPTH、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;71:31-38.142022-12-7血磷水平伴随着肾功能下降而上升Kestenbaum B.J Am Soc Nephrol.2005
9、;16:20.152022-12-7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=174CKD1341CKD2856CKD33
10、54CKD4111CKD50102030N=174CKD1341CKD2856CKD3354CKD4111CKD5162022-12-7CKD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172022-12-7CKD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950 mg/日
11、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182022-12-7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192022-12-7PTH1,25DPhosFGF-23202022-12-7这些因素并非相互独立而是相互依赖212022-12-7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222022-12-7慢性肾脏病-矿物质骨疾病 钙化钙化骨病骨病实验室指标异常实验室指标异常 血管和软组织钙化 异
12、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;76232022-12-7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Dhingra R et al.Arch Intern Med.2007;167:879-885.Framingham 后代研究后代
13、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252022-12-7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血磷水平血磷水平(mg/dL)校正死亡风险（校正死亡风险（HR）272022-12-7血磷水平若高于或低于某
14、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;70:771282022-12-7FGF-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,et al.N Engl J Med.2008;359:584N=400*P 0.05N=1,099292022-1
15、2-7FGF-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;121:4393302022-12-7钙化人体内的钙分布References:1.Houillier P,Froissart M,Maruani G,Blanchard A.What serum calcium can tell us and what it cant.Nephrol Dial Transplantation.2006;21:29-32.2.No
16、rdin 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 using in vivo neutron activation analysis.Q J Med.1973;42:467 479.4.Bushinsky DA.Co
17、ntribution of intestine,bone,kidney,and dialysis to extracellular fluid calcium content.Clin J Am Soc Nephrol.2010;5(suppl 1):S12-S22.322022-12-7CKD 儿童的血管钙负荷Shroff RC et al.Circulation.2008;118:1748-1757.Permission requested.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=0.02332022-12-7在各种
18、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 to Goal Working Group.Kidney Int.2002;62:245-252.Percentage of CKD patientswith coronary
19、artery calcification321342022-12-7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%CAC2011181 MHD51.9%Valve Calcification2012150 CKD 3-5,HD or PDND 35.2%CACPD 72.1%CACHD 79.3%
20、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4期.259-2659.2012.中华肾脏病杂志.28卷5期.355-360352022-12-7钙化的发生不依赖于血钙水平1-5References:1.Russo D,Corrao
21、 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 artery calcification in patients new to hemodialysis.Kidney Int.2005;68:1815-1824.3.Chertow GM,Burke
22、 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 al.Coronary-artery calcification in young adults with end-stage renal disease who are undergoin
23、g 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 chronic kidney disease-mineral and bone disorder(CKD-MBD).Kidney Int.2009;76(suppl 113):S1-S130.36
24、2022-12-7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 P372022-12-7Giachellli CM.J Am Soc Nephrol.2004;15:2959-2964.Pi+Cbfa-1NaPiNaPiPiNa磷升高磷升高钙磷负荷的基质囊泡AP碱性磷酸酶
25、钙结合蛋白富含胶原的细胞外基质基质矿化 Ca x P 主动脉细胞382022-12-7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392022-12-7动脉钙化程度越高，则生存几率越低0 00.250.250.50.50.750.751 1202
26、0404060608080随访（月）随访（月）生存几率生存几率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;38:938-942.402022-12-7CKD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412022-12-7动脉钙化对CKD5期、稳定血液透析患者的影响London GM e
27、t al.Nephrol Dial Transplant.2003;18:1731-1740.422022-12-7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.
28、2.Goodman WG,Goldin 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;342:1478-1483432022-12-7KDIGO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，则限制钙摄入量患者，若出现以下情况，则限制钙摄入量1 1Reference:1.Kidn
29、ey Disease: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-S130.442022-12-7骨病软组织软组织CKD患者的钙代谢骨骼骨骼肾脏肾脏肠道肠道462022-12-7
30、CKD5期患者的骨密度Ott,SM.Nephrology 14:395,2009(age dependent)472022-12-7eGFR10080-10060-8060比值比（比值比（OR）eGFRNickolas et al;JASN;2006482022-12-7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)492022-12-7髋骨骨折对透析患者全因死亡率的影响 Mittalhenkle A,et al.Am J Kidney
31、 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)502022-12-7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512022-12-7CKD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522022-12-7CKD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532022-12-7Questions?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.542022-12-7Thank you!552022-12-7
