IgA肾病治疗进展与问题

IgA肾病

治疗进展与问题

Evidence,ExperienceandComments

内容病情评估治疗选择特殊IgA肾病治疗2023/11/122IgA肾病IgA或以IgA为主的免疫复合物在肾小球系膜区沉积（免疫病理）IgA肾病是一组临床、病理表现多样原发性肾小球疾病2023/11/123发病机制：自身免疫肾脏病？2023/11/124IgA1半乳糖缺失自身抗原抗糖抗体自身抗体免疫复合物肾脏沉积补体激活肾脏损伤ZhuLetal.JASN2015NEJM2014WHO,WHEN,HOW2023/11/125蛋白尿、高血压、病理积分是影响预后的最重要的危险因素BerthouxFetal.JAmSocNephrol.2011;22(4):752-61.法国：332例，随访13年，前瞻性设计2023/11/1262023/11/1272023/11/128随访期间蛋白尿、血压是最重要的可干预危险因素ReichHNetal.JASN2007;18:3177-3183加拿大：542例，随访6.5年，前瞻性设计2023/11/129542IgAN，MeanFU6.5y2023/11/1210IgA肾病的牛津分型OxfordClassificationofIgANephropathy病人入选标准尿蛋白>0.5g/d;起病时eGFR>30ml/min/1.73m2肾活检后随访至少1年以上，1年内内未达到ESRD肾活检标本肾小球数>8个RENALPATHOLOGYSOCIETYIncollaborationwiththeInternationalSocietyofNephrology病人来源多中心回顾性研究亚洲

欧洲

北美

南美8个国家和地区共入选265人（其中儿童59人），平均随访69月（12-268）KidneyInternational(2009)2023/11/12112023/11/1212IgA肾病牛津分型的定义2023/11/1213目前共有17个研究，均为回顾性研究；4个为多中心研究，余为单中心研究；入选人数：54~1147例，平均随访时间38-156；终点事件：ESRD或ESRD和50%eGFR下降或血肌酐倍增；统计学方法：按照牛津分型采用COX回归模型，同时纳入了临床指标和病理指标纳入标准：完全符合牛津分型的研究4个研究对象：8个成人，3个儿童，6个成人+儿童IgA肾病牛津分型外部验证2023/11/12142023/11/1215中国18个肾脏病中心，多中心回顾性研究；入选人数：1026例成人IgA肾病患者，平均随访时间53个月（36-67）；纳入标准：符合牛津分型的研究终点事件：ESRD或ESRD和50%eGFR下降或血肌酐倍增；终点事件数：159（15.5%）统计学方法：按照牛津分型采用COX回归模型，同时纳入了临床指标和病理指标2023/11/121613个欧洲国家，55个肾脏和病理中心；入选人数：1147例

白种人IgA肾病患者，平均随访时间4.7年；纳入标准：符合牛津分型的研究患者

<0.5g/d患者219例；eGFR<30ml/min/1.73m2患者99例终点事件：ESRD或ESRD和50%eGFR下降或血肌酐倍增；统计学方法：按照牛津分型采用COX回归模型，同时纳入了临床指标和病理指标KidneyInternational(2014)2023/11/1217M病变2023/11/12

1.0112Caucasianmulti-centerChinesemulti-centerOxfordcohort16validationstudies0.77(0.56,1.06)0.77(0.55,1.07)0.11(0.01,0.98)0.60(0.47,0.76)0.77(0.56,1.06)0.77(0.55,1.07)0.11(0.01,0.98)0.60(0.47,0.76)

1.0112E病变16validationstudiesChinesemulti-center1.40(0.94,2.09)1.00(0.61,1.63)1.40(0.94,2.09)1.00(0.61,1.63)

1.512Caucasianmulti-centerNAOxfordcohortNACaucasianmulti-center16validationstudiesOxfordcohortChinesemulti-center1.80(1.11,2.92)1.80(1.37,2.36)2.50(0.88,7.12)1.30(0.82,2.06)1.80(1.11,2.92)1.80(1.37,2.36)2.50(0.88,7.12)1.30(0.82,2.06)

1.515S病变T病变18VALIGA—欧洲多中心验证研究M,S,andTlesionsindependentlypredictedthelossofestimatedglomerularfiltrationrate(eGFR)andalowerrenalsurvival.TheirvaluewasalsoassessedinpatientsnotrepresentedintheOxfordcohort.InindividualswitheGFRlessthan30ml/minper1.73m2,theMandTlesionsindependentlypredictedapoorsurvival.Inthosewithproteinuriaunder0.5g/day,bothMandElesionswereassociatedwithariseinproteinuriato1or2g/dayormore.结论2023/11/1219

病理损伤指导治疗？2023/11/1220尿蛋白高血压

肾功能病理损伤是决定IgA肾病预后最强和最可靠的危险因子IgA肾病进展危险因素的评估2023/11/1221治疗目标—non-progressionorregeneration蛋白尿<0.5g/day血压<130/80mmHg肾功能稳定2023/11/1222内容病情评估治疗选择降压与RAAS阻断糖皮质激素其他免疫抑制治疗其他措施：鱼油/扁桃体切除/抗血小板特殊IgA肾病治疗2023/11/1223当蛋白尿>1g/d时，推荐长期使用ACEi或ARB治疗(1B)当蛋白尿为0.5-1g/d时，建议ACEi或ARB治疗(儿童：0.5-1g/d/1.73m2)(2D)若可耐受，建议ACEi或ARB逐渐加量，直至尿蛋白<1g/d(2C)蛋白尿的IgAN患者，血压达标值应为<130/80mmHg；2023/11/1224IgA肾病—KDIGO指南推荐意见关于RAS阻断剂建议持续蛋白尿≥1g/d

(ACEI或ARB等支持治疗3-6月无效)及 GFR>50mL/min患者接受6个月的激素治疗(2B)临床表现肾病综合征而病理为MCD和IgA肾病并存的患者，可以按照MCD的治疗原则应用糖皮质激素(2B)急进性新月体性IgA肾病应用激素联合环磷酰胺治疗， 治疗方案与ANCA相关血管炎类似(2D)糖皮质激素的应用指证2023/11/1225IgA肾病—KDIGO指南推荐意见不建议IgAN患者使用激素联合免疫抑制剂或细胞毒药物，除非有新月体IgAN且肾功能迅速恶化(2D)CTX（不肯定）AZA(否定）MMF（不肯定）不建议GFR<30mL/min的患者使用免疫抑制治疗，除非有新月体IgAN且肾功能迅速恶化(2C)免疫抑制剂（基于目前证据）2023/11/1226IgA肾病—KDIGO指南推荐意见关于降压和RAAS阻断治疗策略2023/11/1227激素在IgA肾病的临床应用ChinaNanjing

Cohort:1155pts(1989-2005);proteinuria>1g/d:51.3%;Immunosuppressivetherapy:19%BeijingCohort:703pts(1994-2011);proteinuria>1g/d:70%;Immunosuppressivetherapy:45%ShanghaiCohort:619pts(1989-2010);proteinuria>1g/d:61.7%;immunosuppressivetherapy:54.7%Othercenters?70%ormoreJapanNationalcohort:2450pts(1995-2002);immunosuppressivetherapy:45.1%CanadaTorontocohort:542pts(1974-2007);TA-proteinuria>1g/d:68%;Immunosuppressivetherapy:15.7%France332pts(1990-1999);proteinuria>1g/day:30%;Immunosuppressivetherapy(atleast):19.6%2023/11/1228JAmSocNephrol2007;18:3177JAmSocNephrol2011;22:752NephrolDialTransplant2012;27:1479PLoSONE2012;7(6):e38904NephrolDialTransplant2009;24:3068RoleofRemissionClinics

intheLongitudinalTreatmentofCKDRamipril*(5-10mg/day)Low-sodium(50-100mEq/day),controlledprotein(0.8g/kg/day)dietLosartan*(50-100mg/day)Verapamil(80-120mg/day)Atovastatin(10-20mg/day)StartRemissionClinic*Up-titrationandcombinedtherapyifserumK+<6mmol/L132021426384ConcomitantdiureticandantihypertensivetherapytotargetserumK+<6mmol/LandBloodpressure<120/80mmHgAlgorithmdescribingthekeystepsoftheRemissionClinicinterventionprotocolJAmSocNephrol20082023/11/1229ProteinuriaremissionrateaccordingtounderlineproteinuriarenaldiseasewithRAASblockage

inRemissionClinicTrialJAmSocNephrol19,2008Proteinuriaremission(%)Proteinuriaremissiondefinedbyurineproteinexcretion<0.3g/d2023/11/1230关于降压和RAAS阻断治疗策略降压目标2023/11/1231基线尿蛋白阴性基线尿蛋白阳性LvJetal.CMAJ.2013Aug6;185(11):949

2023/11/1232血压目标：越低越好？2023/11/1233关于RAAS阻断治疗策略降压目标ACEIorARB?2023/11/1234RAS阻断剂独立于血压以外肾脏保护效应ARBs-3-2-1012-15-10-505-3-2-1012LnRR(majorcardiovascularevents)5SBPreduction(mmHg)B-3-2-1012-16-14-12-10-8-6-4-20246-3-2-10122SBPreduction(mmHg)LnRR(kidneyfailure)ARR0·79,95%CI0·68−0·91;p=0·003XieXFetal.AJKD20152023/11/12352023/11/12362023/11/1237关于RAAS阻断治疗策略降压目标ACEIorARB?影响RAS阻断剂疗效的因素2023/11/1238影响降压和RAAS阻断剂疗效因素RAAS阻断剂足量限盐与RAAS阻断剂联合利尿剂如血压许可避免联合双氢吡啶CCB血磷与RAAS阻断剂RAAS阻断剂双阻断？？2023/11/1239影响ACEI/ARB疗效的可纠正性因素：盐分摄入和利尿剂HighsodiumLowsodiumJAmSocNephrol.2008Feb132023/11/1240病例：难治性蛋白尿血压120/70-80mmHg2023/11/1241JAMA2002;288:2421-2431.肾小球滤过率平均下降率如何联合降压治疗增强RAS阻断剂疗效？？？CCBDifferentialeffectsofcalciumantagonistsubclassesonmarkersofnephropathyprogressionKidneyInt.

2004;65(6):1991-20022023/11/1242影响ACEI/ARB对于CKD临床疗效的可纠正性因素：磷水平REINstudy：JAmSocNephrol.20112023/11/1243VANEPHRONDstudy如何联合降压治疗增强RAS阻断剂疗效？？？ACEI+ARBs2023/11/12442023/11/1245HR,0.78;95%CI,0.58to1.05CKD人群肾脏保护：ACEI+ARBs2023/11/1246学会合理的使用RAAS阻断剂

耐心2023/11/1247糖皮质激素2023/11/124810.3:糖皮质激素10.3.1:建议对于经过3-6月最佳的支持治疗（包括使用ACEi或者ARB和控制血压治疗）后蛋白尿仍然持续性≥1g/d且GFR>50ml/min的病人接受6个月的糖皮质激素治疗。文献PozziCetal.LvJ,etal.MannoCetal.方案在第1、3、5月的最初3天予以1g甲级强的松龙静脉冲击治疗后续予以隔日口服强的松0.5mg/kg治疗6个月6个月口服强的松治疗方案*，起始0.8-1mg/kg/d治疗2月然后在后续的4月中每月减少0.2mg/kg/dIgAN：免疫球蛋白A肾病*强的松和强的松龙是等效的可以同等剂量相互换用在IgAN病人中糖皮质激素治疗方案2023/11/1249使用方法标准口服方案强的松（龙）0.8-1mg/kg/d*2月-规律减量（10%/月）-疗程6-8月‘大剂量’激素冲击方案第1、3、5月甲基强的松龙冲击，间期0.5mg/kg/隔日（相当于15mg/d)2023/11/12502023/11/12512023/11/12522023/11/12532023/11/1254JAmSocNephrol2012,23:1108-16StudyPatientsNo.PatientsSteroidsgroupControlgroupF-up(Mon)Eventnumber(rate,peryear)BenefitsDoublingSCrESKDsteroidcontrolsteroidcontrolPozzi2004(Italy)Scr<1.5mg/dlProteinuria1-3.5g/d86(43/43)MP×3days;then0.5mg/kg/dSupportive821(0.3%)13(4.3%)1(0.3%)5(1.7%)ReducedProteinuria;Improverenalsurvival(definedasdoubleofSCr)Koike2008(Japan)-48(24/24)Pred0.4mg/kg/ddipyridamoleorZilazephydrochloridedipyridamoleorZilazephydrochloride38----ReducedproteinruiaStablizedtherenalsurvivalLvJC2009(China)Proteinuria1-5g/dGFR>30ml/min.63(33/30)Pred0.8-1mg/kg/dCilazaprilmeandosage3.75mg/d27.30(-)2(3.0%)0(-)2(3.0%)ReducedProteinuriaandimprovedrenalsurvival(50%increaseofSCr)Manno2009(Italy)Proteinuria>1g/dayGFR>50ml/min.Moderaterenallesions97(48/49)Pred1mg/kg/dayRamiprilmeandosage7.5mg/d602(0.9%)13(5.7%)1(0.4%)7(3.0%)ReducedProteinuriaandimprovedrenalsurvival(definedasdoublingofSCrandorESKD)Lai1986(China)IgAnephropathywithnephroticsyndrome34(17/17)Pred40-60mg/dNotreatment380(-)0(-)0(-)0(-)ReducedproteinuriaNoeffectontheGFRJulian1993(USA)CCr>25ml/min31(18/17)Pred60mg/qodNotreatment6-241(-)2(-)1(-)2(-)Noeffectonproteinuria;Atrendtopreserverenalfunction(definedby1/SCr,p=0.06)Shoji2000(Japan)Proteinuria<1.5g/dScr<1.5mg/dl19(11/8)Pred0.8mg/kg/dDypiridamole300mg/d12----ReducedProteinuria,noeffectontheGFR;ReducingrenallesioninhistologyKatafuchi2003(Japan)Scr<1.5mg/dl90(43/47)Pred20mg/dDypiredamole150-300mg/d653(1.3%)3(1.2%)3(1.3%)3(1.2%)ReducedproteinruiaNoeffectontherenalsurvival(definedasESKD)Hogg

2006(USA)Proteinuria(UP/C)>1.0or>0.5withrenallesionsatrisk;GFR>5064(33/31)Pred60mgqodplacebo24----NoeffectonProteinuriareductionorrenalsurvival(definedas60%decreaseofGFR)RCTsinIgANephropathy2023/11/1255Effectofsteroidsoncompositerenalendpoint(doublingofserumcreatinineandend-stagekidneydisease)inpatientswithIgAnephropathy2023/11/1256Subgroupanalysisfortheeffectofcorticosteroidoncompositerenalendpoint2023/11/1257

不良事件：

（包括高血压、糖尿病/糖耐量异常、消化道出血、Cushing表现、失眠心悸多汗头痛）NOTE:WeightsarefromrandomeffectsanalysisOverallShoji2000Lai1986Pozzi2004Lv2009Julian1993Katafuchi2003Manno20090/117/1712/435/337/173/434/481/86/1710/431/301/180/472/491.63(0.91,2.95)0.25(0.01,5.45)1.17(0.49,2.75)1.20(0.58,2.48)4.55(0.56,36.72)7.41(1.02,54.10)7.64(0.41,143.70)RR(95%CI)2.04(0.39,10.63)1.63(0.91,2.95)(I²=17.7%,p=0.30)0.25(0.01,5.45)1.17(0.49,2.75)1.20(0.58,2.48)4.55(0.56,36.72)7.41(1.02,54.10)7.64(0.41,143.70)2.04(0.39,10.63)

1.5110StudySteroidsgroupevent/totalControlgroupevent/total38/21221/2122023/11/1258ResponsetoCSandRASBcomparedwithRASBaloneinpropensity-matchedindividuals.VladimirTesaretal.JASNdoi:10.1681/ASN.2014070697获益

与风险2023/11/1260TwoMajorOngoingTrials2023/11/1261TESTING

TherapeuticEvaluationofSTeroidsinIgANephropathyGlobalstudy

“AcollaborationbetweenthePekingUniversityInstituteofNephrology,theGeorgeInstituteforGlobalHealthandrenalresearchersaroundtheworld”研究启动2012年5月2023/11/1262TESTING研究地区分布图

全球100家医院入选1300例印度新加坡2023/11/1263Beijing:N=8ShijiazhuangN=2Huhehaote:N=2tianjin:N=1Taiyuan:N=1jinanN=3nanjingN=3ShanghaiN=5HangzhouN=2GuangzhouN=1ShenzhenN=1WuhanN=3ZhengzhouN=2ChengduN=2LuoyangN=1YantaiN=1ZhengzhouN=2ChineseSitesofTESTINGStudy40sitesinitiated2023/11/1264V1(-4wks)RegisterV2(-2wks)Run-inAdditionalvisitξV3(0m)RandomizationV4(1m)V5(2m)V6(3m)V7(6m)V9(9m)V10(12m)V11-final(every3month)ACEinhibitorsorARBstofulldose*bloodpressurecontrollasguidelinesPlaceboPrednisone1mg/kg/d(maximal60mg/d)Х2monTappered10mg/dayeverymonStoppedat6-8monACEinhibitorsorARBstofulldosebloodpressurecontrollasguidelinesFinalvisitScreeningandrun-inphase4to8weeks(2011-2013)Steroidstreatment6to8monthsFollowupto4-6yrs(average5yrs)Visitevery6months(2011-2017)Note:ξ

Forserumcreatinine(SCr)fromVisit1toVisit2apart<20%,patientsarerandomizedatVisit3ForserumcreatinefromVisit1toVisit2apart≥20%,patientsaresheduletoanadditionalvisit1timeatleast4weeksapart,iftheSCrconcentrationchange<20%patientsundergorandomization,otherwiseregardedasscreeningfailure.*ForACEinbhitors(orARBifuntoleranttoACEinhibitors)titratetofulldoseasguidelinesrecommended.ACEinhibitorsorARBstofulldosebloodpressurecontrollasguidelinesSTUDYPROCEDURESFundingandprogressCountryNo.SitesPlanned

participantNo.StatusFundsChina43620RecruitingRMB6MANZ660RecruitingNHMRCAU$2.7MHongKong310ReadyforrecruitingLocalCanada10100SiteECapplicationunderway,tobeinitiatedNov-Dec.2014CIHR:CA$800,000India10150Regulatoryapprovalpending,tobeinitiatedQ22015LocalMalaysia640RegulatoryandECapplicationunderway,tobeinitiatedQ22015NHMRCEurope60320GrantapplicationsubmittedLocalTotal1381300(samplesizeincurrentprotocol)2023/11/1266全球入选病人1300列，随访5年CentralExecutiveCommittee Chair:HaiyanWang

DeputyChair:VladoPerkovic

StudyDirector:HongZhangInternationalstudyphysician:JichengLv中国研究者引领的研究者启动的国际RCT研究。具有一定的国际影响力。TESTING

TherapeuticEvaluationofSTeroidsin

IgANephropathyGlobalstudy2023/11/1267IgA肾病治疗策略中国人回答！No.InterventionDesignSamplesizeExpectedcompletetimeSponsor/LocationNCT01758120PrednisonepluscyclophosphamideRCT-openlabel1202015DecGuangdongGeneralHospital/ChinaNCT01854814MycophenolatemofetilRCT-openlabel2322018JunNanfangHospital/ChinaNCT00498368IntravenousRituximabRCT-openlabel542014MarMayoClinic/USANCT00657059MycophenolatemofetilRCT-openlabel1502013JunSunYat-senUniversity/ChinaNCT00554502SupportiveandimmunosuppressivetherapyRCT-openlabel1482013DecRWTHAachenUniversity/GermanyNCT01560052SupportiveandMethylprednisoloneRCT-DoubleBlind13002017SepPekingUniversity/China

AserviceoftheU.S.NationalInstitutesofHealthOngoingTrials2023/11/1269内容病情评估治疗选择特殊IgA肾病治疗新月体型IgA肾病：参照血管炎治疗轻微病变型IgA肾病肾病综合征：参照微小病变肾病治疗毛细血管内增生性IgA肾病???免疫抑制治疗2023/11/1270新月体IgA肾病KDIGO指南制定依据71StudyDesignNofPatientsCriteriaTreatmentFollow-upResultProteinuriaRenalfunctionPathologyTangZ,etal.2002Retrospective,Observational25,10ofthemlostfollow-upCrescent>50%MPIV1g/d*3dCTXIV0.5-0.75/m2/m29.8(8-92)mo↓（3.51→1.31g/d)33%ESKD33%Scrwithinnormalrange33%CRFNATumlinJA,etal.2003Prospective,Open12

receivedimmunosuppressivetherapy；12historicalcontrolCrescent>>10%+hypertension+UTP>1g/dMPIV1g/d*3dCTXIV0.5/m2/m*6m36mo↓（3.70→1.35g/d)Treatmentgroup:1/12

ESKD;Control:

5/12

ESKDLossofcrescentandEndocapillaryhypercellularity，intersitialfibrosisdidnotaggreviatePankhurstT,etal.2009Retrospective,Observational34

IgAN33

HSPVasculiticlesionsteriod（22%）；steriod+CTX/AZA（55%）；plasmaexchange1%，untreated21%32.4(0-90)mo↓（1.67→0.14g/d)GFR46.63→45.17ml/min.1.73m2NA2023/11/122023/11/127273LvJetal.JAmSocNephrol2013新月体IgA肾病预后模型的建立0%20%40%60%80%100%02468101214SerumCreatinineatRenalBiopsy,mg/dlLogisti