內(nèi)科學(xué)教學(xué)課件：32 Chronic Renal Failure

ChronicRenalFailureDefinitionCRF:aclinicalsyndromecausedbytheprogressionofvariousCRD(CKD)leadingtoinexorableattritionofnephronnumberandfunctionwhichresultsintheretentionofmetabolicproductsandpoisonoussubstance,disordersinfluid,electrolyteandacid-basebalance,andendocrinedysfunction.DefinitionCRD(CKD):apathophysiologicprocesswithmultipleetiologies,resultingintheinexorableattritionofnephronnumber&function,whichlastmorethan3months.CKD定義和分期NKF-KDOQICKD的定義：腎臟損傷（腎臟結(jié)構(gòu)或功能異常）≥3個(gè)月，伴或不伴腎小球?yàn)V過(guò)率（GFR）下降，臨床上表現(xiàn)為腎臟病理學(xué)檢查異常或腎臟損傷（血、尿成分或影像學(xué)檢查異常）；GFR<60ml/（min?1.73m2）≥3個(gè)月，有或無(wú)腎臟損傷。CKD定義和分期分期 腎臟損傷

eGFR*(ml/min/1.73m2)1+≥902+60-893NA

30-594NA

15-295NA

<15(或透析)(*采用簡(jiǎn)化MDRD公式通過(guò)血清肌酐水平計(jì)算獲得；NA=不適用；結(jié)果需持續(xù)≥3個(gè)月)TheimportanceofChronicRenalFailureWorldwide,theprevalenceofCRFisincreasingbymorethan5%annuallyThecostofrenalreplacementtherapyhasanincreasingimpactonhealtheconomicsinbothdevelopedanddevelopingcountriesKeithDSetal.ArchInternMed2004;164:659-663患者%K/DOQICKD分期對(duì)27,998例CKD患者進(jìn)行為期最長(zhǎng)66個(gè)月的隨訪

1.119.51.324.319.945.7CKD全因死亡與CV事件1120295名成人受試者，均進(jìn)行血清肌酐檢測(cè)，均未進(jìn)行透析或腎臟移植，中位隨訪2.84年GoAS,etal.NEnglJMed2004;351:1296-305.GACG:G1-5(G3：A&B)A:Ualb/crA1:<30A2:30-300A3:>300C:CausesPlasmaCreatinineandGFRNormalGFR100-125ml/min/1.73m2GFRdeclinesbyabout1ml/min/1.73m2/yearPlasmacreatinineconcentrationcanbeusedtomonitorrenalfunctionwhenGFR<50ml/minMassscreeningofplasmacreatininecannotprovideearlydetectionofrenaldiseasesinthegeneralpopulation美國(guó)20歲以上人群中，每7.6人中有1人為CKD

CKD3期患病率較4-5期患病率高出10倍～20倍

分期發(fā)病率患病人數(shù)(%)(x106)11.783.623.246.5

37.6915.540.350.750.200.4全部1-413.0726.3CoreshJ,etal.JAMA2007;298(17):2038-2047.美國(guó)CKD流行病學(xué):

NHANES(KDOQI-Based:1999-2004)不同年齡組CKD3期發(fā)病率CKD3期占60%！?。ausesofCRFGlomerulardiseasesaccountfor60%ofCRFDiabeticnephropathyaccountfor10-15%ofCRF(inUSAabout50%)Hypertension:10-15%Polycystickidneydiseases:5%Obstructiveuropathy:3-4%Lupusnephropathy:2-3%UnderminedOrigin:5-10%EvolutionofCRFGlomerulardiseaseswillbedecreasedDiabeticandhypertensivenephropathy↑Chronicnephrotoxicitybyenvironmentalpollutants,drugsandherbs↑IncidenceofESRD:100-200permillionThemechanismsofCRFuremictoxinmalnutritiontrade-offhypothesisEndocrine-metabolicdisorders：EPO、VitD、PTHClinicmanifestationofCRFDeteriorationofrenalfunctionisinvariableonceGFRisreducedbymorethan25%Serialplotsofthereciprocalofcrvs.timefollowsastraightlineOftenremainasymptomaticwhenGFR=25%UraemicsyndromeClinicmanifestationofCRFDigestivesystemCardiovascularsystemHematologicsystemRespiratorysystemNeuromascularsystemClinicmanifestationofCRFDermatologicabnomalitiesBonediseaseEndocrineandmetabolicsystemInfectionMetobolicacidosisFluidandelectrolytedisordersGastrointestinalabnormalitiesNausea,vomiting,dyspepsiahemorrhageGastritisandulcerCardiovascularabnormalitiesarterialatherosclerosishypertensionpericarditisheartfailureHematologicabnormalitiesanemiableedingRespiratoryabnormalitiespulmonaryedemauremicpneumonitispleuritisNeuromascularabnormalitieuremicencephalopathyuremicneurotoxinuremicmyopathyDermatologicabnormalitiesuremicpruritusuremicfrostBonediseases-renalosteodystrophyhighboneturnoverdiseaselowboneturnoverdiseaseDisordersofcalciumandphosphatemetabolismEndocrine-metabolicdisordersVitDandPTHEPOinfectionNon-specificimmuneSpecificimmunemetabolicacidosisClinicalmenifestationNeurologicalsystemRespiratorysystemCirculatorysystemfluidandelectrolytedisordersSodiumHomeostasisWaterHomeostasisPotassiumHomeostasisHypocalcemiaorhypercalcemiahyperphosphatemiaClinicalDiagnosisofCRFAcuteorchronic?OftenpresentsacutelywhenGFRsuddenlydropsfrom20%to10%orlessToassesstheseverityofrenalimpairmentToelucidatethecausesofrenalfailureToascertainwhethertherenalfailureisacute,oracute-on-chronicToassessthepatientforrenalreplacementtherapyDiagnosisofprimarydiseaseHistoryandPhysicalExaminationLaboratoryInvestigationsImagingStudiesRenalBiopsyDifferentialdiagnosisDistinguishCRFfromARFHistoryofdiseaseVolumeofurineChangeofHbChangeofskinChangeofskelectonChangeofScrKidneysizeDifferentialdiagnosisDiseasesofdigestivesystemDiseasesofcardiovascularsystemDiseasesofhematologicsystemClinicalInvestigationsThehistoryshouldincludeadiligentsearchforpotentialnephrotoxicagentsApositivefamilymayindicateheredofamilialdiseasesPallor,scratchmarks,peripheraloedemaandpalpablemassesintheabdomenAfullexaminationisimportant,especiallyinpatientswithdiabetesCommonInvestigationsRenalfunctionprofileUrinalysisQuantitationofproteinuriaDeterminationofcreatinineclearanceLiverfunctionprofileHepatitisBandCstatusCommonInvestigationsSerologicaltestsuchasanti-nuclearantibodies,complements,immunoglobulinlevels,C-reactiveproteinandanti-neutrophilcytoplasmantibodiesLipidprofileUltrasonogramofkidneysformeasurementofkidneysizeandexclusionofstructuralabnormalitiesDopplerexaminationofrenalarterieswhenindicatedManagementofCRDTreatmentofprimarydiseaseTreatmentofhypertensionUsingACEIorangiotensin-IIreceptorblockersAvoidingnephrotoxicagentsLowdietaryproteinintakePhosphatecontrolEarlycorrectionofaneamiaTreatmentofHypertensionThetargetofbloodpressure:<130/80mmHgMultipleagentsarerequiredACEI,ARB,B-B,CCB,α-B，diureticsBloodpressurecontrolledfor24hr0-2-4-6-8-10-12-14-16-9.4-4-14.4-5.7-7-1.3-2.8-3.89811294105mmHg11010090mL/min/yr.平均動(dòng)脈壓試驗(yàn)終點(diǎn)最初的腎小球?yàn)V過(guò)率的降低[<4個(gè)月]最終的腎小球?yàn)V過(guò)率的降低[試驗(yàn)終點(diǎn)(1-6年)]BakrisNielsen(低的血壓目標(biāo))(常規(guī)的血壓目標(biāo))(N=18)(N=21)(N=293)(N=292)

對(duì)于糖尿病腎病和非趟尿病腎病的患者進(jìn)行的1-6年的隨訪中，腎小球?yàn)V過(guò)率最初的下降和最終下降的關(guān)系。在所有的這些試驗(yàn)中ACEI均作為一線用藥。請(qǐng)注意試驗(yàn)中的血壓的控制，因?yàn)檠獕旱乃脚c腎功能的下降相關(guān)。上圖根據(jù)Bakri和sWeir的數(shù)據(jù)做出嚴(yán)格的血壓控制使腎功能下降的速度減慢AmericanJorunalofKidneyDiseases,Vo.,36,No3(September),2000:pp646-661血壓下降程度與GFR下降程度的關(guān)系控制血壓與減少心血管事件HOT試驗(yàn)：1501個(gè)糖尿病病人，按舒張壓（≥90mmHg、＜90≥85mmHg、＜85mmHg）分為三組，發(fā)現(xiàn)血壓最低組，心血管事件下降40%；ABCD與MDRD，均有一亞組舒張壓＜75~83mmHg，心血管事件顯著減少；嚴(yán)格降壓安全性已獲證實(shí)。****P<0.05與嚴(yán)格的血糖控制相比嚴(yán)格的血糖控制嚴(yán)格的血壓控制中風(fēng)糖尿病終點(diǎn)事件糖尿病死亡微血管合并癥%0-10-20-30-40-50與嚴(yán)格的血糖控制相比，嚴(yán)格的血壓控制更有意義AmericanJorunalofKidneyDiseases,Vo.,36,No3(September),2000:pp646-6611234UKPDS(<85mmHg-舒張壓)ABCD(<75mmHg-舒張壓)MDRD(<92mmHg平均動(dòng)脈壓)HOT(<80mmHg-舒張壓)AASK(<92mmHg平均動(dòng)脈壓)抗高血壓藥物種類(lèi)將血壓控制在較低水平所需的抗高血壓藥的種類(lèi)AmericanJorunalofKidneyDiseases,Vo.,36,No3(September),2000:pp646-661ACEIORARB

ReducingintraglomerularpressureReducingproteinuriaDedcreasedextracellularmatrixsynthesisIncreaseddegradationofextracellularmatrix

ACE抑制劑在1型糖尿病中的作用

%病人基礎(chǔ)變量亞組（n=409)所有病人 100性別男性 53 女性 47種族 黑人 8 白人 89年齡(歲) 35 54 ≥35 46糖尿病 20 48持續(xù)時(shí)間(年)≥20 52基礎(chǔ)基值 無(wú) 25高血壓 有 75坐位MAP 105 57(mmHg) ≥105 43血清肌酐 1.5 75(mg/dL) ≥1.5 25尿蛋白 2 52排泄量(g/24h)≥2 48尿素氮 10 47排泄量(g/24h)≥10 53糖化血紅 12 60蛋白(g/dL) ≥12 40

LewisEJ,etal.NEnglJMed.1993;329:1456–1462.%降低的危險(xiǎn)率(95%CI)

血清肌酐翻倍 ESRD或死亡危險(xiǎn)率增加危險(xiǎn)率降低危險(xiǎn)率增加危險(xiǎn)率降低-60 0 100-90 0 90ACE抑制劑對(duì)2型糖尿病中血清肌酐和蛋白尿的作用*與安慰劑相比

P<0.05RavidM,etal.AnnInternMed.1993;118:577–581.100/cr的初始值的百分比安慰劑*依那普利1101009080012345年安慰劑依那普利*135年024蛋白尿(mg/24h)50042034026018010020

Benazepril(n=300) Placebo(n=283)血清肌酐翻倍 輕度(71%RR) 5/120 15/107 P=0.01

中度(46%RR) 26/180 42/176 P=0.01

腎小球疾病 11/94 27/98 糖尿病腎病 1/6 7/15 混合病因/不明 6/61 9/43 多囊腎 8/30 9/34 腎硬化 2/52 1/45 間質(zhì)性腎炎 3/57 4/48血壓 收縮壓 –4.5to–8.0mmHg +1.0to+3.7mmHg

舒張壓 –3.5to–5.0mmHg +0.2to+1.5mmHg蛋白尿 –29% +9%

1g/d 31%RR 1到3g/d 53%RR 3g/d 66%RR

31 57 P

0.001

ACE抑制劑與慢性腎功能不全

AIPRI試驗(yàn)ACE

抑制劑與伴有蛋白尿的非糖尿病腎病REIN試驗(yàn)GISENGroup.Lancet.1997;349:1857–1863.基礎(chǔ)蛋白尿排泄量(g/24h)n=20

7.0n=364.5–7.0n=613–4.5GFR平均下降率

%基礎(chǔ)Cr翻倍或ESRD的病人安慰劑雷米普利基礎(chǔ)蛋白尿排泄量(g/24h)n=31

7.0n=484.5–7.0n=873–4.56050403020100701.21.00.80.60.40.20.01.61.4AfricanAmericanStudyofKidneyDiseaseAndHypertension(AASK)Trial

TheAASKtrialenrolled1,094AfricanAmericanpatientswithrenaldiseaseat21U.S.centers,andrandomizedthemtoreceiveoneofthreestudydrugsRamipril-ACEIorAmlodipine-CCBorMetoprolol-?-blockerTreatmenttooneoftwoBPtargets125/75or140/90mmHgSource:DrugsFoundtoProtecttheKidneys,NationalInstituteofHealth,Oct13,2000InterimAASKTrialResults1.6foldrelativeriskwithamlodipinecomparedtoramiprilforthecombinedevent(decreaseinGFR,dialysis,ordeath)whichwashighlystatisticallysignificantTheNationalInstituteofHealth(NIH)calledanearlyhalttotheamlodipinearmofthetrialSource:DrugsFoundtoProtecttheKidneys,NationalInstituteofHealth,Oct13,2000InterimAASKTrialResultsRamipril(ACEI)andmetoprolol(

Blocker)exertedsignificantlysuperiorrenalprotectiveeffectscomparedtotheCCBamlodipine(Norvasc)inpatientswithhypertensiverenaldiseasewhohadatleastonegramofproteinina24-hoursampleofurineBloodpressureswerecomparableSource:DrugsFoundtoProtecttheKidneys,NationalInstituteofHealth,Oct13,2000研究者發(fā)起的、多中心、三盲、隨機(jī)、安慰劑對(duì)照的研究，評(píng)價(jià)氯沙坦對(duì)2型糖尿病腎病病人的腎臟保護(hù)作用1513名病人;250個(gè)中心;29個(gè)國(guó)家

SteeringCommittee Chair B.M.Brenner,M.D.DataandSafetyMonitoringCommittee Chair C.E.Mogensen,M.D.ClinicalEndpointAdjudicationCommittee Chair S.Haffner,M.D.CoordinatingCenter:MerckResearchLabs StudyDirector S.Shahinfar,M.D.RENAAL

AIIA氯沙坦(科素亞)在NIDDM病人中的終點(diǎn)研究RENAAL--研究設(shè)計(jì)Dataonfile,MSD

4周科素亞100mgqd(+常規(guī)治療*)

維持常規(guī)的降壓治療(不包括ACEi,AIIA)科素亞100mgqd(+常規(guī)治療*)安慰劑(+常規(guī)治療*)目標(biāo)血壓:<140/<90mmHg

n=1513安慰劑(+常規(guī)治療*)科素亞50mgqd(+常規(guī)治療*)安慰劑(+常規(guī)治療*)8周

6周平均隨訪3.4年*常規(guī)治療:開(kāi)放標(biāo)簽的鈣拮抗劑、利尿劑、β-受體阻斷劑或α-受體阻斷劑RENAAL

首要終點(diǎn)終末期腎病終末期腎病或死亡血肌酐加倍012243648月01020304050事件%p=0.010危險(xiǎn)性下降:20%751714625375696969696969762715610347424242424242012243648月0102030事件%

p=0.006危險(xiǎn)性下降:25%751692583329525252525252762689554295363636363636012243648月事件%0102030762715610347424242424242751714625375696969696969p=0.002危險(xiǎn)性下降:28%PLPLPLDataonfile,MSDP(+常規(guī)治療)L(+常規(guī)治療)P(+常規(guī)治療)L(+常規(guī)治療)P(+常規(guī)治療)L(+常規(guī)治療)RENAAL

蛋白尿自基線的變化值Proteinuriameasuredastheurinealbumin:creatinineratiofromafirstmorningvoid.012243648Months中位數(shù)變化%-60-40-2002040751661558438167167167167167167p=0.0001762632529390130130130130130130PL35%OverallReductionDataonfile,MSDP(+常規(guī)治療)L(+常規(guī)治療)RENAAL

因心衰所致的首次住院012243648月05101520事件%危險(xiǎn)性下降:32%p=0.0057626856163755375170163738874PLDataonfile,MSDP(+常規(guī)治療)L(+常規(guī)治療)IDNT研究設(shè)計(jì)1,715名高血壓，2型糖尿病，尿蛋白3900mg/天的患者治療(雙盲)5周初篩/入選對(duì)照組*氨氯地平*最短隨訪時(shí)間：近2年

(平均隨訪時(shí)間為2.6年)伊貝沙坦**

聯(lián)用其它抗高血壓藥物治療(不包括ACEI，AIIRA，CCB)

以使得各治療組獲得相同的目標(biāo)血壓LewisEJetal.NEnglJMed2001;345:851-860.IDNT

收縮壓，平均動(dòng)脈壓和舒張壓LewisEJetal.NEnglJMed2001;345:851-860.血壓(mmHg)伊貝沙坦氨氯地平對(duì)照組061218243036424854隨訪時(shí)間(月)80100120140160SBPMeanDBP伊貝沙坦組和氨氯地平患者平均聯(lián)用3個(gè)藥物，對(duì)照組患者平均聯(lián)用3.3個(gè)藥物。IDNT主要終點(diǎn)

進(jìn)展至血肌酐升高一倍，ESRD或死亡的時(shí)間LewisEJetal.NEnglJMed2001;345:851-860.患者比例(%)061218243036424854隨訪時(shí)間(月)60010203040506070伊貝沙坦氨氯地平對(duì)照組RRR20%

P=0.02P=NSRRR23%

P=0.006UsingACEIorARBACEIcancausesanunacceptablecoughinasubstantialnumberofpatientsTheriskofhyperkalaemiaissmallthoughreal.ARFcanbehappenedinpatientswithsevererenalarterystenosis.AvoidingnephrotoxicAgentsNon-steroidalanti-inflammatorydrugsareusedtooliberallyHerbs:patientsoftenresorttoalternativemedicineandingestawidecombinationofherbswhichleadstoarapiddemiseofremainingkidneyfunction.ManagementofCRFUrinaryobstructionandinfectionshouldbetreatedpromptlyFluidsoverloadingshouldbeavoidedEarlyreferredtonephrologist(GFR<30ml/min)ManagementofCRFPhosphatebindersaregivenwitheachmealtobinddietaryphosphatesinthegutCalciumsupplementationisneededActiveVitaminDmetabolitesareprescribedwhenPTHishighManagementofCRFMetabolicacidosisiscorrectedwithsodiumbicarbonateErythopoietincancorrects