陈春教授:DKD发病机理研究与药物治疗靶点探索丨CSN2019

2019-09-19 missoct MedSci原创

中华医学会肾脏病学分会2019年学术年会已于9.17日起在杭州正式召开,在今天下午进行的糖尿病肾病专题中,华中科技大学同济医学院附属协和医院陈春教授为我们介绍了糖尿病肾病(DKD)发病机理研究与药物治疗的靶点探索。我国DKD的发病率和住院率逐年提升,是目前引起终末肾衰竭的首要原因。 治疗DKD需要遵循的原则包括:生活方式指导、控制血糖、控制血压、纠正脂质代谢紊乱、肾脏替代治疗、其他治疗药



中华医学会肾脏病学分会2019年学术年会已于9.17日起在杭州正式召开,在今天下午进行的糖尿病肾病专题中,华中科技大学同济医学院附属协和医院陈春教授为我们介绍了糖尿病肾病(DKD)发病机理研究与药物治疗的靶点探索。

我国DKD的发病率和住院率逐年提升,是目前引起终末肾衰竭的首要原因。


 
治疗DKD需要遵循的原则包括:生活方式指导、控制血糖、控制血压、纠正脂质代谢紊乱、肾脏替代治疗、其他治疗药物等。其中,血糖控制的目标为HbA1c≤7。血压的控制目标为130/80mmHg,对于尿蛋白>1.0/24h者,血压控制目标为125/75mmHg。当血LDL-C>3.38mm/L,TG>2.26mm/L时需干预治疗。为达到这些控制的目标,药物的选择至关重要。

DKD的药物治疗:非降糖药物的临床研究证据

DKD非降糖的常用治疗药物包括ACEI/ARB、肾素抑制剂、醛固酮受体拮抗剂等。张春教授汇总了近几年的相关研究并指出,这些药物在临床上单独使用时都被证实可延缓DKD肾功能的恶化,且新一代非甾体类MRA Finerenone与ACEI/ARB连用可降低DN患者尿蛋白水平。

但在ACEI/ARB的基础上联合使用肾素抑制剂阿利吉仑或安慰剂治疗时尽管血压和尿蛋白水平有所降低,但阿利吉仑组高血钾和低血压发生率明显增加,提示在ACEI/ARB基础上,联合肾素抑制剂并未进一步获益。

舒洛地特是肝素样分子,是一种对动脉和静脉均有较强抗血栓形成作用的葡糖胺聚糖,它可增加肝素肝素本身或其他抗凝剂的抗凝作用。早期临床研究显示舒洛地特对于1型/2型DM、微量或大量蛋白尿的DN,均能有效降低其尿蛋白,但后来陆续的研究则未能显示其对伴大量蛋白尿的2型DM患者的肾脏保护作用及降低患者尿蛋白的作用。


DKD的药物治疗:降糖药物的临床研究证据

这类药物包括:肠促胰岛素激动剂(GLP-1受体激动剂)、DPP-4抑制剂、SGLT2抑制剂等。艾塞那肽和利拉鲁肽是目前在我国已上市的2种GLP-1受体激动剂,其中利拉鲁肽能延缓2型糖尿病患者肾损害,但因其经肾脏清除,不推荐用于CKD4-5期患者。

DPP-4抑制剂利格列汀联用RAAS抑制剂可有效降低2型糖尿病患者尿蛋白,且此作用不受血糖或血压影响。

SGLT2抑制剂恩格列净、卡格列净和达格列净均能延缓2型糖尿病患者肾损害,对于伴有动脉硬化患者,达格列净并未减少主要心血管事件(MACE),卡格列净的CREDENCE研究显示:卡格列净能显著改善DKD患者肾脏结局,包括明显减轻蛋白尿、显著延缓GFR下降,显著减少ESRD,透析,移植和肾脏死亡。
 

SGLT2抑制剂的作用机制


基于DKD发病机理研究的治疗进展

糖尿病肾病的病理表现为:足细胞肥大缺失,内皮细胞损伤,系膜细胞增殖,壁层上皮细胞增殖,GBM增厚,ECM聚集,肾小球硬化,肾间质纤维化,血管病变。

 肾脏病的发病机制


基于糖尿病肾病的病理和发病机制,一些相关靶点的药物研究也取得了一定进展。

基于DKD发病机理的干预靶点
 

PKC-β抑制剂Ruboxistaurin延缓DKD肾功能进展
 



NOX2和NOX4抑制剂延缓DN进展
 

抑制NLRP3炎症小体活化改善了DKD足细胞损伤
 

体外敲低MDM2可减轻高糖所致足细胞有丝分裂灾难及足细胞损伤
 

目前这些研究尚处于动物实验阶段,但也为糖尿病肾病的诊治带来了新的可能性。

最后陈春教授对本次分享做出了总结:对于糖尿病肾病患者来说,生活方式、血糖/血压/血脂控制是DKD治疗的基石,临床研究为延缓DKD进展的药物获得了许多证据,基于DKD发病机制的干预药物取得了诸多进展。同时,期待更多的临床证据出现为糖尿病肾病的诊治带来新的希望。





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  4. [GetPortalCommentsPageByObjectIdResponse(id=1973844, encodeId=916b19e384411, content=<a href='/topic/show?id=77793e918a2' target=_blank style='color:#2F92EE;'>#发病机理#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=48, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37918, encryptionId=77793e918a2, topicName=发病机理)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLx96cCLjNYsHar1XErTVibOydfEC9iaYgrXp3SicXwntSAEDeQAlM2vLqTfm6oPORxaib3UIgyHQJJ7A/132, createdBy=36f02500138, createdName=ms6980045490879608, createdTime=Mon Jul 27 13:46:00 CST 2020, time=2020-07-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1895391, encodeId=625e189539166, content=<a href='/topic/show?id=18ae64e21d3' target=_blank style='color:#2F92EE;'>#治疗靶点#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64721, encryptionId=18ae64e21d3, topicName=治疗靶点)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=80c5136, createdName=drj2003, createdTime=Thu Mar 12 17:46:00 CST 2020, time=2020-03-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2077618, encodeId=a03120e761841, content=<a href='/topic/show?id=3cb85351a4' target=_blank style='color:#2F92EE;'>#CSN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5351, encryptionId=3cb85351a4, topicName=CSN)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTKUdkK5dVTue7YQDvwqM1ugOuEpDZEzvXhoGClFiavehcrNAYDuPbks3MkKLPpyAEicgic80KguxwicYQ/132, createdBy=ec952500165, createdName=ms5187542471278033, createdTime=Fri Feb 21 01:46:00 CST 2020, time=2020-02-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1545515, encodeId=97541545515c8, content=<a href='/topic/show?id=aa77602136' target=_blank style='color:#2F92EE;'>#DKD#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=6021, encryptionId=aa77602136, topicName=DKD)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=773213763478, createdName=12498b08m94暂无昵称, createdTime=Sat Sep 21 14:46:00 CST 2019, time=2019-09-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=372981, encodeId=646c3e298151, content=学习了,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzTetibytbqFDmFITWHyBWbxU7S9MYibgPSqvu0sYteH0N6zXqbU0Kf3Mbdb7yWM1Kud3zPgYBibE2SZ/0, createdBy=da7696924, createdName=qingfengqishi5, createdTime=Fri Sep 20 22:27:49 CST 2019, time=2019-09-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=372955, encodeId=a7cf3e295585, content=谢谢了,学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=81, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=30331616752, createdName=txqjm, createdTime=Fri Sep 20 07:03:33 CST 2019, time=2019-09-20, status=1, ipAttribution=)]
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    2019-09-20 qingfengqishi5

    学习了,学习了

    0

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    2019-09-20 txqjm

    谢谢了,学习

    0

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