高血压合并肾损害的处理

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1、高血压合并肾损害的处理高血压合并肾损害的处理初少莉初少莉上海交大医学院上海交大医学院 附属瑞金医院附属瑞金医院上海市高血压研究所、高血压科上海市高血压研究所、高血压科概述概述高血压伴高血压伴CKD的处理的处理 内内 容容高血压与主要器官间的关系CKD主要原因之一主要原因之一高血压高血压50%-75%CKD美国美国CKD患病率患病率(AJKD 2004)人群（人群（10万）万）National kidney foundation K/DOQI guideline Am J Kidney Dis. 2004:Suppt.1-234304076535915GFR(ml/min)15-2930-596

2、0-8990 中国中国CKD流行病学资料流行病学资料地区地区人群人群例数例数蛋白尿蛋白尿CKD广州广州1北京北京2浙江浙江3上海上海* 20岁岁40岁岁18岁岁原高原高(住院住院)2213 240077051689.7(6.2)7.610.3(10.4)-16.1(10.1)11.013.510.6 ( 3期期)1余学清等余学清等,中华肾脏病杂志中华肾脏病杂志,2007,23(3)147-1512张路霞等张路霞等,中华肾脏病杂志中华肾脏病杂志,2006,22(2)69-713张路霞等张路霞等,中华肾脏病杂志中华肾脏病杂志,2007,23(3)152-155CKD在不同人群中的患病率(%)Ear

3、ly detection and intervention of CKD and associated factors in Beijing15.920.79.3Incident Rates by Primary DiagnosisUS Renal Data System.USRDS 2000 Annual Data Report.Bethesda,MD:National Institutes of Health;2000.校正的风险比校正的风险比（所有原因死亡（所有原因死亡 心血管事件心血管事件 任何原因住院的）任何原因住院的）N=1,120,295 , Ambulatory Adults

4、According to the eGFReGFR*所有原因死亡所有原因死亡CV事件事件任何原因住院任何原因住院Adjusted Hazard Ratio (95% Cl)=60ml/min/1.73m21.001.001.0045-59ml/min/1.73m21.2(1.1-1.2)1.4(1.4-1.5)1.1(1.1-1.1)30-44ml/min/1.73m21.8(1.7-1.9)2.0(1.9-2.1)1.5(1.5-1.5)15-29ml/min/1.73m23.2(3.1-3.4)2.8(2.6-2.9)2.1(2.0-2.2)15ml/min/1.73m25.9(5.4-6

5、.5)3.4(3.1-3.8)3.1(3.0-3.3)* 校正年龄校正年龄,收入收入,教育教育,肾透析肾透析,冠心病冠心病,慢性心衰慢性心衰,缺血性卒中缺血性卒中,TIA,PAD,DM,HT,DL,肿瘤肿瘤,痴呆痴呆,慢慢性肝病性肝病,慢性肺病慢性肺病,蛋白尿蛋白尿,住院住院. Go AS et al.N Engl J Med .2004;351:1296-1305高血压增加心血管病与肾脏病的危险疾病疾病疾病疾病 相对危险相对危险相对危险相对危险(RR)(RR)肾衰肾衰肾衰肾衰(ESRD) 2.8(ESRD) 2.8卒中卒中卒中卒中 2.72.7心衰心衰心衰心衰 1.51.5心梗心梗心梗心梗

6、1.6 1.6 周围血管病周围血管病周围血管病周围血管病 1.81.8冠心病冠心病冠心病冠心病 1.51.5Am J Hypertens 2000,13:3S-10S Hypertension 1995,25:587-594N Engl J.Med. 1996,334:13-18 控制血压 保护肾脏 减少有效肾单位增加肾小球增加肾小球内压内压肾硬化与纤维化肾硬化与纤维化肾小球肥厚肾小球肥厚高血压高血压Wang H.Y in APCC高血压伴高血压伴CKD患者增加心血管危险患者增加心血管危险的可能机制的可能机制同型半胱酸增加同型半胱酸增加交感活性增加交感活性增加血浆非对称性二甲基精氨酸（血浆非对

7、称性二甲基精氨酸（asymmetric dimethylarginine , ADMA) 浓度增高浓度增高血管钙化的危险性增加血管钙化的危险性增加Updatared from Zoccali C.Kidney Int.2006;70:26-33概述概述高血压伴高血压伴CKD的处理的处理 内内 容容CKD的处理的处理以抗高血压治疗为主的综合干预以抗高血压治疗为主的综合干预非药物治疗非药物治疗: 改善生活方式及专科的营养治疗改善生活方式及专科的营养治疗药物治疗药物治疗: 抗高血压药物治疗抗高血压药物治疗 降压目标降压目标 降压药物的选择降压药物的选择 联合治疗联合治疗 多重危险因素的控制（调脂、抗

8、血小板等）多重危险因素的控制（调脂、抗血小板等）CKD患者均应进行抗高血压治疗患者均应进行抗高血压治疗降压降压降低心血管病的危险降低心血管病的危险(不论是否有高血压不论是否有高血压)延缓肾脏病进展延缓肾脏病进展(不论是否有高血压不论是否有高血压)National kidney foundation K/DOQI guideline Am J Kidney Dis. 2004:Suppt.1-234降压目标：降压目标： CKD为心血管病的极高危因素，治疗要兼顾延为心血管病的极高危因素，治疗要兼顾延缓肾功能不全进展及降低心血管病危险：缓肾功能不全进展及降低心血管病危险： 1、严格控制血压、严格控制

9、血压 (1g/日可更低日可更低) 2、降低蛋白尿，使其尽可能恢复正常、降低蛋白尿，使其尽可能恢复正常抗高血压药物的选择与应用选择的原则：选择的原则： 遵循指南遵循指南 坚持个化治疗坚持个化治疗首选药物首选药物: （兼有降压、降蛋白尿、延缓（兼有降压、降蛋白尿、延缓GFR降低）降低） 各主要权威指南 ESC/ESH(2007) ACEI or ARBESC/ESH(2007) ACEI or ARB ADA (2004) ACEI or ABRADA (2004) ACEI or ABR NKF:DOQI-BP(2004) ACEI or ABRNKF:DOQI-BP(2004) ACEI or

10、 ABR KDQI-CKD(2002) ACEI or ABRKDQI-CKD(2002) ACEI or ABR JNC7JNC7（20032003） ACEI or ABRACEI or ABR CHINA(2005) ACEI or ARBCHINA(2005) ACEI or ARB CANADIAN (2002) ACEI or ABRCANADIAN (2002) ACEI or ABR WHO/ISH(1999) ACEIWHO/ISH(1999) ACEI（兼有降压、降蛋白尿、延缓（兼有降压、降蛋白尿、延缓GFR降低）降低） 对对CKD患者治疗患者治疗ACEI vs ARB 孰

11、优孰劣？孰优孰劣？ Head-to-head trials Hypertension 0Diabetes type 1 0 type 2 0 with nephropathy 0Post MI (heart failure) OPTIMAAL, VALIANTChronic Heart Failure ELITE IIPervention of disease progression 0High CV risk OntargetHypertension with CKD 0ONTARGET The ONgoing Telmisartan Alone and in combination wit

12、h Ramipril Global Endpoint Trial WWW.NEJM.ORG ON MARCH 31,2008 N ENGL J MED, 2008;358:1547-1559ONTARGETQuestions: 1. Is telmisartan “non-inferior” to ramipril ? 2. Is the combination superior to ramipril ?Outcome:Primary: CV death, MI, stroke, CHF hospKey secondary: CV death, MI, stroke (HOPE trial

13、outcome)Design: Single blind run-in (n=29,019) Randomized, double blind, double dummy study conducted in 733 centers in 40 countries (n=25,620) 56 months follow-up with 99.8% outcome ascertainmentChange in BP (mmHg)RamiprilTelmisartanCombinationSystolic-6.0-6.9-8.4Diastolic-4.6-5.2-6.0Time to Primar

14、y OutcomeONTARGETPrimary Outcome & HOPE Primary OutcomeRamTelTel vs RamN (%)N (%)RR (95% CI)P (non-inf)N85768542Primary OutcomeCV Death, MI, Stroke, CHF Hosp1412 (16.46%)1423 (16.66%)1.01 (0.94-1.09)0.0038(Adjusted for SBP)1.02 (0.95-1.10)0.0055HOPE Primary OutcomeCV Death, MI, Stroke1210 (14.11%)11

15、90 (13.93%)0.99 (0.91-1.07)0.0009(Adjusted for SBP)0.99 (0.91-1.07)0.0012Time to Permanent Discontinuation of Study MedicationONTARGETYears of Follow-upCumulative Hazard Rates0.00.10.20.30.401234TelmisartanRamipril# at Risk Yr 1Yr 2Yr 3Yr 4T85427954738469096478R 85767796716566816254Reasons for Perma

16、nently Stopping Study MedicationsTelN=8542RamN=8576Tel vs. RamRR PHypotension229(2.7)149(1.7)1.540.0001Syncope19(0.2)15(0.2)1.270.4850Cough93(1.1)360(4.2)0.260.0001Diarrhea19(0.2)12(0.1)1.590.20Angioedema10(0.1)25(0.3)0.400.0115Renal Impairment68(0.8)60(0.7)1.140.46All discontinuation1962 (23.0)2099

17、(24.5)0.940.02Save money ?Prefer tolerability ?ARBARBACEIACEITelmisartan is as effective as ramipril, with a slightly better tolerability.高血压只有高血压只有30%单药能够达标单药能够达标高血压伴高血压伴CKD时增加额外的降压难度时增加额外的降压难度 （难治性高血压多，目标血压（难治性高血压多，目标血压 130/80mmHg）Number of BP MedicationsUKPDS (85 mm Hg, diastolic)4321MDRD (92 mm

18、Hg, MAP)HOT (80 mm Hg, diastolic)AASK (92 mm Hg, MAP)RENAAL (140/90 mm Hg)IDNT (135/85 mm Hg)联合降压治疗联合降压治疗利尿剂利尿剂受体阻滞剂受体阻滞剂 ATAT1 1- -受体阻滞剂受体阻滞剂 a a受体阻滞剂受体阻滞剂 钙离子拮抗剂钙离子拮抗剂ACEIESH/ESC2007: 降压联合治疗方案降压联合治疗方案ACEI与与ARB联合治疗联合治疗(伴伴CKD)BenefitClear role in CHF (CHARM-added, Val-HeFT )Clear role in non-diabeti

19、c nephropathy (COOPERATE)Unclear role in diabetic nephropathy (CALM II ) Small effect in HT 2007ASH in ChicagoEffect on proteinuriaACEI+ARB vs ACEI alone 30% reduction (95%CI 23-37%)ACEI+ARB vs ARB alone 39% reduction (95%CI 31-48%) (Eight trial reported data on proteinuria, albuminuria, or ACR)Doul

20、tonDoulton TW,etTW,et al. Hypertension.2005;45:880-886 al. Hypertension.2005;45:880-886Time to Primary Outcome（ARB与与ACEI联合）联合）ONTARGETTel + RamRam aloneReasons for Permanently Stopping Study MedicationsR + TN=8502RN=8576R + T vs. RRR PHypotension4061492.750.0001Syncope29151.950.032Cough3923601.100.1

21、885Diarrhea39123.280.0001Angioedema18250.730.30Renal Impairment94601.580.0050Total249520991.201.5mg/dl基础血肌酐基础血肌酐 1.5mg/dl肌酐清除率肌酐清除率 60ml/分分/1.73m2肌酐清除率肌酐清除率60ml/分分/1.73m2所有所有 n = 15,601HOT研究肾脏病患者亚组数据分析证实非洛地平对肾功能无不良影响Hypertension Unit. J Am Soc Nephrol 2001; 12: 218-25 Avoiding Cardiovascular Events

22、through COMbination Therapy in Patients LIving with Systolic HypertensionTargeted Population for Recruitment into the ACCOMPLISH StudyMen or women age 55 yearsSBP 160 mmHg or currently on antihypertensive therapyEvidence of cardiovascular or renal disease or target organ damageDSMB Oct 17 2007Pre-sp

23、ecified efficacy boundary was crossed with 60% of the expected trial informationExecutive Committee accepted the recommendationLast patient last visit was Jan 24, 2008Total of 1176 unique patients with events95.3% of primary events are adjudicatedSystolic Blood Pressure Over Timemm HgMonth5731538752

24、064999480442852520104557095377515449804831428625941075PatientsACEI / HCTZN=5733CCB / ACEIN=5713*Mean values are taken at 30 months F/U visit129.3 mmHg130mmHgDifference of 0.7 mmHg p0.05*DBP: 71.1DBP: 72.8差差1.7mmHgBaseline Control Rates37.237.9ACCOMPLISH: Exceptional Control Rates with Initial Combin

25、ation TherapyACEI / HCTZN=5733Control rate (%)CCB / ACEIN=571310203040506070809078.581.7P0.001 at 30 months follow-up Control defined as 140/90 mmHgKaplan Meier for Primary EndpointCumulative event rateHR (95% CI): 0.80 (0.72, 0.90)20% Risk ReductionTime to 1st CV morbidity/mortality (days)p = 0ACEI

26、 / HCTZCCB / ACEI650526.0002INTERIM RESULTS Mar 08提提 示示1.联合治疗可获得非常好的血压控制；联合治疗可获得非常好的血压控制；2. 初始初始 ACEI / CCB优于优于ACEI/DD的联合治疗，的联合治疗，这对以这对以DD作为降压基础治疗的观点提出挑作为降压基础治疗的观点提出挑战战Initial combinations of Medications diureticsACEI or ARBCCB利尿治疗的利弊 利尿药抑肾脏钠（镁）重吸收抑肾脏钠（镁）重吸收低镁血症低钠血症低钠血症心排心排低钾血症低钾血症体位性体位性低血压低血压肾血流肾血流

27、PRAGRF糖耐量异常糖耐量异常 高尿酸血症或痛风高尿酸血症或痛风（排泄减少、吸收增加）（排泄减少、吸收增加）其它血容量血容量 限制利尿药的剂量，也限制利尿药的降压作用限制利尿药的剂量，也限制利尿药的降压作用其它机制其它机制高血压伴高血压伴CKD的处理的处理（小（小 结）结）应以降压为主的综合治疗应以降压为主的综合治疗降压需达标（降压需达标（130/80mmHg)首选降压药物：首选降压药物：ACEI或或ARB（靶剂量）（靶剂量）大多数患者需要联合治疗大多数患者需要联合治疗 RASi ARB还需验证（伴还需验证（伴CKD） RASi CCB潜在优势潜在优势 RASiDD（顽固、容量增加时优先）（顽固、容量增加时优先）个体化治疗尤为重要个体化治疗尤为重要谢 谢谢谢 谢谢上海瑞金医院上海瑞金医院