慢性肾脏病矿物质骨代谢异常

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 Statement,The 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 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 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. 2004,351:1296-1305.,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.,透析患者的心血管疾病死亡率更高,Foley RN, et al. Am J Kidney Dis. 1998;32(suppl 3):S112-S119.,透析患者的死亡原因,Stenvinkel et al. Comprehensive Clin Neph 2007,慢性肾脏病的危险因素,Stenvinkel et al. Comprehensive Clin Neph 2007,慢性肾脏病的危险因素,Stenvinkel et al. Comprehensive Clin Neph 2007,CKD-MBD的病理生理学,磷代谢平衡,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）,Levin A, et al. Kidney Int. 2007;71:31-38.,CKD 各期的血清 FGF-23 水平,ESRD =终末期肾病,Pande S et al. Nephron Physiol. 2006;104:p23-p32.,FGF-23 与 PTH 的对比,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,Levin A, et al. Kidney Int. 2007;71:31-38.,血磷水平伴随着肾功能下降而上升,Kestenbaum B. J Am Soc Nephrol. 2005;16:20.,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.,CKD中磷代谢平衡被打破,CKD中磷代谢平衡被打破,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-23,FGF-23和PTH 均促进尿磷排泄,PTH,1,25D,Phos,FGF-23,这些因素并非相互独立而是相互依赖,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,慢性肾脏病-矿物质骨疾病,PTH = 甲状旁腺激素; FGF-23 = 成纤维细胞生长因子-23.,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-MBD,Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. Kidney Int. 2009;76,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.,血磷越高，则肾功能衰退速度越快,中位随访时间= 337 （31-1442） 天,Voormolen N et al. Nephrol Dial Transplant. 2007;22:2909-2916.,透析前CKD患者的血磷与死亡率的关系,Kestenbaum B et al. J Am Soc Nephrol. 2005;16:520-528.,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;70:771,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, et al. N Engl J Med. 2008;359:584,N = 400*P 0.05,N = 1,099,FGF-23 诱导大鼠左心室肥厚,7 days 14 days,7 days 14 days,未治疗,心肌内直接注射溶媒,心肌内直接注射FGF-23,J Clin Invest. 2011;121:4393,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. 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 using 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.,CKD 儿童的血管钙负荷,Shroff RC et al. Circulation. 2008;118:1748-1757. Permission requested.,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,Adapted from Russo D, Corrao S, Miranda I, et al. Am J Nephrol. 2007;27:152-158.Spiegel DM, Raggi P, Mehta R, et al. Hemodialysis Int. 2004;8:265-272.Chertow GM, Burke SK, Raggi P; For Treat to Goal Working Group. Kidney Int. 2002;62:245-252.,中国CKD和透析患者中的钙化情况,2005. 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. 81-85,2010. 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. 355-360,钙化的发生不依赖于血钙水平1-5,References: 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 artery 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 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 chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int. 2009;76(suppl 113):S1-S130.,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),mM,(mg/dL),250,150,100,50,0,200,细胞内钙含量 (g/mg Protein),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P,Giachellli CM. J Am Soc Nephrol. 2004;15:2959-2964.,主动脉细胞,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.,动脉钙化程度越高，则生存几率越低,0,0.25,0.5,0.75,1,20,40,60,80,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.0001,Adapted from Blacher J et al. Hypertension. 2001;38:938-942.,CKD中的动脉钙化,动脉粥样硬化钙化动脉内膜钙化,Mnkeberg 动脉钙化动脉中膜钙化,动脉钙化对CKD5期、稳定血液透析患者的影响,London GM et al. Nephrol Dial Transplant. 2003;18:1731-1740.,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1,2,References: 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, 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;342:1478-1483,KDIGO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1,Reference: 1. 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-