ARB降低CKD患者心血管危险的新认识-4-14倪兆慧

Slide Title,Body Text,Second Level,Third Level,Fourth Level,ARB,降低,CKD,患者心血管危险的新认识,倪兆慧,上海交通大学医学院附属仁济医院肾脏科,Evaluation Warning : The document was created with Spire.Presentation for .NET,内,容,容,为何要,强,强调CKD患者心,血,血管危,险,险的早,期,期干预,？,？,CKD患者的,心,心血管,危,危险因,素,素:AngII的作用,ARB在CKD患者心,血,血管危,险,险干预,中,中的价,值,值,Evaluation Warning : The document was created with Spire.Presentation for .NET,CVD是导致ESRD的,主要死,亡,亡原因,Evaluation Warning : The document was created with Spire.Presentation for .NET,中国血,透,透患者,的,的主要,死,死因,Chinese Dialysis andTransplantationRegistration Reportin2000,Evaluation Warning : The document was created with Spire.Presentation for .NET,CKD,ESRD,CVD,CKD人群同,时,时面临,ESRD和CVD的双重威,胁,胁,CKD患者在,发,发展到ESRD之前可,能,能已死,于,于CVD并发症,HostetterT.NEnglJ Med.2004;351,:,:1344-6.,Evaluation Warning : The document was created with Spire.Presentation for .NET,在透析,开,开始前,就,就已经,存,存在,动脉粥,样,样硬化,对照组302例，Scr652mol,/,/l,CRF110例,Scr56443mol,/,/l,HD345例,Scr1003 1,mol,/,/l,Evaluation Warning : The document was created with Spire.Presentation for .NET,对照组,CKDII、III期,CKDIV、V期,CKDIIV期,既往动,脉,脉粥样,硬,硬化史,比,比例,20.0%,45.7%,44.4%,45.0%,早中期CKD患者ASCVD史比例,明,明显升,高,高,CKDII,III期94例（46）,CKDIV，V期108例（54）,周文彦,，,，倪兆,慧,慧，方,炜,炜等中华肾,脏,脏病杂,志,志2007,Evaluation Warning : The document was created with Spire.Presentation for .NET,肾功能,不,不全早,期,期即存,在,在冠脉,微,微循环,异,异常,ChadeAR,etal,.,. KidneyInternational.2006,;,;69,:,:266-71.,n=605，正常,或,或轻微,冠,冠脉异,常,常的患,者,者,GFR,(,(ml,/,/min/1,.,.73m2),冠脉血,流,流储备,GFR,60ml/min,/,/1.73m2vsGFR,60ml/min,/,/1.73m2，P0,.,.001,3.00.8,3.050.8,3.030.7,2.690.6,2.630.6,0,1,2,3,4,80,Evaluation Warning : The document was created with Spire.Presentation for .NET,最新荟,萃,萃分析,证,证实,CKD并发的CVD死亡率,高,高于一,般,般人群,14项研究,，,，n=100,064,未进行,透,透析的CKD患者,TonelliM,etal.JAmSocNephrol.2006;17:20342047,Evaluation Warning : The document was created with Spire.Presentation for .NET,CVD是CKD患者的,首,首要死,亡,亡原因,CVD死亡率,占,占CKD患者总,死,死亡率,的,的40-50%,CKD14期：,死于CVD的比例,约,约为死,于,于肾病,的,的3倍，很,多,多病人,在,在透析,或,或肾移,植,植前即,因,因CVD死亡,CKD5期：,年死亡,率,率约为20-23%，其中,心,心血管,原,原因占,到,到45,透析：,CVD死亡率,占,占病人,总,总死亡,率,率的44.2(上海地,区,区)51.0（全,国,国）,CulletonBF,etal,.,. Seminars in Dialysis.2003;16(2,),):95-100.Kundhal K, et al.Nephron ClinPract2005;101,:,:c47c52,上海市,肾,肾脏病,心,心血管,并,并发症,调,调查协,作,作组.中华肾,脏,脏病杂,志,志, 2001,;,;17,(,(2),:,:91,94,Evaluation Warning : The document was created with Spire.Presentation for .NET,CKD：心血,管,管等危,病,病,大量证,据,据表明,：,：,不仅肾,衰,衰(CKD5期)患者是,心,心血管,发,发病和,死,死亡的,高,高危人,群,群，CKD早期即,已,已高发,心,心血管,事,事件，应当重,视,视心血,管,管疾病,的,的早期,干,干预,AHA最新指,南,南：,将CKD作为心,血,血管等,危,危病，,并,并认为所有阶,段,段的CKD患者均,为,为心血,管,管疾病,的,的“最高危,人,人群”,MenonV,etal.Kidney International,.,. 2005,;,;68,:,:14131418,Evaluation Warning : The document was created with Spire.Presentation for .NET,CKD并发心,血,血管病,的,的特点,CKD并发CVD主要表,现,现为两,类,类:,动脉血,管,管疾病,：,：动脉,粥,粥样硬,化,化和小,动,动脉硬,化,化,心肌疾,病,病：左,心,心室肥,厚,厚(LVH)和左心,室,室扩张,CKD并发的CVD以缺血,性,性ST-T变化、,心,心衰和,心,心律失,常,常最常,见，心,脏,脏超声,检,检测以,左,左室功,能,能异常,为,为主(上海地,区,区),CVD并发的CVD死亡原,因,因以心,衰,衰、脑,血,血管意,外,外和心,律,律失常,最,最多见(上海地,区,区),上海市,肾,肾脏病,心,心血管,并,并发症,调,调查协,作,作组.中华肾,脏,脏病杂,志,志, 2001,;,;17,(,(2),:,:91,94,Evaluation Warning : The document was created with Spire.Presentation for .NET,内,容,容,为何要,强,强调CKD患者心,血,血管危,险,险的早,期,期干预,？,？,CKD患者的,心,心血管,危,危险因,素,素:AngII的作用,ARB在CKD患者心,血,血管危,险,险干预,中,中的价,值,值,Evaluation Warning : The document was created with Spire.Presentation for .NET,CKD通过传,统,统/非传统,危,危险因,素,素引起CVD,MenonV,etal.Kidney International,.,. 2005,;,;68,:,:14131418,肾病,传统和,非,非传统,危,危险因,素,素,心肌重,建,建,血管重,建,建,心肌病,左室肥,厚,厚、舒,张,张和收,缩,缩期功,能,能障碍,动脉粥,样,样硬化,和,和动脉硬,化,化,缺血性,心,心脏病,、,、心衰,和,和心血,管,管死亡,Evaluation Warning : The document was created with Spire.Presentation for .NET,CKD高发CVD的传统/非传统,危,危险因,素,素,传统危险因素,非传统危险因素,老年,男性,高血压,血管疾病,左室肥厚,(LVH),脂代谢紊乱,糖尿病,吸烟,体力活动,白蛋白尿,贫血,钙,/,磷代谢异常,氧化应激,炎症,营养不良,同型半胱氨酸,脂蛋白,容量负荷过度,高凝状态,内皮功能障碍,交感神经活性,胰岛素抵抗,/,代谢综合征,GFR,MenonV,etal.Kidney International,.,. 2005,;,;68,:,:14131418,Evaluation Warning : The document was created with Spire.Presentation for .NET,CKD患者普,遍,遍存在,高,高血压,上海多,中,中心研,究,究2000,Evaluation Warning : The document was created with Spire.Presentation for .NET,血压每,升,升高20/10mmHg,心血管,死,死亡风,险,险加倍,*,*,*个体年,龄,龄40-69岁,最低血,压,压BP115,/,/75mmHg,.,.,LewingtonS et al.Lancet. 2002,;,;360:1903,-,-1913.,心血管死亡,风险,收缩压/舒张压(mmHg,),),0,1,2,3,4,5,6,7,8,115,/,/75,135,/,/85,155,/,/95,175,/,/105,Evaluation Warning : The document was created with Spire.Presentation for .NET,LIFE亚组研,究,究,蛋白尿,水,水平与CVD患病率,成,成正相,关,关,Wachtelletal.JHypertens2002;20:405,12,LIFE试验, 8,029名高血,压,压受试,者,者伴左,心,心室肥,大,大,平均年,龄,龄66岁,CVD患病率(%),40,30,20,10,0,糖尿病,脑,脑血管,疾,疾病,外,外,周,周血管,疾,疾病冠状血,管,管疾病,正常尿,蛋,蛋白,微量蛋,白,白尿(白蛋白/肌酐3.5 mg/mmol),大量蛋,白,白尿(白蛋白/肌酐35mg,/,/mmol),Evaluation Warning : The document was created with Spire.Presentation for .NET,RENAALPostHoc分析,基线蛋,白,白尿是DN患者心,血,血管危,险,险的强,预,预测因,子,子,蛋白尿,每,每增加1g/g,心血管,复,复合终,点,点和心,力,力衰竭,危,危险增,加,加17%和26%,60,40,20,0,0,12,24,36,48,60,40,20,0,0,12,24,36,48,心血管,复,复合终,点,点,心血管,复,复合终,点,点(%,),),月,3.0g/g,1.53,.,.0g,/,/g,1.5g/g,心力衰,竭,竭终点,(,(%),心力衰,竭,竭,月,3.0g/g,1.53,.,.0g,/,/g,1.5g/g,蛋白尿,以,以晨尿,标,标本的,尿,尿白蛋,白,白:肌,酐,酐比率,计,计算,ZeeuwDD,etal.Circulation,.,. 2004,;,; 110:921-927,Evaluation Warning : The document was created with Spire.Presentation for .NET,RENAALPostHoc分析：,治疗后,最,最初6个月蛋,白,白尿下,降,降程度与DN患者的,心,心血管,预,预后高,度,度相关,蛋白尿,每,每减少50%,心血管,复,复合终,点,点和心,力,力衰竭,危,危险减,少,少18%和27%,2.0,1.5,1.0,0.5,0.0,-90,-25,0,25,50,72,2.0,1.5,1.0,0.5,0.0,-90,-25,0,25,50,72,心力衰,竭,竭,心力衰,竭,竭风险,比,比,蛋白尿,下,下降程,度,度(%,),),心血管,复,复合终,点,点,心血管,事,事件风,险,险比,蛋白尿,下,下降程,度,度(%,),),ZeeuwDD,etal.Circulation,.,. 2004,;,; 110:921-927,Evaluation Warning : The document was created with Spire.Presentation for .NET,MDRD研究CRP是CKD患者CVD死亡率,的,的独立,预,预测因,素,素,MenonV,etal.Kidney International,.,. 2005,;,;68,:,:76672,CRP,3.0mg,/,/L,CRP,3.0mg,/,/L,时间(月),P0,.,.0001,3期和4期CKD患者，CRP,3.0mg,/,/L(n=414)，CRP,3.0mg,/,/L(n=283),生存率,Evaluation Warning : The document was created with Spire.Presentation for .NET,AngII和心脏,血,血管结,构,构重塑,AngII,血管活,性,性,促进增,殖,殖,氧化应,激,激,炎症反,应,应,VSMC Ca,+,血管收,缩,缩,高血压,致癌基,因,因,c-fos,c-jun,生长因,子,子,TGF,-,-B1,PDGF,PAI,-,-1,巨噬细,胞,胞,内皮细,胞,胞NO,Lipoxygenase,0x-LDL,MCP,-,-1,VCAM,单核细,胞,胞聚集,白细胞,黏,黏附,内皮细,胞,胞功能,障,障碍,泡,泡,沫,沫细胞,形,形成,内皮细,胞,胞凋亡VSMC增殖,细胞外,基,基质堆,积,积,纤,纤维化,心脏血,管,管结构,重,重塑,VolpeM,etal.JAmSocNephrol. 2002,;,;13,:,: S173,S178,Evaluation Warning : The document was created with Spire.Presentation for .NET,内,容,容,为何要,强,强调CKD患者心,血,血管危,险,险的早,期,期干预,？,？,CKD患者的,心,心血管,危,危险因,素,素:AngII的作用,ARB在CKD患者心,血,血管危,险,险干预,中,中的价,值,值,Evaluation Warning : The document was created with Spire.Presentation for .NET,科素亚50mg,科素亚50-100mg,荟萃分,析,析43项临床,研,研究,Losatan强效降,压,压疗效,卓,卓著,收缩压,与基线,变化,-16,-10,.,.4,mmHg,-10,mmHg,-2,-4,-6,-8,-10,-12,-14,Conlin,PRetal.AJH 2000,;,;13,:,:418426,-18,-8.2,mmHg,-13,.,.1,mmHg,n=2359,n=2217,收缩压,舒张压,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,与,与硝苯,地,地平控,释,释片降,压,压疗效,相,相当,血压,与基,线的,变化,(mmHg),氯沙坦,+,HCTZ,(n=110),硝苯地平控释片,(n=113),治疗周,氯沙坦50mg(37%)氯沙坦50mgHCTZ12.5mg(32%,),)氯沙坦50mgHCTZ25mg,(,(31,%,%),硝苯地,平,平30mg(38%)硝苯地,平,平60mg(34%)硝苯地,平,平90mg（28%）,Matthew MR,etal.ClinTher1996;18(3),:,: 411-428,P=0,.,.78,P=0,.,.64,P=0,.,.35,硝苯地平控释片,30mg,氯沙坦,50mg,8.9,mmHg,9.3,mmHg,治疗,4,周,Evaluation Warning : The document was created with Spire.Presentation for .NET,LIFE研究氯沙坦,有,有效降,低,低高血,压,压患者,白,白蛋白,尿,尿,*Wilcoxon队列均p0,.,.001,事件(年),相比于,基,基线的,中,中位数,变,变化(mg,/,/mmol),*,*,*,*,*,IbsenetalJ.Hypertension22,:,: 1805,-,-1811,2004,-0.5,-0.4,-0.3,-0.2,-0.1,0,0.1,1,2,3,4,5,阿替洛,尔,尔,氯沙坦,氯沙坦,比,比阿替,洛,洛尔更有效,降,降低心,血,血管事,件,件的益处，20%可以用,氯,氯沙坦,更,更显著,降,降低白,蛋,蛋白尿,来,来解释,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,有,有效降,低,低蛋白,尿,尿在各种,肾,肾脏病,变,变中得,到,到验证,氯沙坦,降低蛋,白,白尿,与氨氯,地,地平,的比较,-55%,-,-29%,-,-47%,-,-63%,-,-50,%,%,科素亚,与,与氨氯,地,地平治,疗,疗非糖,尿,尿病性,肾,肾病20周,两者降,压,压幅度,相,相似，,但,但科素,亚,亚降低,蛋,蛋白尿,更,更显著,PragaM,etal.KidneyInt.2002,suppl82:S42-46,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,预,预防足,突,突细胞,应,应激,Desmin染色,Chol组：接,受,受2胆固,醇,醇喂食2周大鼠,Chol+mols,/,/los组：采,用,用吗多,明,明或氯,沙,沙坦预,处,处理2周后接,受,受2胆固,醇,醇治疗,L-NNA组：接,受,受40mg/kg L,-,-NNA饮食2周,L-NNA,+,+los组：接,受,受氯沙,坦,坦预处,理,理2周后接,受,受40mg/kg L,-,-NNA治疗2周,*P0.05vs对照组,；,；,P0.05vschol组；,#P0.05vsL-NNA组,ATTIADM,etal,.,. JAmSoc Nephrol,.,.2004;15:949957,足突细,胞,胞应激(Desmin评分),对照组Chol组,Chol+mols组,Chol+los组,L-NNA组,L-NNA+los组,*,*,#,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,抑,抑制血,管,管炎症,反,反应,CanLi, et al.Transplantation,.,.2005;68:27872793,.,.,CRP阳性细,胞,胞,*,*,入球小,动,动脉病,变,变(%),*,对照组,CsA组,CsA+氯沙坦,组,组,对照组,CsA组,CsA+氯沙坦,组,组,*P0.01vs对照组P0,.,.05vsCsA组,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,抑,抑制氧,自,自由基,合,合成,Berry,etal,.,.Circulation.2000;101,:,:2206-2212.,.,体外试,验,验：人,颈,颈内动,脉,脉（IMA）分别,与,与血管,紧,紧张素II、氯沙,坦,坦或血,管,管紧张,素,素II和氯沙,坦,坦共同,孵,孵化4小时，,采,采用光,泽,泽精化,学,学发光,法,法（lucigeninchemiluminescence）测量,超,超氧阴,离,离子,超氧阴,离,离子(pmol/min/mg组织),P=0.0001,P=0.2,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,治,治疗有,效,效改善,血,血管结,构,构,D Gomez-GarreetalKidneyInternational (2006)69,12371244.,n=22，高血,压,压初治,患,患者,*P0,.,.05,;,; *,*,* P,0.01vs治疗前,时间（,月,月）,M/L（自基,线,线的变,化,化）,P0,.,.05，组间,比,比较,M/L：血管,中,中层厚,度,度与内,腔,腔比值,收缩压(mmHg),舒张压(mmHg),Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,抗,抗动脉,粥,粥样硬,化,化作用,SuganumaE,etal.JAmSocNephrol.2006;17:433,441,单侧肾,切,切除小,鼠,鼠或对,照,照小鼠,接,接受氯,沙,沙坦或,肼,肼苯哒,嗪,嗪治疗12周，评,估,估主动,脉,脉粥样,硬,硬化性,损,损伤,*P0.05vs对照组,P0,.,.05vs单侧肾,切,切除组,P0.05vs单侧肾,切,切除+氯沙坦,组,组,对照组,单侧肾,切,切除组,单侧肾,切,切除+氯沙坦,组,组,单侧肾,切,切除+肼苯哒,嗪,嗪组,损伤面,积,积(m2103),*,*,Evaluation Warning : The document was created with Spire.Presentation for .NET,BakrisGL,etal.ArchInternMed.2003;163,:,: 1555,-,-1565,RENAAL研究,氯沙坦,有,有效逆,转,转DN患者左,室,室肥厚,6.2%,6.3%,Cornell product,Sokolow-Lyon,Evaluation Warning : The document was created with Spire.Presentation for .NET,RENAAL研究,氯沙坦,减,减少因,心,心衰所,致,致的首,次,次住院,0,12,24,36,48,月,0,5,10,15,20,事件%,762,685,616,375,53,751,701,637,388,74,P (,+,+,传统治,疗,疗,),L (,+,+,传统治,疗,疗,),P=安慰剂L=氯沙坦,32%,P=0,.,.005,氯沙坦,安慰剂,ShahinfarS,etal.ExpertOpinPharmacother2006;7(5,),):623,-,-630,Evaluation Warning : The document was created with Spire.Presentation for .NET,ARB有效降,低,低2型DN患者的,心,心血管,事,事件,BerlT,etal.JAmSocNephrol2004,15:S71-76,0.85（95%CI0.73-0,.,.98）,P=0,.,.034,到达CV终点,患者比,例,例%,安慰剂,N=1532,ARBs,N=1719,0,15,10,5,20,25,30,荟萃分,析,析RENAAL、IDNT和IRMA2研究,ARB可降低,心,心血管,危,危险达15%,Evaluation Warning : The document was created with Spire.Presentation for .NET,LIFE研究：,氯,氯沙坦,更,更有效,逆,逆转LVH,-18,-16,-14,-12,-10,-8,-6,-4,-2,0,Cornell Product,Sokolow-Lyon,自基线,的,的平均,改,改变(%),氯沙坦,阿替洛,尔,尔,p0,.,.0001,DahlfBetalLancet2002;359,:,:995-1003.,10.2 %,9.0,%,%,15.3 %,4.4,%,%,p0,.,.0001,Evaluation Warning : The document was created with Spire.Presentation for .NET,LIFE研究：,氯,氯沙坦,更,更有效,降,降低颈,动,动脉肥,厚,厚,内皮中,层,层的变,化,化(%),内膜中,层,层厚度,在,在第3年时自,基,基线的,变,变化,7.9 %,1.7 %,p0,.,.05,9,8,7,6,5,4,3,2,1,0,阿替洛,尔,尔(n=22),氯沙坦(n=23),MichaelHO,etal.BloodPressure.2005;14,:,: 177183,Evaluation Warning : The document was created with Spire.Presentation for .NET,LIFE研究：,氯,氯沙坦,是,是唯一,与,与活性,抗,抗高血,压,压药物,比,比较在同等,降,降压幅,度,度下，,进,进一步,降,降低脑,卒,卒中危,险,险的ARB,氯沙坦,阿替洛,尔,尔,研究月,份,份,0,6,12,18,24,30,36,42,48,54,60,66,0,1,2,3,4,5,6,7,8,DahlfBetalLancet2002;359,:,:995-1003,.,致死性,和,和非致,死,死性脑,卒,卒中,发生首,次,次事件,的,的患者,比,比例(%),25%,P=0.001,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,非,非AT1阻断带,来,来的益,处,处,抑制血,小,小板聚,集,集,降低尿,酸,酸,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦及其代,谢,谢产物,的,的不同,作,作用,Cl,R,1,N,N,N,N,N,N,R,2,AT1,亲和力,氯沙坦,EXP3179 EXP3174,CYP,2C/3A,CYP,2C/3A,中,低,低,很,很,高,高,作用,降低,抑,抑制阻断,尿酸,血,血,小,小板聚,集,集AngII,Evaluation Warning : The document was created with Spire.Presentation for .NET,EXP3179与阻断AngII无关的,抗动脉,粥,粥样硬,化,化作用,促进eNOS生成和,抑,抑制TNF,-,-诱导的,内,内皮细,胞,胞凋亡,WatanabeT et al,Circulation2005;112:1798-1805,抑制LPS诱导的,内,内皮细,胞,胞ICAM-1上调,阻断LPS诱导的,内,内皮细,胞,胞Cox-2上调,抑制TXA2诱导的,血,血小板,聚,聚集,KramerC et al,CircRes2002;90:770,-,-776,Evaluation Warning : The document was created with Spire.Presentation for .NET,ARB中氯沙,坦,坦及其,代,代谢产,物,物对TxA2受体阻,断,断作用,最,最强,对照组,坎地沙,坦,坦,缬沙坦,氯沙坦,EXP,-,-3174,0,25,50,75,100,EC50,nM,Ferrario,CM,.,. CurrentMedicalResearchandOpinions20, 1797,-,-1804,2004.,EXP,-,-3179,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,母,母体促,进,进尿酸,排,排泄,SicaDAandSchoolwerthAC,CurrOpinNephrolHypertens2002;11:475-482,G,S,1,S,2,S,3,滤过100100,重吸收9999,重吸收4010,排泄(%)1030,分泌4939,基线,氯,氯沙坦,氯沙坦,比,比阿替,洛,洛尔更有效,降,降低心,血,血管事,件,件的益处，29%可以用,氯,氯沙坦,更,更显著,降,降低,血清尿,酸,酸水平来解释,HieggenA et al KidneyInt2004;65:1,9.,Evaluation Warning : The document was created with Spire.Presentation for .NET,氯沙坦,独,独特的,降,降尿酸作用,周,700,600,500,400,300,200,0,基线,4,8,氯沙坦,厄贝沙,坦,坦,Dang A, et al.J HumHyper2006;20,:,: 45-50,N=351,伴高尿,酸,酸血症,的,的中国,高,高血压,患,患者,血清尿,酸,酸(mol/L),P0,.,.001,P0,.,.001,Evaluation Warning : The document was created with Spire.Presentation for .NET,总 结,重视CKD患者心,血,血管危,险,险的早,期,期干预,ARB能够有,效,效干预CKD患者多,种,种传统/非传统,心,心血管,危,危险因,素,素,LIFE和RENAAL研究证,实,实：,氯沙坦,可,可强效,降,降压、,降,降蛋白,尿,尿，逆,转,转血管,和,和心脏,结,结构重,塑,塑，全,面,面降低,心,心血管,危,危险,Evaluation Warning : The document was created with Spire.Presentation for .NET,