Eur Heart J Cardiovasc Pharmacother:慢性心力衰竭患者的肾脏保护:关注沙库巴曲/缬沙坦

2021-04-12 心关注 心关注

慢性肾脏病(CKD)在慢性心力衰竭(CHF)患者中非常普遍,并且对全球和心血管(CV)死亡率造成相当不利的预后负担[1]。关键的CHF试验数据显示CKD的患病率在32%到50%之间,在大约30%的心力

慢性肾脏病(CKD)在慢性心力衰竭(CHF)患者中非常普遍,并且对全球和心血管(CV)死亡率造成相当不利的预后负担。关键的CHF试验数据显示CKD的患病率在32%到50%之间,在大约30%的心力衰竭(HF)患者中观察到肾功能恶化。此外,CKD是CV后遗症和死亡的危险因素。

尽管有证据表明血管紧张素转换酶抑制剂(ACE-I)有效,CKD阻碍了心力衰竭标准药物治疗的优化,并导致肾素-血管紧张素-醛固酮系统(RAAS)抑制剂和醛固酮拮抗剂(mineralocorticoid receptor antagonists; MRA)的使用不足,血管紧张素受体阻滞剂(ARB)和MRA在降低CHF死亡率中的作用。因此,需要其他治疗方案来优化伴有CKD的CHF患者的治疗结果。

沙库巴曲/缬沙坦是首款血管紧张素受体脑啡肽酶抑制剂(ARNIs)。沙库巴曲是一种前体药物,进入体内后经过酯酶代谢为活性产物 LBQ657,抑制 NEP 活性,进而使利钠肽系统活性增强,发挥降压和靶器官保护作用。

一些荟萃分析表明,与单独的RAAS抑制相比,联合应用neprilysin-RAAS抑制与沙库巴曲/缬沙坦或omapatrilat可能对HF患者的肾功能有有益的影响。然而,关于沙库巴曲/缬沙坦对HFrEF患者肾功能保护作用的数据有限。这篇叙述性综述讨论了沙库巴曲/缬沙坦在HFrEF患者中提供额外肾脏益处的作用的证据。

CHF心肾相互作用的病理生理学研究

CHF和CKD有几个共同的病因危险因素,包括“传统”的CV危险因素,如年龄、性别、高血压、血脂异常和糖尿病。除了病因危险因素外,还存在各自病理生理学的相互作用。在CHF中,影响心动周期的结构或功能异常损害了心脏维持组织灌注以满足代谢需要和适应静脉回流的能力。

2型糖尿病的存在进一步加速了CHF患者肾功能的恶化。在CHF中,心功能受损,心输出量减少,肾血流和灌注梯度降低,加重肾血流动力学改变。当衰竭的心脏试图维持足够的功能时,一些代偿机制随之出现,包括增加心输出量、心室重构和激活神经激素系统以增加平均动脉压。与HFrEF相比,射血分数保留的HF(HFpEF)的病理生理学更具异质性,但HFpEF和HFrEF的血清肌酐增加基本相似,因此导致肾损害的机制可能相似。

在PARADIGM-HF中,与依那普利相比,尽管血压值略低,但沙库巴曲/缬沙坦提供了更大的肾保护。此外,对PARADIGM-HF的肾功能影响与CV和肾功能转归之间关系的分析表明,ARNI治疗相关的尿白蛋白排泄适度增加与肾脏终点的高风险无关,表明随着时间的推移尿白蛋白/肌酐比值的升高可能是介导的肾小球通透性增加不会导致肾功能进行性降低的机制。与依那普利相比,沙库巴曲/缬沙坦治疗对心衰住院患者心血管死亡率的有利影响进一步证明了这一点。因此,J曲线现象受到沙库巴曲/缬沙坦(图2)在抑制脑啡肽酶和血管紧张素II方面独特的双重作用机制的挑战。这被认为是由于在沙库巴曲/缬沙坦治疗下在肾小球水平发生的特殊病理生理学改变,综合起来,尽管全身血压显着降低,但可能导致肾功能的保留。

图2

双重血管紧张素-脑啡肽酶对心力衰竭的抑制作用

沙库巴曲/缬沙坦双重血管紧张素-脑啡肽酶抑制内源性利钠肽的降解,以及其他血管活性肽,包括心钠素(ANP)、血管紧张素II、缓激肽、肾上腺髓质素、内皮素、脑(B型)利钠肽(BNP)和C型利钠肽(CNP),增加这些物质的含量。尼泊尔溶素的激活增加细胞内cGMP,进而导致血管扩张、利尿,抑制心肌纤维化和肥大,抑制RAAS。这些作用是由利钠肽受体(NPR)、NPR-A和NPR-B介导的,而NPR-C的主要作用是结合和内化利钠肽,将其从循环中清除,尽管它们也可能介导抗纤维化作用。

沙库巴曲/缬沙坦同时阻断血管紧张素Ⅱ1型受体也可抵消可能由尼泊尔溶素抑制引起的RAAS过度激活(即血压、钠和水潴留增加)的潜在长期有害影响。也有证据表明,在实验模型中,增加利钠肽的活性可发挥直接的抗氧化、抗炎和抗纤维化作用,沙库必利/缬沙坦可预防纤维化,减少氧化应激、细胞凋亡,心肾综合征动物模型肾脏和心脏组织线粒体损伤的观察。

对临床实践的启示

心衰患者心脏和肾脏在调节体液和电解质稳态方面复杂的相互联系的功能显着改变,其中CKD是心血管疾病的一个常见伴随条件和独立危险因素。随着心衰的进展,维持血管收缩、钠潴留、血管舒张和钠尿相关系统和过程之间的必要平衡以确保循环完整性变得困难,钠和水潴留的增强增加了心衰相关的心脏应激和心肌损伤的衰弱症状。因此,允许肾脏维持肾小球和肾小管功能的CHF疗法将有助于防止充血,有助于延缓疾病进展,提高与HF相关的发病率和死亡率。PARADIGM-HF显示沙库巴曲/缬沙坦在HFrEF中提供了优于传统RAAS抑制的CV保护,并且PARADIGM-HF的数据首次表明沙库巴曲/缬沙坦在HFrEF 中具有更好的肾保护作用,这在CKD患者和糖尿病患者中得到了证实。此外,PARADIGM-HF显示,沙库巴曲/缬沙坦引起的高钾血症少于ACE-I标准治疗,脑啡肽酶抑制可降低高钾血症的风险,并有助于同时进行MRA的处方和减少患者管理中使用环路利尿剂的选择。

结论

脑啡肽酶通过改善肾血流量和GFR,抑制肾素释放,对肾脏和肾小管产生直接的生物效应,通过减少钠重吸收,从而影响肾小球。因此,在利尿、利尿和保护肾功能方面有净效益。这些机制结合起来,有助于解释ARNI诱导的HFrEF患者残余肾功能的保存。尽管双重血管紧张素-脑啡肽酶抑制HFrEF的长期肾脏效应仍有待于充分阐明,但现有的证据表明,沙库巴曲/缬沙坦是一种有效的治疗选择,至少在eGFR>30ml/min/1.73m2的HFrEF患者中,沙库巴曲/缬沙坦可能替代ACE-I和ARBs。全面实施目前的护理标准有可能改善HFrEF的结果。

原始出处:

Roberto Pontremoli, Claudio Borghi, et al. Pasquale Perrone Filardi. Renal protection in chronic heart failure: focus on sacubitril/valsartan. European Heart Journal - Cardiovascular Pharmacotherapy, pvab030.

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    2022-02-27 quxin068
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    2021-11-29 jj000001
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  6. [GetPortalCommentsPageByObjectIdResponse(id=1939154, encodeId=1e251939154d3, content=<a href='/topic/show?id=1c292818fd' target=_blank style='color:#2F92EE;'>#ASC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2818, encryptionId=1c292818fd, topicName=ASC)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=74808, createdName=quxin068, createdTime=Sun Feb 27 08:05:04 CST 2022, time=2022-02-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1787711, encodeId=33a11e87711e9, content=<a href='/topic/show?id=fa03141591e' target=_blank style='color:#2F92EE;'>#Pharm#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14159, encryptionId=fa03141591e, topicName=Pharm)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8942242, createdName=jj000001, createdTime=Mon Nov 29 13:05:04 CST 2021, time=2021-11-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1996398, encodeId=198c19963986d, content=<a href='/topic/show?id=ed881120ec8' target=_blank style='color:#2F92EE;'>#MAC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11207, encryptionId=ed881120ec8, topicName=MAC)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4b65161, createdName=yb6560, createdTime=Thu Jul 01 07:05:04 CST 2021, time=2021-07-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1908629, encodeId=db9a190862938, content=<a href='/topic/show?id=a8d0141605e' target=_blank style='color:#2F92EE;'>#pharma#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14160, encryptionId=a8d0141605e, topicName=pharma)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f634250, createdName=chentianping, createdTime=Sun Sep 19 02:05:04 CST 2021, time=2021-09-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1251816, encodeId=8c5e125181679, content=<a href='/topic/show?id=ac5d5351ea8' target=_blank style='color:#2F92EE;'>#慢性心力衰竭#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=53517, encryptionId=ac5d5351ea8, topicName=慢性心力衰竭)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=395f25, createdName=bioon1, createdTime=Wed Apr 14 08:05:04 CST 2021, time=2021-04-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1357687, encodeId=4fb7135e687ff, content=<a href='/topic/show?id=b0702e84b9' target=_blank style='color:#2F92EE;'>#ART#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2784, encryptionId=b0702e84b9, topicName=ART)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=zhaojie88, createdTime=Wed Apr 14 08:05:04 CST 2021, time=2021-04-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1367686, encodeId=1184136e6861c, content=<a href='/topic/show?id=9334e9305c7' target=_blank style='color:#2F92EE;'>#缬沙坦#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79305, encryptionId=9334e9305c7, topicName=缬沙坦)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f73a255, createdName=medscijoin, createdTime=Wed Apr 14 08:05:04 CST 2021, time=2021-04-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1563443, encodeId=b4dc15634430b, content=<a href='/topic/show?id=f69d864413' target=_blank style='color:#2F92EE;'>#HEART#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=8644, encryptionId=f69d864413, topicName=HEART)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=80d715270048, createdName=slcumt, createdTime=Wed Apr 14 08:05:04 CST 2021, time=2021-04-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=956249, encodeId=dbc995624969, content=好文章!, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20160806/IMG57A5698BDB0244113.jpg, createdBy=32a91358059, createdName=jyzxjiangqin, createdTime=Mon Apr 12 18:11:24 CST 2021, time=2021-04-12, status=1, ipAttribution=)]
    2021-04-14 zhaojie88
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    2021-04-14 slcumt
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    2021-04-12 jyzxjiangqin

    好文章!

    0

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