慢性肾脏病诊治新常态描述.ppt

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,慢性肾脏病诊治新常态,人类社会的发展 成就与挑战,世界的城市化进程,糖尿病和高血压,:,导致,ESRD,主要原因,进入透析的患者的初步诊断分类,Diabetes,50.1%,Hypertension,27%,Glomerulonephritis,13%,Other,10%,United States Renal Data System.Annual data report.2000.,No.of patients,Projection,95%CI,1984,1986,1988,1990,1992,1994,1996,1998,2000,2002,2004,2006,2008,2010,0,100,200,300,400,500,600,700,R,2,=99.8%,243,524,281,355,520,240,No.of dialysis patients,0 600 1200 1800 2400,Rate per million population,Taiwan,United states,Japan,Shanghai,Turkey,Korea,HK,Germany,Finland,prevalence of,ESRD,2007,1.Taiwan 2,288,2.Japan 2,060,3.USA 1,698,4.Germany 1,114,8.Canada 1,037,9.HK 1,027,14.Korea 973,28.Malasia 690,36.Shanghai 447,37.Thailand 420,USRDS 2009,Canada,Thailand,Malaysia,Chinese Society of Blood Purification(CSBP)ESRD Registration Program,End of 2007 End of,2008,ESRD patients 65,047 102,863,On HD/PD,Point 51.7pmp 79.1pmp,prevalence,52.9%,Zou L and wang M for the Chinese Society of Blood Purification,Clinical Nephrology,Vol.73-Suppl.1/2010,27/31(87%)provinces responded to this survey,There were big regional&provincial differences,China:ESRD Growth Rate to Exceed That of Population,2020,2000,2002,2004,2006,2008,2010,2012,2014,2016,2018,ACTUAL,PROJECTED,0.7%per year,population,1.0-1.2%per year,ESRD patients,300,000,250,000,200,000,150,000,100,000,50,000,0,1,150,000,000,1,200,000,000,1,250,000,000,1,300,000,000,1,350,000,000,1,400,000,000,1,450,000,000,Total pappulation,ESRD patients,Smith DH et al.J Am Soc Nephrol.2004;15:1363.,Collins AJ et al.Am J Kidney Dis.2008;51:S1,CKD,医疗费用巨大,美国,CDK,的医疗人群，占医疗总预算的,24%,。,中国一位尿毒症透析患者，一年的医疗费,10,万元。,尿毒症患者，只是,CKD,患者的冰山一角。,CKD,患者的医疗费用？,2009 KDIGO,伦敦研讨会,：,Prognosis Matters,www.kdigo.org/meetings_events/CKD_Controversies_Conference.php,Andrew S.Levey,MD,波士顿塔夫茨新英格兰医学中心肾脏科主任、教授,NKF,临床实践指南发展和执行中心主席,KDIGO 2009,伦敦研讨会计划委员会主席,KDOQI 2004CKD,高血压和降压药物指南工作组主席,KDOQI 2002CKD,临床实践指南工作组主席,2002,从,DOQI,到,KDOQI,指南,:,从终末期肾病到,CKD,全程管理,National Kidney Foundation.Am J Kidney Dis 2002;39(2 Suppl 1):S1-266.,.,为提高所有肾病患者的预后,包括最早期的肾脏损害,各个进展阶段，到肾衰的患者,.1999,年,NKF,启动指南制定新篇章,，,即将指南的范围扩大到包括全程的肾脏疾病,D for“dialysis”was changed to D for“disease”,CKD,概念的进展,从,KDOQI,到,KDIGO:,什么需要改变？,新的研究新的资料,新的视野,2005 KDIGO,修订,CKD,分期的目的：同样致力于改善,CKD,患者预后,KDIGO,成立的使命：改善全球,CKD,预后,2004,年,11,月,KDIGO,第一次国际研讨会探讨,CKD,定义和分期，,2005,年发表声明修订,CKD,分期：,“,Development,dissemination,and implementation of clinical practice guidelines are means to,improve outcomes of CKD,.”,2.Levey AS,et al.Kidney Int 2005;67(6):2089-100.,1.www.kdigo.org/,2009 KDIGO,伦敦研讨会：,The Debate Should Be About Prognosis,Prognosis,CKD,的主要转归？,CKD,检测有哪些进展,(eGFR,，白蛋白尿,),？,决定预后的主要因素是什么,(eGFR,，白蛋白尿，其他,),？,目前,CKD,分期标准是否需要增加与预后有关的因素？,现有的,CKD,定义和分期是否应该修改？,Eckardt KU,et al.Am J Kidney Dis 2009;53(6):915-20.,2009 KDIGO,研讨会关于,CKD,定义分期系统的重要变化之一：,判断,CKD,预后的终点,在全因死亡的基础上增加心血管死亡,www.kdigo.org/meetings_events/CKD_Controversies_Conference.php,在全因死亡的基础上增加,CV,死亡,，肾脏终点在终末期肾病（,ESRD,）的基础上增加进展性肾病和急性肾损伤（,AKI,）,www.kdigo.org/meetings_events/CKD_Controversies_Conference.php,白蛋白尿,(mg/g),300,GFR,分期,(mL/min/1.73m,2,),1,正常或增加,90,2,轻度,60-89,3a,轻,-,中度,45-59,3b,中,-,重度,30-44,4,重度,15-29,5,肾衰,15,2009 KDIGO,研讨会关于,CKD,定义分期系统的重要变化之二,：,在,GRF,分期基础上增加白蛋白尿分期,Glomerular Damage,PLASMA PROTEINS,Lysosomal rupture,Tubular,Epithelium,Macrophage,Infiltration,NH3,Activated,complement,Cytokines,PDGF,TGF,Fibroblast,activation,ECM,Interstitium,Transferrin iron,cytotoxicity,MCP-1,Lipids,ET-1,RANTES,Cytokines,PDGF,ET-1CTGF,Albumin,Fatty acids,cytotoxicity,Lipoproteins,LDL,HDL,Complement,Vasoconstriction,Ischemia,蛋白尿在肾脏病进展中的作用,Burton G AJKD 1996;27(6):765-775,AGEs,NFkB,CKD,患者尿白蛋白水平与,ESRD,、,CV,死亡及非,CV,死亡均显著相关,10,年,ESRD,危险比,HUNT 2,研究：,ESRD,Hallan SI,et al.J Am Soc Nephrol 2009;20(5):1069-77.,Hillege et al.Circulation 2002;106(14):177782,.,65589,名成人受试者，随访,10.3,年,非,CV,死亡,CV,死亡,PREVEND,研究：,CV,及非,CV,死亡,40548,名成人受试者，中位随访,961,天,2009 NKF,和,FDA,研讨会：,“正常”白蛋白尿并不正常，应关注更早期白蛋白尿,Levey AS,et al.Am J Kidney Dis 2009;54(2):205-26.,“,高值白蛋白尿”,取代“微量白蛋白尿”,“,极高值白蛋白尿”,取代“大量白蛋白尿”,NKF,和,FDA,研讨会在原来处于“正常”范围（,30mg/d,）的白蛋白尿中增加了“低值白蛋白尿（,10-29mg/d,）”的定义，将人们关注的视线从“微量白蛋白尿”往前转移，表明了,NKF,和,FDA,对于更早期白蛋白尿的关注和重视！,增加“低值白蛋白尿”的定义,以往被定义为“正常”白蛋白尿水平,www.kdigo.org/meetings_events/CKD_Controversies_Conference.php,白蛋白尿,(mg/g),300,GFR,分期,(mL/min/1.73m,2,),1,正常或增加,90,2,轻度,60-89,3a,轻,-,中度,45-59,3b,中,-,重度,30-44,4,重度,15-29,5,肾衰,15,2009 KDIGO,研讨会关于,CKD,定义分期系统的重要变化之三：,CKD 3,期分为,2,个亚期,（,GFR 30-44,及,45-59ml/min/1.73m,2,）,www.kdigo.org/meetings_events/CKD_Controversies_Conference.php,2009 KDIGO,研讨会关于,CKD,定义分期系统的重要变化之四：,在分期的基础上强调根据病因（如已知）进行分类,CKD,发展模式图的演变预示,CKD,干预策略的转变,-,进展，但同时,可逆转,Conceptual Model for CKD,2002 KDOQI Guidelines,Conceptual Model for CKD(revised),Levey AS.Am J Kidney Dis 2009,2009 KDIGO,伦敦研讨会：,Is CKD treatable?,CKD,的,治疗,干预,www.kdigo.org/meetings_events/CKD_Controversies_Conference.php,Raise GFR,None so far,Slowing Progression,Lower BP goal,ACEI,ARB,Preventing and Treating Complications,ESA,phosphate binders,vitamin D,analogues,calcimimetics,Reducing CVD Risk,Lower BP goal,ACEI,ARB,statins(subgroup analyses),Reducing Infection Risk,Immunizations,Improving Patient Safety,Accurate drug dosing;avoiding NSAID,contrast toxicity,phosphate bowel preps,RAS,阻断治疗的发展,我国肾脏内科应用,RASI,简史,RASI,在我国肾内科的应用简史：,1982,国产巯甲丙脯酸应用于肾病高血压治疗,1985,卡托普利,(,进口,),于中国上市,应用于肾科,1994,贝那普利,(,洛汀新,),于中国上市,应用于肾科,1997,福辛普利,(,蒙诺,),于中国上市,其他,ACEI,的登陆,1998,全球第一个治疗高血压的血管紧张素受体拮抗剂（,AIIA,）科素亚在中国上市,1999,代文引入中国市场，随后安博维的到来,2002,美卡素进入中国市场，其他,ARB,ACEI,在肾科应用适应证的演变：,1995,前治疗合并肾脏病的高血压,1995,后治疗有或无高血压的肾脏病,心血管和肾脏保护：,RASI,的作用不仅仅是控制血压,高血压,内皮功能紊乱,新发糖尿病和代谢综合症,心血管和肾脏保护,蛋白尿加剧和肾脏损害,心脏和结构改变,BP-,依赖,效应,AII-,介导,效应,AII-,介导,效应,Volpe M,et al.Int J Cardiol Pract 2007;,in press,G F R,TIME,无干预,DD,型,ACEI,治疗,I D or I I,型,ACEI,治疗,停,ACEI,ARB/ACEI,延缓慢性肾衰的进展,ARB,治疗,阻断肾素血管紧张素系统有利於肾脏疾病的临床验证,APRIL,REIN,RENNAL,IDNT,IRMA-2,LEWIS,CORPORATIVE,DETAIL,Risk reduction of ESRD achieved by angiotensin-converting enzyme inhibition or angiotensin receptor blockade,versus,placebo plus conventional treatment in large,prospective trials in patients with and without diabetes and overt nephropathy.,Laverman:J Am Soc Nephrol,Volume 15(1)Supplement 1.January 2004.S64-S70,Strippoli et al,BMJ 2004;329:828-39,Meta-analysis of ACEI&,ARB trials in people with,diabetic nephropathy,on,all cause mortality,renal outcomes,Renal outcomes*&ACEI,*,Progression from micro-to macroalbuminuria,Strippoli et al,BMJ 2004,Meta-analysis of ACEI,&ARB trials in people,with,diabetic nephropathy,on,all cause mortality,renal outcomes,Renal outcomes*&,ARB,Progression from micro-to macroalbuminuria,RASI,能预防新发糖尿病肾病吗？,RASI,预防微量白蛋白尿的发生,研究,（年）,患者人群,(N),治疗,随访,主要结果（,P,值）,预防,MAU,BENEDICT,（,2006,年）,高血压合并,T2DM(1204),群多普利,vs,维拉帕米,vs,群多普利,+,维拉帕米,vs,安慰剂,3.6,年,ACEI+CCB,较安慰剂：,MAU,风险,61%(0.01),ACEI,较安慰剂：,MAU,风险,53%(0.01),ROADMAP,（,2009,年）,T2DM(4449),奥美沙坦,vs,安慰剂,3.2,年,奥美沙坦较安慰剂：,MAU,风险,23%(0.0104),NAVIGATOR,（,2010,年）,IGT,合并,CV,风险,(9306),缬沙坦,vs,安慰剂,5,年,缬沙坦较安慰剂：,MAU,风险,32%(0.0001),DIRECT-RP,和,RASS,研究,:RASI,不能预防糖尿病肾病,？,RASS,研究,与安慰剂相比，依那普利及氯沙坦并不降低血压和尿白蛋白均正常的,1,型糖尿病患者的微量白蛋白尿发生率,DIRECT-RP,研究,与安慰剂相比，坎地沙坦并不降低糖尿病患者微量白蛋白尿发生风险,5231,例正常白蛋白尿的糖尿病患者，随机接受坎地沙坦或安慰剂治疗。至少随访,4,年。,285,例血压正常、微量白蛋白正常范围的,1,型糖尿病患者，将其随机分为氯沙坦组（,100mg/d,）、依那普利组（,20mg/d,）及安慰剂组，随访,5,年,Bilous R,et al.Ann Intern Med 2009;151(1):11-20.,Mauer M,et al.N Engl J Med 2009;361(1):40-51.,研究启示,对于,2,型糖尿病伴危险因素,(,如高血压,高血脂,),ARB,或,ACEI,可以预防新发微量蛋白尿的发生,对于低危的糖尿病患者,(,如血压正常,),ARB,或,ACEI,并不降低糖尿病患者微量,白蛋白尿发生风险,如何使,RAS,抑制效果最佳？,剂量,联合应用,其它靶环节,平均动脉压,(MAP)mmHg,推荐,降压剂量,可耐受的,最佳肾保护,剂量,？,120,110,100,90,80,Laverman GD,et al.Kidney Int 2005;94Suppl,S54-59,剂量增加,推荐,降蛋白尿肾保护,剂量,使降压疗效最大化,以蛋白尿达标为标准,探索可耐受的最大肾保护剂量,正确使用,ARB,兼顾血压和蛋白尿达标？,厄贝沙坦,300mg,降低尿蛋白,有效剂量300,mg（,初始降压剂量的,2,倍,）,相对基线改变,%,9%,-6%,-46%,3,6,12,18,24,20,10,0,-10,-20,-30,-40,-50,N,Engl J Med,2001;345:870-8,安慰剂,伊贝沙坦,300 mg,伊贝沙坦,150 mg,随访（月）,NS,P,0.001,BP,目标值：,135/85mmHg,使用肾保护剂量的理由,氯沙坦和,ACEI,治疗非糖尿病蛋白尿的交叉研究,45,Hypertension.2002;39:129,肾脏局部,RAS,活力远较系统,RAS,活力强,间质液,血浆,肾脏,对照组 依那普利,1,7.5,血浆,ACE,活性,肾脏,ACE,活性,Ang I,Ang II,(mmol/L or pmol/g),p0.01,0,1,2,3,4,*,*,*,*,80,60,40,20,0,2.0,1.0,1.5,0.5,0,对照组 依那普利,1,7.5,TGF-1mRNA,的表达,Marker sham uuo7d uuo14d uuo21d l507d l5014d l5021d l5007d l50014d l50021d,TGF-1,GAPDH,*,P0.05 vs.UUO;,*,P0.01 vs.UUO,.,*,*,*,*,*,*,*,*,由,Ang,结合,AT1-R,触发并通过细胞内炎症径路而增生的炎症细胞，反过来又会产生,Ang,和促进,AT1-R,的表达，这样就建立了一种正反馈的恶性循环。试验表明大剂量的,ARB,能更有效地打断这种循环，从而有效地起到阻止肾纤维化的作用。,*p,0.05 vs 160 mg;*p=0.021 vs.160 mg,Hollenberg NK,et al.J Hypertens 2007;25:1921,6,25%,57%,66%*,30,周时,BP130/80mmHg,患者的,UAER,较基线的中位变化,(%),12%,19%,30,周时,UAER20,g,/min,的患者比例,(%),24%*,大剂量缬沙坦更显著降低蛋白尿,缬沙坦,160 mg,缬沙坦,320 mg,缬沙坦,640 mg,缬沙坦,160 mg,缬沙坦,320 mg,缬沙坦,640 mg,-70,-60,-50,-40,-30,-20,-10,0,0,5,10,15,20,25,30,n=44,n=32,n=32,n=131,n=130,n=130,肾保护剂量的新知,剂量依赖性,每种药可能不同,大多数,2-4,倍,如何使,RAS,抑制效果最佳？,剂量,联合应用,其它靶环节,ARB,联合,ACEI,是否可提高肾保护的效果,?,CKD,时联合使用,ACEI,与,ARB,的理论基础,阻,断,ARB,Pepine CJ.Vascular Biology 2002;Vol 2,No.1 1-8.,肽链,内切酶,血管舒张,抗增殖,无活性肽,Ang-(1-7),AT,(,1-7),受体,AT,1,受体,血管紧张素原,肾素,Ang I,Ang II,AT,2,受体,AT,3,受体,AT,4,受体,血管收缩,增殖,基质形成,醛固酮分泌,血管舒张,抗增殖,凋亡,血管完整性,PAI-1,？,血管舒张,一氧化氮,前列腺素,EDHF,无活性肽,激肽原,缓激肽,激肽释放酶,BK B,2,受体,ACE,ACE,ACEI,抑,制,抑,制,Ang-(1-7),和缓激肽：协同拮抗,Ang,的不良作用,缓激肽,Ang-(1-7),血管舒张,抗增殖,纤溶增强,抗氧化应激,Ang II,血管收缩,增殖,纤溶减弱,氧化应激,升高,Pepine CJ.Vascular Biology 2002;Vol 2,No.1 1-8.,CALM,研究,ARB,和,ACEI,治疗糖尿病微量蛋白尿研究,CALM:,结果,ARB,16 mg od,n=42,ACEI,20 mg od,n=43,ARB,16 mg od+,ACEI,20 mg od,n=46,ARB,16 mg od,n=49,ACEI,20 mg od,n=46,ARB,16 mg od+,ACEI,20 mg od,n=49,0,-10,-20,-30,-40,-50,-60,UACR,%,P=0.04,DBP,mm Hg,P0.001,P0.001,0,-5,-10,-15,-20,24,周治疗后尿白蛋白,/,肌酐比,(UACR),的降低以及舒张压,(DBP),的降低,联合治疗组中前,12,周接受单药治疗,ONTARGET,试验计划,The ONTARGET/TRANSCEND Investigators.Am Heart J 2004;148:5261,Because of an extraordinary effort by investigators in 40 countries,it was possible to complete recruitment for the ONTARGET study in May 2003,seven months ahead of the scheduled timeline.,The ONTARGET trial currently recruited 25,621 patients.,研究设计,*,*,计划例数。实际,=25,620,计划例数。实际,=5,926,筛查,随机化（,n=23,400,）*,随机化（,n=6,000,）,第,6,周随访,第,6,周随访,每,6,月随访一次，共,5.5,年,每,6,月随访一次，共,5.5,年,雷米普利,10 mg,日,+,安慰剂,安慰剂,美卡素,80 mg,日,+,安慰剂,美卡素,80 mg,日,美卡素,80 mg,日,+,雷米普利,10 mg,日,ONTARGET,试验计划,主要复合心血管终点：,心血管死亡,非致命性心肌梗死,非致命性卒中,因充血性心衰而住院,The ONTARGET Trial Progamme protocol,主要终点,ONTARGET,试验计划,新诊断为充血性心衰,心血管血运重建术,新发糖尿病,认知能力下降痴呆,新发房颤,肾病,The ONTARGET Trial Progamme protocol,次要终点,ONTARGET:,三组主要终点,随访时间（年）,The ONTARGET Investigators.N Engl J Med 2008;358:1547-59.,Secondary and Other Outcomes.,Ramipril Telmisartan Combination Therapy Telmisartan Combination Therapy,Outcome,(N=8576)(N=8542)(N=8502)vs.Ramipril vs.Ramipril,number(percent)relative risk(95%CI),Revascularization 1269(14.8)1290(15.1)1303(15.3)1.03(0.951.11)1.04(0.971.13),Hospitalization 925(10.8)954(11.2)952(11.2)1.04(0.951.14)1.04(0.951.14),for angina,Worsening or 567(6.6)536(6.3)538(6.3)0.95(0.841.07)0.96(0.851.08),new angina,New diagnosis 366(6.7)399(7.5)323(6.1)1.12(0.971.29)0.91(0.781.06),of diabetes*,Any heart failure 514(6.0)537(6.3)478(5.6)1.05(0.931.19)0.94(0.831.07),New atrial fibrillation 570(6.9)550(6.7)537(6.5)0.97(0.861.09)0.96(0.851.07),Renal impairment 871(10.2)906(10.6)1148(13.5)1.04(0.961.14)1.33(1.221.44),Renal failure 48(0.6)52(0.6)65(0.8)1.09(0.741.61)1.37(0.941.98),requiring dialysis,*The numbers of patients included in this analysis were 5427 in the ramipril group,5294 in the telmisartan group,and 5280 in the combination-therapy group.,This category includes only patients who did not have atrial fibrillation at baseline:8296 in the ramipril group,8259 in the telmisartan group,and 8218 in the combination-therapy group.,No specific definitions were used.A determination of renal impairment was based on the clinical investigators report of an event that led to the discontinuation of a study drug.,P0.001.,Copyright,n engl j med 358;15 www.nejm.org april 10,2008,0.5,1.0,1.5,ONTARGET:Secondary and other endpoints,Revascularisation,Hospitalisation for angina,Worsening or new angina,New diagnosis of diabetes,Any heart failure,New atrial fibrillation,Renal impairment,Renal impairment requiring dialysis,Risk Ratio(95%),Favors,Ramipril+Telmisartan,Favors,Ramipril,1.04(0.971.13),1.04(0.95-1.14),0.96(0.85-1.08),0.91(0.78-1.06),0.94(0.83-1.07),0.96(0.85-1.07),1.33(1.22-1.44),1.37(0.94-1.98),The ONTARGET Investigators.N Engl J Med 2008;358:1547-59.,-10%+10%,讨论,怎样正确理解,ONTARGET,研究的肾脏次要终点结果？,对于心血管高危病人，,ARB+ACEI,的联合治疗需要注意哪些问题？,ONTARGET,研究对象不是肾脏病,以心血管高危的老年患者为研究对象,并不是,CKD,患者,;,85%,患者有动脉粥样硬化性心血管疾病,69%,为高血压患者,38%,患者患有糖尿病,心血管病变对肾脏的危害,伴有严重心血管病变的病例,全身血管病变可以造成血管调节功能障碍，以至血流动力学调节不良,心脏功能不良可能导致肾脏灌注不良,Ontarget,研究病例中不能排除肾动脉狭窄的存在,冠心病的病人在做冠脉造影的同时做肾动脉造影,发现有,20%,的病人同时存在肾动脉粥样硬化,(,狭窄程度大于,50%,当狭窄程度大于,60%,时方开始有临床表现,),具有外周血管动脉粥样硬化的病人作肾动脉造影显示,70%,同时有肾动脉狭窄,但,Ontarget,研究中肾脏,MRI,血管造影等资料缺乏,事实上，,T+R,组比,R,组降蛋白尿要明显,Lancet 2008:372:547,Ontarget,研究亚组分析,对蛋白尿的影响,大剂量,ACEI,大剂量,ARB,的应用证据：大剂量缬沙坦在大剂量赖诺普利的基础上进一步显著降低微量白蛋白尿,VALERIA,研究：,133,例高血压合并微量白蛋白尿患者，随机接受赖诺普利,40mg,、缬沙坦,320mg,或缬沙坦,/,赖诺普利,320/20mg,治疗,30,周,*P=NS vs,赖诺普利或缬沙坦,/,赖诺普利,*P,=0.029 vs,赖诺普利,41%,51%*,62%*,UAER,较基线几何平均变化率,(%),MAU,恢复至正常尿蛋白的患者比例,(%),赖诺普利,20mg,缬沙坦,320 mg,缬沙坦,/,赖诺普利,320/20mg,-70,-60,-50,-40,-30,-20,-10,0,0,10,20,30,40,17%,31%,#,38%,#,#,P=NS vs,赖诺普利或缬沙坦,/,赖诺普利,#,P,=0.034 vs,赖诺普利,赖诺普利,20mg,缬沙坦,320 mg,缬沙坦,/,赖诺普利,320/20mg,49,项联合治疗,Meta,分析：,双重阻断,RAS,：,与单用ARB,相比，蛋白尿进一步降低,25%,与单用,ACEI,相比，蛋白尿进一步降低,22%,Ann Intern Med.2008;148:30-48,结论支持,RASS,双重阻断,!,如何使,RAS,抑制效果最佳？,剂量,联合应用,其它靶环节,治疗,24,周，仍有白蛋白尿的患者比例,最大推荐剂量,RAS,抑制剂治疗糖尿病肾病，,66%,患者尿蛋白未恢复,5%,患者进展为临床显性蛋白尿,n=195,n=194,n=201,n=195,n=194,n=201,进展为临床显性蛋白尿的患者比例,安慰剂,厄贝沙坦,150mg,厄贝沙坦,300mg,安慰剂,厄贝沙坦,150mg,厄贝沙坦,300mg,Parving HH,et al.N Engl J Med 2001;345:870-8,RAS,抑制剂治疗糖尿病肾病,仍有,33%-44%,的患者发生肾脏终点事件,40,50,30,20,10,0,12,24,36,48,%,发生终点事件,安慰剂,氯沙坦,RR,降低,16%,p=0.024,月,联合肾脏终点事件,(RENAAL),残余风险,43.5%,联合肾脏终点事件,(IDNT),6,12,18,24,30,36,42,48,50,40,30,20,10,厄贝沙坦,氨氯地平,安慰剂,月,RR p,值,I vs P 0.80 0.024,I vs A 0.77 0.006,A vs P 1.04 ns,%,发生终点事件,0,残余风险,32.6%,Brenner,et al,.N Engl J Med 2001;345:861869.,2,.Lewis,et al,.,N Engl J Med 2001;345:851860,联合肾脏终点：血肌酐倍增，终末期肾病和全因死亡,RAS,抑制剂治疗非糖尿病肾病（,IgAN,）平均尿蛋白排泄仍有,1.23g/,天,(HKVIN),尿蛋白（,g/,天）,周,0 12 24 52 76 104,3,2.5,2,1.5,1,0.5,安慰剂,缬沙坦,P0.001,Li PK.Am J Kid Dis 2006;47:751-60.,多中心、随机、双盲、安慰剂对照研究，入组,109,例中国,IgA,肾病患者,尽管接受,ARB,治疗,糖尿病肾病的高血压患者肾功能下降的,速度,仍然较,快,GFR,的平均下降速度,(mL/min/1.73m,2,/yr),6,0,2,4,8,ARB,抑制,RAS,安慰剂,(,无,RAS,抑制剂,),RENAAL,2,IDNT,3,随着年龄增长，,GFR,的正常下降速度,1.Weber 7(2):45,54.,2.Brenner,et al,.,NEngl J Med 2001;345:861869.,;,3.Lewis,et al,.N Engl J Med 2001;345:851860.,伴肾脏病的高血压患者血压达标率低,达标血压：糖尿病或肾病患者血压,130/80mmHg,，其他患者,140/90mmHg,全国,22,个城市，,100,家三甲医院，共入组,5186,例,患者,血压达标率,胡大一等,.,中华心血管病杂志,.2010;38:230-238,n=812,n=1139,n=1891,n=936,目前的,RAS,抑制剂是否已经足够？,进一步的阻断,RAS,可,能,有更好的肾脏保护作用,ARB,和,ACEI,可延缓肾病的进展；然而肾脏损伤和终末期肾病的进展仅仅是延缓并不能停止,ARB,和,ACEI,肾脏保护作用很有限，,部分原因为,这些药物不能彻底阻断,RAS,与ACEI、ARB不同,，,直接肾素抑制剂,（,DRI,）,作用于,RAS,的源头，,降低PRA,A,n,g,i,o,t,e,n,s,i,n,o,g,e,n,Angiotensinogen,Renin,Ang,I,Ang,II,ACE,AT,1,receptor,ACEI,ARB,A,n,g,i,o,t,e,n,s,i,n,o,g,e,n,血管紧张素原,肾素,Ang,I,Ang,II,ACE,AT,1,受体,ACEI,ARB,阿利吉仑,Renin,肾素,血管紧张素原,阿利吉仑,负反馈环,阿利吉仑,ARB,ACEI,PRA,Ang II,Ang I,Mller DN&Luft FC.,Clin J Am Soc Nephrol 2006;1:2218,;Weber MA 7:4554,阿利吉仑对高血压伴糖尿病患者蛋白尿的影响,Parving H H,et al,N Engl J Med 2008;,358:(23);2433-2446,试验,概述,试验设计,:,双盲、随机、安慰剂对照,