【摘要】經(jīng)皮冠狀動脈介入治療是急性冠脈綜合征的主要治療措施。對比劑腎病是經(jīng)皮冠狀動脈介入治療術(shù)后常見并發(fā)癥之一。對于對比劑腎病缺乏有效治療措施。術(shù)前做好對比劑腎病高危因素評估,識別高?;颊撸瑖中g(shù)期水化是最為有效的防治措施。另外,他汀類藥物和N-乙酰半胱氨酸是研究最多的藥物?,F(xiàn)對急性冠脈綜合征患者經(jīng)皮冠狀動脈介入治療術(shù)后對比劑腎病防治進(jìn)展進(jìn)行綜述。
【關(guān)鍵詞】對比劑腎?。患毙怨诿}綜合征;經(jīng)皮冠狀動脈介入治療;防治
【DOI】10.16806/j.cnki.issn.1004-3934.2023.02.007
【Abstract】Percutaneous coronary intervention has been the main treatment for acute coronary syndrome.Contrast induced nephropathy (CIN) is one of the common complications after percutaneous coronary intervention.There are no effective treatment for CIN.Preoperative assessment of risk factors before emergency percutaneous coronary intervention, identification of high-risk patients, and perioperative adequately hydration are the most effective measures for prevention of CIN.In addition, statins and N-acetylcysteine have been the most extensively studied drugs.This article reviews the progress in the prevention of contrast induced nephropathy after percutaneous coronary intervention in patients with acute coronary syndrome.
【Key words】Contrast induced nephropathy;Acute coronary syndrome;Percutaneous coronary intervention;Prevention
經(jīng)皮冠狀動脈介入治療(percutaneous coronary intervention, PCI)是急性冠脈綜合征(acute coronary syndrome, ACS)患者的首選治療措施,對比劑廣泛應(yīng)用于PCI術(shù)中,PCI術(shù)中應(yīng)用對比劑后出現(xiàn)的急性腎損傷(acute kidney injury, AKI)稱作對比劑誘導(dǎo)的急性腎損傷(contrast-induced acute kidney injury, CI-AKI)或?qū)Ρ葎┫嚓P(guān)的急性腎損傷(contrast associated acute kidney injury, CAAKI)或?qū)Ρ葎┠I病(contrast induced nephropathy, CIN),是ACS患者常見的并發(fā)癥,增加遠(yuǎn)期死亡率,是不良預(yù)后指標(biāo)[1]。臨床上CIN的早期定義為在排除腎毒性藥物、缺血性腎病等因素影響后,血管內(nèi)注射對比劑后肌酐48 h內(nèi)較基線增加25%或≥0.5 mg/dL(44 μmol/L) [2]。2012年改善全球腎臟病預(yù)后組織(KDIGO)將其定義為血管內(nèi)注射對比劑后72 h內(nèi)肌酐較基線增加≥0.3 mg/dL(26.5 μmol/L),或1周內(nèi)增加50%以上,或持續(xù)6 h以上尿量<0.5 mL/(kg·h)[3]。多數(shù)患者為一過性肌酐升高,3~5 d肌酐達(dá)峰值,7~10 d恢復(fù)到基線水平[2],但是對于高危患者仍可能出現(xiàn)持續(xù)性腎功能不全。CI-AKI的發(fā)生顯著增加ACS患者死亡率及主要不良心腦血管事件,是患者遠(yuǎn)期不良預(yù)后的獨(dú)立預(yù)測因素[4-5]。目前對ACS患者CIN的防治是以生理鹽水水化為主的支持治療,尚無有效治療措施,現(xiàn)從術(shù)前風(fēng)險(xiǎn)評估、水化治療、他汀類藥物、N-乙酰半胱氨酸、對比劑應(yīng)用、腎臟替代治療等方面對ACS患者PCI術(shù)后CIN的防治進(jìn)行綜述。
1"術(shù)前風(fēng)險(xiǎn)評估
ACS患者PCI術(shù)后CIN的危險(xiǎn)因素包括腎功能不全、糖尿病、高血壓、高齡、心力衰竭、對比劑劑量>200 mL、心源性休克、腎毒性藥物應(yīng)用、貧血、低蛋白血癥、主動脈內(nèi)球囊反搏的使用[6-9],慢性腎臟病是最重要的危險(xiǎn)因素,慢性腎臟病患者多合并高血壓、糖尿病,死亡風(fēng)險(xiǎn)更高[1]。高尿酸血癥也是CIN發(fā)生的重要危險(xiǎn)因素[10]。
Mehran評分包括低血壓、應(yīng)用主動脈內(nèi)球囊反搏、充血性心力衰竭、年齡≥75歲、貧血、糖尿病、對比劑應(yīng)用>100 mL、肌酐基礎(chǔ)值>1.5 mg/dL(132 μmol/L)、估算腎小球?yàn)V過率(estimated glomerular filtration rate,eGFR)<20 mL/(min·1.73 m2)或20 mL/(min·1.73 m2)≤eGFR≤40 mL/(min·1.73 m2)或40 mL/(min·1.73 m2)<eGFR≤60 mL/(min·1.73 m2)等指標(biāo),評分越高,急性心肌梗死患者術(shù)后CIN風(fēng)險(xiǎn)及出現(xiàn)持續(xù)腎功能不全和遠(yuǎn)期臨床結(jié)局的風(fēng)險(xiǎn)越高[11] 。Mehran評分包括術(shù)中對比劑劑量指標(biāo),術(shù)前難以完成詳細(xì)評估,而由高齡、左室射血分?jǐn)?shù)下降、腎小球?yàn)V過率下降組成的AGEF評分能預(yù)測ST段抬高心肌梗死(ST segment elevation myocardial infarction,STEMI)患者急診PCI術(shù)后CIN發(fā)生(OR=5.19,P<0.001,AUC=0.88)[12]。由心率>100 次/min、收縮壓<100 mm Hg(1 mm Hg=0.133 3 kPa)、年齡≥75歲 和Killip>1四項(xiàng)指標(biāo)組成的C-ACS評分系統(tǒng)對STEMI患者PCI術(shù)后CIN及臨床預(yù)后有良好的預(yù)測價(jià)值[13]。CHA2DS2-VASc評分可預(yù)測ACS患者PCI術(shù)后CIN的發(fā)生(AUC=0.769,95%CI 0.733~0.805,P<0.001),CHA2DS2-VASc 評分≥4分是CIN 發(fā)生率的獨(dú)立預(yù)測因素[14]。另外術(shù)中罪犯血管Syntax評分>10分,是STEMI患者急診PCI術(shù)后發(fā)生CI-AKI的重要決定因素[15]。對于擬行急診PCI的患者,這些評分系統(tǒng)可能更有利于對CIN風(fēng)險(xiǎn)做出初步評估。
2"水化
水化治療能增加腎血流量、稀釋對比劑,是預(yù)防PCI術(shù)后CIN的重要措施,口服和靜脈補(bǔ)液進(jìn)行水化均可有效減少CIN的發(fā)生[16]。一項(xiàng)包括3項(xiàng)隨機(jī)對照研究納入924例行急診PCI的STEMI患者的薈萃分析[17]顯示,圍手術(shù)期行生理鹽水水化可顯著降低CIN發(fā)生率(水化組16.9% vs對照組26.4%,RR=0.64,95% CI 0.50~0.82,P=0.000 5),但并不減少術(shù)后腎臟替代治療需要和死亡率。另一項(xiàng)納入1 074例行急診PCI的STEMI患者的薈萃分析[18]表明,和未水化的對照組比較,急診PCI時(shí)靜脈水化對CIN發(fā)生率降低42%(RR=0.58,95%CI 0.45~0.74,P<0.001)。對于行急診PCI的ACS患者,常合并存在心力衰竭、容量負(fù)荷不足、低血壓等情況,補(bǔ)液水化是最重要的治療措施。近期Liu等[19]對560例STEMI患者的多中心隨機(jī)對照研究表明,根據(jù)左心室舒張末壓積極水化,CI-AKI發(fā)生率較常規(guī)水化更低(21.8% vs 31.1%),兩組急性心力衰竭的發(fā)生率并無顯著差異,積極水化在CI-AKI防治上有更好的療效,尤其是對于腎功能不全、非左前降支病變的急性心肌梗死患者。ACS患者是CIN高危人群,術(shù)前開始水化治療是安全有效的預(yù)防措施。
水化晶體的選擇臨床上主要以生理鹽水為主,而碳酸氫鈉的堿化作用,可以中和氧自由基的腎損傷作用,既往有研究顯示碳酸氫鈉水化可減少CIN的發(fā)生。CINSTEMI研究[20]是對720例行急診PCI的STEMI患者的隨機(jī)對照研究,相對于生理鹽水(n=181),碳酸氫鈉(n=181)水化可以減少CIN的發(fā)生,但二者無統(tǒng)計(jì)學(xué)差異(20.1% vs 26.5%,P=0.43)。PRESERVE研究[21]中對行PCI的合并慢性腎臟病的穩(wěn)定型冠心病的亞組分析,其中2 511例行碳酸氫鈉水化,2 482例行生理鹽水水化,兩組CAAKI發(fā)生率并無顯著差異(4.4% vs 4.7%,P=0.62)。相對于生理鹽水,碳酸氫鈉水化在ACS患者CIN的防治上并無優(yōu)勢,目前指南對于CIN的防治,推薦足夠的生理鹽水水化治療作為基礎(chǔ)治療,尤其是對于腎功能不全的高危患者,建議術(shù)前術(shù)后生理鹽水水化,術(shù)前12 h開始1 mL/(kg·h)水化,術(shù)后持續(xù)24 h,對于左室射血分?jǐn)?shù)≤35%或心功能(NYHA分級)>2級者,可予以0.5 mL/(kg·h)水化[22-23]。
3"他汀類藥物
關(guān)于他汀類藥物在CIN中的應(yīng)用,多為PCI術(shù)前高劑量負(fù)荷應(yīng)用,他汀類藥物對ACS患者有著明確的心血管保護(hù)作用,其對CIN防治上的具體機(jī)制不詳。對9項(xiàng)臨床隨機(jī)對照試驗(yàn)(n=5 212)的薈萃分析[24]顯示,術(shù)前短期強(qiáng)化他汀類藥物治療可顯著降低ACS患者CI-AKI的風(fēng)險(xiǎn)(RR=0.37,95%CI 0.25~0.55,P<0.000 1),而對非ACS患者的相關(guān)風(fēng)險(xiǎn)并無顯著降低趨勢(RR=0.65,95%CI 0.41~1.03,P=0.07)。ACS患者PCI術(shù)前短期高劑量瑞舒伐他汀可減少CI-AKI發(fā)生,他汀類藥物的腎臟保護(hù)可能與抗炎作用相關(guān)[25]。中國一項(xiàng)納入496例ACS患者的前瞻性隨機(jī)對照研究[26]顯示術(shù)前高劑量阿托伐他汀可顯著降低ACS患者CIN發(fā)生率(6.4% vs 12.6%,P=0.02)。然而美國一項(xiàng)納入2 055例患者的觀察性臨床研究[27]顯示術(shù)前他汀類藥物應(yīng)用并不減少ACS患者在內(nèi)的冠心病患者PCI術(shù)后CI-AKI的發(fā)生。盡管他汀類藥物對ACS患者有一定的腎臟保護(hù)作用,目前具體保護(hù)機(jī)制仍不明確,可能與其心血管保護(hù)作用相關(guān),2022年加拿大放射學(xué)會指南[28]不推薦他汀類藥物作為CI-AKI的常規(guī)預(yù)防策略。鑒于其抗炎、抗氧化、調(diào)脂、穩(wěn)定斑塊等作用,可考慮對ACS患者術(shù)前短期高劑量他汀類藥物治療。
4"N-乙酰半胱氨酸
N-乙酰半胱氨酸能清除氧自由基、減輕術(shù)后氧化應(yīng)激、減低對比劑的腎毒性,曾被認(rèn)為是CIN防治的重要藥物。然而另一項(xiàng)納入7項(xiàng)臨床對照研究的meta分析[29](n=1 710)指出,和未使用N-乙酰半胱氨酸的對照組比較,對行急診PCI的STEMI患者應(yīng)用N-乙酰半胱氨酸可顯著降低CAAKI的發(fā)生風(fēng)險(xiǎn)。2016年一項(xiàng)納入43項(xiàng)隨機(jī)對照研究(n=3 277)的薈萃分析[30]指出,ACS亞組中N-乙酰半胱氨酸應(yīng)用使CI-AKI發(fā)生率有下降趨勢,但組間差異無統(tǒng)計(jì)學(xué)意義(OR=0.758,95%CI 0.538~1.066,I2=38.56%,P=0.111),而非ACS亞組分析N-乙酰半胱氨酸應(yīng)用可顯著減少CI-AKI發(fā)生(OR=0.642,95%CI 0.492~0.838,I2=33.73%,P=0.001)。Garcia等[31]進(jìn)行的PRESERVE研究是一項(xiàng)大樣本的臨床隨機(jī)對照研究,對行PCI術(shù)的1 161例患者的亞組分析表明,N-乙酰半胱氨酸并不能降低合并慢性腎臟病的高危穩(wěn)定型冠心病患者PCI術(shù)后CA-AKI發(fā)生風(fēng)險(xiǎn)。關(guān)于N-乙酰半胱氨酸在CIN防治中的作用,多項(xiàng)臨床研究結(jié)果差異較大,近來Huang等[32]對6項(xiàng)臨床研究(n=199)進(jìn)行的薈萃分析表明N-乙酰半胱氨酸可使肌酐水平下降,而對胱抑素C無影響,肌酐檢測并不能真實(shí)反映腎功能,可能無法對CIN做出準(zhǔn)確診斷。因此2022年加拿大CIN防治指南[23]不推薦使用N-乙酰半胱氨酸防治CIN。
5"對比劑應(yīng)用
高滲對比劑發(fā)生CIN的風(fēng)險(xiǎn)高于等滲對比劑和次高滲對比劑,離子型對比劑發(fā)生CIN的風(fēng)險(xiǎn)高于非離子型對比劑。有臨床隨機(jī)對照研究[33]顯示STEMI急診PCI 術(shù)中使用次高滲對比劑出現(xiàn)CI-AKI的風(fēng)險(xiǎn)與等滲對比劑并無差異。薈萃分析[34]結(jié)果表明不同的次高滲對比劑之間發(fā)生CIN的風(fēng)險(xiǎn)并無顯著差異。近期美國一項(xiàng)納入536 013例患者的回顧性臨床研究[35]表明,應(yīng)用等滲對比劑發(fā)生不良腎臟和心血管事件的風(fēng)險(xiǎn)較次高滲對比劑低,尤其是在慢性腎臟病、糖尿病和慢性冠狀動脈閉塞患者中有明顯差異。然而另一項(xiàng)包括50 389例患者的薈萃分析[36]顯示等滲對比劑和次高滲對比劑在ACS亞組中CI-AKI發(fā)生率無統(tǒng)計(jì)學(xué)差異。目前指南[22,28]建議使用非離子型次高滲或等滲對比劑降低CIN風(fēng)險(xiǎn),并不推薦優(yōu)先使用等滲對比劑以降低CIN發(fā)生風(fēng)險(xiǎn)。關(guān)于等滲對比劑和次高滲對比劑發(fā)生CI-AKI風(fēng)險(xiǎn)是否不同,以及不同的次高滲對比劑或等滲對比劑之間發(fā)生CIN的風(fēng)險(xiǎn)是否存在差異并不明確。
使用更高劑量的對比劑與CIN發(fā)生率及死亡率增加相關(guān),臨床上應(yīng)盡可能選擇滿足診療需求的最低劑量。有研究[37]支持以5×體重(kg)/基線肌酐(mg/dL)作為術(shù)中對比劑應(yīng)用的最大可接受劑量。對比劑劑量與基線eGFR比值(CV/eGFR)是CIN發(fā)生的重要預(yù)測因素,一項(xiàng)對470例行急診PCI術(shù)的STEMI患者的臨床研究[38]顯示應(yīng)用CV/eGFR預(yù)測CI-AKI優(yōu)勢明顯,其比值<2.5時(shí)可顯著降低CI-AKI發(fā)生風(fēng)險(xiǎn)。Kurogi等[39]對952例AMI患者的觀察性研究顯示CV/eGFR>3.45是急診PCI術(shù)后發(fā)生持續(xù)腎功能不全的重要預(yù)測指標(biāo),PCI術(shù)中對比劑的使用需充分考慮患者腎功能,2018年歐洲心肌血運(yùn)重建指南[22]建議使術(shù)中CV/eGFR<3.7。
6"腎臟替代治療
對于慢性腎臟病患者行血液透析可以加速對比劑的排泄,但由于導(dǎo)管的放置和感染相關(guān)風(fēng)險(xiǎn),CIN患者存在腎功能進(jìn)一步惡化的風(fēng)險(xiǎn)。ACS患者合并嚴(yán)重腎功能不全和心力衰竭時(shí),PCI術(shù)后積極血液透析可能對患者生存率有所改善[40],一項(xiàng)納入1 010例患者的薈萃分析[41]顯示對于合并慢性腎臟病的擇期PCI的患者,腎臟替代治療并不降低CIN的發(fā)生風(fēng)險(xiǎn)。2020年一項(xiàng)回顧性研究[42]顯示大流量間歇性血液透析可能減少嚴(yán)重慢性腎臟病患者PCI后CIN的發(fā)生。腎臟替代治療對ACS患者CIN防治研究相對較少,由于有創(chuàng)性及出血風(fēng)險(xiǎn)高,需要進(jìn)一步研究評估特定的最大受益人群,2021 ACC/AHA/SCAI血運(yùn)重建指南不推薦腎臟替代治療作為降低CI-AKI風(fēng)險(xiǎn)的預(yù)防措施[23]。
7"其他防治措施
粥樣硬化性栓塞可能與AKI發(fā)生相關(guān),經(jīng)股動脈介入路徑臨近腎動脈,可能會增加AKI發(fā)生風(fēng)險(xiǎn),近期一項(xiàng)納入46 816例患者的meta分析[43]表明選擇經(jīng)橈動脈路徑可降低PCI術(shù)后AKI風(fēng)險(xiǎn)(OR=0.66,95%CI 0.54~0.81,P<0.000 1,I2=74%)。小樣本單中心隨機(jī)對照研究顯示缺血后適應(yīng)[44]、遠(yuǎn)端缺血預(yù)適應(yīng)[45]可降低ACS患者PCI術(shù)后CIN的發(fā)生率,目前其在CIN預(yù)防中的作用尚不確定,需要大規(guī)模的臨床研究進(jìn)一步探索。
8"總結(jié)
CIN是ACS患者PCI術(shù)后的常見并發(fā)癥,增加術(shù)后主要不良心血管事件發(fā)生率,目前尚無有效治療措施,做好術(shù)前風(fēng)險(xiǎn)評估、使用腎毒性小的等滲或次高滲對比劑、盡可能減少對比劑使用劑量、PCI圍手術(shù)期充分水化是有效防治策略,對于ACS患者不應(yīng)因CIN發(fā)生風(fēng)險(xiǎn)高而延遲行血運(yùn)重建治療。
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