【摘要】：背景:隨著冠脈造影(CAG)及經(jīng)皮冠狀動(dòng)脈介入治療(PCI)的發(fā)展,隨之而來的是對(duì)比劑應(yīng)用所導(dǎo)致的對(duì)比劑腎病(CIN)的發(fā)病率逐漸升高。CIN通常是指在應(yīng)用對(duì)比劑之后48小時(shí)內(nèi),肌酐值較基礎(chǔ)值升高25%或超過0.5 mg/d L(44μmol/L)。發(fā)生后無特殊的臨床表現(xiàn),多表現(xiàn)為非少尿腎衰,7-10天可恢復(fù),部分需要短暫透析維持。其發(fā)病率介于0-20%之間,危險(xiǎn)因素(腎功能不全、糖尿病、心衰、低血壓、對(duì)比劑用量大等)越多,發(fā)病率越高。CIN會(huì)使患者住院時(shí)間延長(zhǎng),增加透析及死亡風(fēng)險(xiǎn)。由于CIN無特殊治療方案,預(yù)防至關(guān)重要。目前關(guān)于CIN的預(yù)防措施研究頗多,但除了水化治療,其他方法的效果尚不確定。水化治療是目前公認(rèn)的預(yù)防CIN的措施,但水化對(duì)于心血管病人來說,尤其是心衰患者,也存在著增加心臟負(fù)荷的風(fēng)險(xiǎn)。因此,CIN已成為繼支架術(shù)后“血栓形成”及支架術(shù)后“再狹窄”之后的第三大難題。如何將CIN發(fā)病率降至最低以及積極尋求CIN的有效預(yù)防措施已成為心血管醫(yī)生的重要課題。而且,臨床上冠心病合并慢性腎臟疾病(CKD)的發(fā)生率也逐漸增多,文獻(xiàn)報(bào)道其發(fā)生率可達(dá)20~40%,這部分患者接受CAG甚至PCI的病例也逐年增加,怎樣預(yù)防對(duì)比劑進(jìn)一步損害腎臟功能,也成為臨床實(shí)踐中的棘手問題!腦利鈉肽(BNP)是心室分泌的一種多肽,具有舒張血管、降低心臟的前后負(fù)荷、抑制心室重構(gòu)、拮抗腎素-血管緊張素-醛固酮系統(tǒng)(RAAS)和交感神經(jīng)系統(tǒng)(SNS)、增加腎小球?yàn)V過率,降低近端小管和集合管對(duì)鈉的重吸收等多種心腎保護(hù)作用。因此BNP有可能對(duì)預(yù)防CIN有效,已有研究顯示BNP對(duì)腹部和心臟外科手術(shù)圍手術(shù)期的腎功能有改善作用,但BNP對(duì)于CAG或PCI圍手術(shù)期CIN的預(yù)防作用研究,尚未見報(bào)道。本研究旨在明確重組人腦利鈉肽(rh BNP)對(duì)CAG或PCI圍手術(shù)期CIN的發(fā)生是否有預(yù)防作用,為提出新的CIN的預(yù)防措施提供臨床依據(jù)。第一部分冠脈造影、冠脈介入治療導(dǎo)致對(duì)比劑腎病的發(fā)生率及危險(xiǎn)因素目的:本研究旨在調(diào)查,不穩(wěn)定型心絞痛患者在接受CAG或非急診PCI時(shí),在水化治療基礎(chǔ)上CIN的發(fā)生率及其危險(xiǎn)因素分析。方法:經(jīng)過醫(yī)院的倫理委員會(huì)批準(zhǔn)并且簽訂知情同意書后500名不穩(wěn)定型心絞痛患者入選本研究。采集入選研究患者的一般情況。所有患者于CAG或非急診PCI前進(jìn)行水化治療(術(shù)前12小時(shí)至術(shù)后12小時(shí)靜脈輸注0.9%氯化鈉1.0ml/kg/h),并于術(shù)前、術(shù)后24小時(shí)、48小時(shí)、72小時(shí)及1周測(cè)定患者胱抑素C(Cys C)、血清肌酐水平(Scr)及腎小球?yàn)V過率(e GFR),計(jì)算入選患者CIN的發(fā)生率。CIN定義為使用對(duì)比劑后48小時(shí)內(nèi)出現(xiàn)血肌酐上升超過其基礎(chǔ)值的25%或超過0.5mg/d L(44μmol/L)。并依據(jù)CIN發(fā)生與否,將患者分為CIN組及非CIN組,比較兩組一般情況。評(píng)估CIN組CAG或非急診PCI前后腎功能變化情況。對(duì)兩組患者進(jìn)行CIN危險(xiǎn)評(píng)分(Mehran評(píng)分系統(tǒng)),探討CIN發(fā)生的危險(xiǎn)因素。結(jié)果:(1)500例入選患者中72例發(fā)生了CIN,發(fā)生率14.4%,其中行PCI患者的CIN發(fā)生率高于CAG者(16.9%vs 9.7%,P0.05),差異有統(tǒng)計(jì)學(xué)意義。依據(jù)CIN發(fā)生與否將患者分為CIN組及非CIN組,比較兩組一般情況,可見年齡、入院Cys C、Scr、e GFR、高血壓史、糖尿病史、冠脈嚴(yán)重程度、手術(shù)操作方式、對(duì)比劑用量及Mehran評(píng)分差異有統(tǒng)計(jì)學(xué)意義,而其他一般情況無統(tǒng)計(jì)學(xué)意義。(2)CIN組Scr于造影后24小時(shí)開始升高,48小時(shí)達(dá)峰,72小時(shí)逐漸回落,一周基本恢復(fù)至基線水平。e GFR變化規(guī)律同Scr。而Cys C于造影后24小時(shí)達(dá)峰,48小時(shí)便開始回落,72小時(shí)恢復(fù)至基線水平。(3)經(jīng)過危險(xiǎn)因素分析,結(jié)果顯示:對(duì)比劑的用量(OR=3.57,95%CI 1.25~5.88,P0.05)、糖尿病病史(OR=1.92,95%CI 0.88~3.36,P0.05)、入院Cys C(OR=2.20,95%CI1.62~4.11,P0.05)、e GFR(OR=3.10,95%CI 1.99~5.48,P0.05)及Mehran評(píng)分(OR=4.46,95%CI 2.16~6.88,P0.01)是CIN的獨(dú)立預(yù)測(cè)因子,其中Mehran評(píng)分相關(guān)性最好。結(jié)論:CIN在行CAG或非急診PCI的不穩(wěn)定型心絞痛患者中很常見,即使預(yù)防性應(yīng)用水化治療發(fā)病率仍然很高。Cys C對(duì)CIN的評(píng)估較為敏感,將Cys C及Scr結(jié)合起來,有利于提高CIN的檢出率。糖尿病病史、基礎(chǔ)腎功能不全、對(duì)比劑用量及Mehran評(píng)分是CIN的獨(dú)立危險(xiǎn)因素,其中Mehran評(píng)分相關(guān)性最好。不穩(wěn)定型心絞痛患者在行CAG或非急診PCI前最好應(yīng)用Mehran評(píng)分進(jìn)行危險(xiǎn)分層,有利于識(shí)別CIN的高危人群。在條件允許情況下,盡量減少對(duì)比劑的用量,以減少CIN的發(fā)生。第二部分重組人腦利鈉肽預(yù)防對(duì)比劑腎病的機(jī)制目的:探討不穩(wěn)定型心絞痛患者在接受CAG或非急診PCI時(shí),rh BNP對(duì)CIN是否有預(yù)防作用。方法:經(jīng)過醫(yī)院的倫理委員會(huì)批準(zhǔn)并且簽訂知情同意書后1000名不穩(wěn)定型心絞痛患者自愿者入選本研究。采集入選研究患者的一般情況。將所有入選患者隨機(jī)分為兩組:水化組,n=500,于CAG或非急診PCI術(shù)前12小時(shí)至術(shù)后12小時(shí)給予0.9%氯化鈉以1.0ml/kg/h靜點(diǎn);rh BNP組,n=500,于CAG或非急診PCI術(shù)前24小時(shí)給予低劑量的rh BNP(0.005μg/kg/min)。所有患者于術(shù)前及術(shù)后24小時(shí)、48小時(shí)、72小時(shí)和第7天檢測(cè)Cys C,Scr和e GFR,評(píng)估兩組CIN的發(fā)生率及CAG或非急診PCI術(shù)前后腎功能的變化情況。并觀察術(shù)前、術(shù)后24小時(shí)血清腫瘤壞死因子α(TNF-α)和醛固酮(Adl)變化情況。結(jié)果:(1)兩組術(shù)前一般情況比較無統(tǒng)計(jì)學(xué)差異。(2)rh BNP組CIN的發(fā)生率顯著低于水化治療組(5.6%vs 14.4%,P0.01)。兩組行PCI的患者CIN發(fā)生率均高于行CAG的患者(P0.05)。(3)兩組受試者在CAG或非急診PCI前Cys C、Scr及e GFR差異無統(tǒng)計(jì)學(xué)意義(P0.05)。在術(shù)后24小時(shí)、48小時(shí)及72小時(shí),rh BNP組的e GFR較對(duì)照組更高,而Cys C和Scr較對(duì)照組更低,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。兩組Cys C、Scr及e GFR術(shù)后24小時(shí)、48小時(shí)與術(shù)前差異有統(tǒng)計(jì)學(xué)意義,72小時(shí)差異無統(tǒng)計(jì)學(xué)意義,三項(xiàng)指標(biāo)均于7天時(shí)恢復(fù)到基線水平。(4)對(duì)于發(fā)生CIN的患者,rh BNP組Scr術(shù)后24小時(shí)、48小時(shí)、72小時(shí)均低于水化組,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。兩組術(shù)后24小時(shí)和48小時(shí)Scr值均高于術(shù)前(P0.05)。術(shù)后72小時(shí),水化肌酐值仍明顯高于術(shù)前,但rh BNP組差異無統(tǒng)計(jì)學(xué)意義。(5)兩組術(shù)前TNF-α和Adl基線水平無統(tǒng)計(jì)學(xué)差異(P0.05),術(shù)后24小時(shí)TNF-α和Adl較術(shù)前均有明顯升高(P0.05)。與rh BNP組比較水化組升高更明顯(P0.05)。結(jié)論:CAG或非急診PCI術(shù)前使用低劑量的rh BNP對(duì)預(yù)防CIN有效,其效果優(yōu)于水化治療。即使發(fā)生CIN,rh BNP也能減輕腎功能損傷程度,并且縮短腎功能恢復(fù)正常的時(shí)間。rh BNP預(yù)防CIN的作用可能是通過抑制炎癥反應(yīng)和RAAS的機(jī)制實(shí)現(xiàn)的。第三部分重組人腦利鈉肽預(yù)防對(duì)比劑進(jìn)一步加重腎臟損害的機(jī)制目的:探討合并中度慢性腎功不全(CKD)的不穩(wěn)定型心絞痛患者在接受CAG或非急診PCI時(shí),rh BNP對(duì)CIN預(yù)防的作用。方法:將合并中度CKD的不穩(wěn)定型心絞痛患者(30ml/min/1.73m2≤e GFR60ml/min/1.73m2),隨機(jī)分為兩組:水化組,n=103,于CAG或非急診PCI術(shù)前12小時(shí)至術(shù)后12小時(shí)給予0.9%氯化鈉以1.0ml/kg/h靜點(diǎn);rh BNP組,n=106,于CAG或非急診PCI術(shù)前24小時(shí)給予低劑量的rh BNP(0.005μg/kg/min)。分別于CAG或非急診PCI術(shù)前、造影后24小時(shí)、48小時(shí)、1周、1月采集Cys C、SCr、e GFR等指標(biāo)。主要終點(diǎn)事件為CIN的發(fā)生率,次要終點(diǎn)觀察Cys C、SCr、e GFR手術(shù)前后的變化。并觀察術(shù)前、術(shù)后24小時(shí)血清腫瘤壞死因子α(TNF-α)和醛固酮(Adl)變化情況。結(jié)果:(1)兩組術(shù)前一般情況比較無統(tǒng)計(jì)學(xué)差異。(2)rh BNP組CIN的發(fā)生率顯著低于水化治療組(8.5%vs 23.3%,P0.01)。兩組行PCI的患者CIN發(fā)生率均高于行CAG的患者(P0.05)。(3)兩組患者在CAG或非急診PCI前Cys C、Scr及e GFR差異無統(tǒng)計(jì)學(xué)意義(P0.05)。rh BNP組的e GFR在術(shù)后48小時(shí)及1周較水化組更高,而Scr及Cys C較水化組更低,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。水化組Cys C、Scr在術(shù)后24小時(shí)開始升高,1周達(dá)峰,1月時(shí)恢復(fù)至基線水平。e GFR變化規(guī)律同Scr。rh BNP組腎功能恢復(fù)較快,Cys C、Scr于術(shù)后24小時(shí)開始升高,48小時(shí)達(dá)峰,1周便已接近基線水平。(4)兩組術(shù)前TNF-α和Adl基線水平無統(tǒng)計(jì)學(xué)差異(P0.05),術(shù)后24小時(shí)TNF-α和Adl較術(shù)前均有明顯升高(P0.05)。與rh BNP組比較水化組升高更明顯(P0.05)。結(jié)論:合并中度CKD的不穩(wěn)定型心絞痛患者行CAG或非急診PCI后更易發(fā)生CIN,即使預(yù)防性應(yīng)用水化治療和等滲對(duì)比劑,發(fā)病率仍然很高。于CAG或非急診PCI術(shù)前使用低劑量的rh BNP預(yù)防CIN安全、有效,其效果優(yōu)于水化治療。而且rh BNP也能減輕腎功能損傷程度,并且縮短腎功能恢復(fù)時(shí)間。rh BNP預(yù)防CIN的作用可能是通過抑制炎癥反應(yīng)和RAAS的機(jī)制實(shí)現(xiàn)的。
[Abstract]:Background: with the development of coronary angiography (CAG) and percutaneous coronary intervention (PCI), the incidence of contrast agent nephropathy (CIN), resulting from contrast agent application, is gradually increased by 25% or more than 0.5 mg/d L (44 mol/L) within 48 hours after the use of contrast agents. The clinical manifestation is non oliguria renal failure, 7-10 days can be recovered, part of the need for temporary dialysis maintenance. Its incidence is between 0-20%, the risk factors (renal insufficiency, diabetes, heart failure, hypotension, the amount of contrast medium), the higher the incidence of.CIN will prolong the patient's time of hospitalization, increase the risk of dialysis and death. Because of CIN The prevention of special treatment is very important. There is a lot of study on the prevention of CIN, but the effect of other methods is still uncertain except for hydration therapy. Hydration therapy is currently recognized as a measure to prevent CIN. But hydration has a risk of increasing heart load for cardiovascular patients, especially heart failure. Therefore, CIN has already been used. It has become the third major problem following "thrombosis" after stenting and "restenosis" after stenting. How to minimize the incidence of CIN and to actively seek effective preventive measures for CIN have become an important subject for cardiovascular doctors. Moreover, the incidence of chronic renal disease (CKD) in clinical coronary heart disease is increasing, and the literature is also increasing. It is reported that its incidence is up to 20~40%, and the cases of this part of patients receiving CAG and even PCI are increasing year by year. How to prevent the contrast agent to further damage the renal function is also a difficult problem in clinical practice. Brain natriuretic peptide (BNP) is a polypeptide of ventricular secreting, which has Shu Zhangxue tube, reduces the load of the heart, inhibits ventricular remodeling and antagonism. The renin angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS) increase the glomerular filtration rate and reduce a variety of cardionenal protective effects on the reabsorption of sodium in the proximal tubules and collecting tubes. Therefore, BNP may be effective in preventing CIN. Studies have shown that BNP has improved the renal function in the perioperative period of abdominal and cardiac surgery. But the study of the preventive effect of BNP on CIN in the perioperative period of CAG or PCI has not been reported. This study aims to clarify whether the recombinant human brain natriuretic peptide (RH BNP) has a preventive effect on the occurrence of CIN in the perioperative period of CAG or PCI, and provides a clinical basis for the prophylaxis of new CIN. First division coronary angiography, coronary intervention leads to contrast nephropathy. Incidence and risk factors: the purpose of this study was to investigate the incidence and risk factors of CIN on the basis of hydration therapy for patients with unstable angina pectoris at CAG or non emergency PCI. Methods: 500 patients with unstable angina pectoris after the hospital ethics committee approved and signed the informed consent book. The general condition of the patients was collected. All patients were treated with hydration before CAG or non emergency PCI (12 hours before operation to 12 hours of intravenous infusion of sodium chloride 1.0ml/kg/h), and before operation, 24 hours, 48 hours, 72 hours and 1 weeks after the operation, the serum creatinine level (Scr) and glomerular filtration rate (E GFR) were measured. The incidence of CIN was defined as 25% or more than 25% or more than 0.5mg/d L (44 mu mol/L) in the 48 hours after the use of contrast agents. According to CIN or not, the patients were divided into CIN group and non CIN group, and the two groups were compared. The changes of renal function before and after the CIN group CAG or non emergency PCI were evaluated. Two The CIN risk score (Mehran scoring system) was used to investigate the risk factors of CIN. Results: (1) 72 of the 500 patients were selected, and the incidence of CIN was 14.4%. The incidence of CIN in the patients with PCI was higher than that of CAG (16.9%vs 9.7%, P0.05), and the difference was statistically significant. The patients were divided into CIN group and non CIN group according to the occurrence of CIN. Two groups of general conditions, visible age, admission Cys C, Scr, e GFR, hypertension history, diabetes history, coronary severity, operation mode, contrast agent dosage and Mehran score difference is statistically significant, but the other general situation is not statistically significant. (2) CIN group Scr in 24 hours after the film began to rise, 48 hours to peak, 72 hours gradually fell down. The change of.E GFR at baseline was basically the same as that of Scr. while Cys C reached the peak 24 hours after the contrast. It began to fall at 48 hours and recovered to the baseline level for 72 hours. (3) through the analysis of risk factors, the results showed that the dosage of contrast agent (OR=3.57,95%CI 1.25~5.88, P0.05), the history of diabetes mellitus (OR=1.92,95%CI 0.88~3.36, P0.05), hospitalized Cys 20,95%CI1.62~4.11, P0.05), e GFR (OR=3.10,95%CI 1.99~5.48, P0.05) and Mehran score (OR=4.46,95%CI 2.16~6.88, P0.01) are independent predictors of CIN. High.Cys C is more sensitive to CIN evaluation. Combining Cys C and Scr is beneficial to improve the detection rate of CIN. The history of diabetes, basic renal insufficiency, the dosage of contrast agent and Mehran score are independent risk factors of CIN, and the Mehran score is best. Risk stratification is beneficial to identify high-risk groups of CIN. Reduce the amount of contrast agents to reduce the incidence of CIN under condition permitting conditions. Second the mechanism of recombinant human brain natriuretic peptide prevention of contrast nephropathy is to explore the prevention of CIN in patients with unstable angina pectoris in CAG or non emergency PCI, and whether RH BNP has the prevention of CIN. Methods: 1000 patients with unstable angina pectoris were selected after the hospital ethics committee approved and signed the informed consent book. The general situation of the patients was collected and studied. All the selected patients were randomly divided into two groups: the hydrated group, n=500, 12 hours before the CAG or the non emergency PCI operation to 0.9% after the 12 hours after the operation. Sodium chloride was given with 1.0ml/kg/h static point; RH BNP group, n=500, low dose RH BNP (0.005 g/kg/min) were given 24 hours before CAG or non emergency PCI. All patients were tested for Cys C before and 24 hours, 48 hours, 72 hours and seventh days after operation. The incidence of two groups and the changes of renal function before and after non emergency surgery were evaluated. The changes of serum tumor necrosis factor - alpha (TNF- - alpha) and aldosterone (Adl) were observed 24 hours before the operation. Results: (1) there was no statistical difference between the two groups before operation. (2) the incidence of CIN in group RH BNP was significantly lower than that in the hydrated group (5.6%vs 14.4%, P0.01). The incidence of CIN in the two group of PCI patients was higher than that in the patients with CAG (P0.05). (3) two groups. There was no significant difference in Cys C, Scr and E GFR before the CAG or non emergency PCI (P0.05). The e GFR in the RH BNP group was higher than the control group at 24 hours, 48 hours and 72 hours after the operation, and the difference was statistically significant. The difference was statistically significant at 24 hours after the operation and 48 hours after the operation. The difference between the 72 hours was not statistically significant, and the three indexes were all recovered to the baseline level at 7 days. (4) for patients with CIN, Rh BNP group Scr 24 hours, 48 hours, 72 hours were lower than the hydration group, the difference was statistically significant (P0.05). The Scr value of 24 hours and 48 hours after operation in two group was higher than before operation (P0.05). Water creatinine was hydrated after operation after operation (P0.05). There was no significant difference in the value of RH BNP group. (5) there was no statistical difference between the baseline levels of TNF- alpha and Adl before operation (P0.05), and TNF- alpha and Adl were significantly higher than before the operation (P0.05). Compared with the RH BNP group, the hydration group increased more significantly (P0.05). CIN effective, its effect is better than hydration treatment. Even if CIN, Rh BNP can reduce the degree of renal function damage, and shorten the time of renal function recovery..rh BNP to prevent CIN may be achieved by inhibiting the mechanism of inflammation and RAAS. The third part of recombinant human brain natriuretic peptide prevents the contrast agent to further aggravate the renal damage. Objective: To investigate the effect of RH BNP on the prevention of CIN in patients with unstable angina pectoris with moderate chronic renal insufficiency (CKD) when receiving CAG or non emergency PCI. Methods: the patients with moderate CKD of unstable angina pectoris (30ml/min/1.73m2 < e GFR60ml/min/1.73m2) were randomly divided into two groups: the hydration group, n=103, in CAG or non emergency treatment. 12 hours before operation to 12 hours after operation, 0.9% sodium chloride was given with 1.0ml/kg/h static point; RH BNP group, n=106, low dose RH BNP (0.005 u g/kg/min) were given 24 hours before CAG or non emergency PCI. Before CAG or non emergency PCI, 24 hours, 48 hours, and 1 weeks after the angiography. Rate, secondary end point was observed before and after Cys C, SCr, e GFR, and the changes of serum tumor necrosis factor alpha (TNF- a) and aldosterone (Adl) were observed 24 hours after operation. Results: (1) there was no statistical difference between the two groups before operation. (2) the incidence of CIN in RH BNP group was significantly lower than that in the hydration group (8.5%vs 23.3%, P0.01). Two groups were treated. The incidence of CIN in patients with CAG was higher than that of patients with CAG (P0.05). (3) there was no significant difference in Cys C, Scr and E GFR before PCI in CAG or non emergency PCI group (P0.05) Time began to rise, 1 Zhou Dafeng, January to the baseline level of.E GFR change law and Scr.rh BNP group renal function recovery faster, Cys C, Scr at 24 hours after the operation began to rise, 48 hours of peak, 1 weeks already close to the baseline level. (4) before the two group TNF- a and Adl baseline level of no difference (P0.05), 24 hours postoperatively, TNF- alpha and Adl compared before the operation were all before the operation. There was a significant increase (P0.05). Compared with the RH BNP group, the increase in the hydration group was more obvious (P0.05). Conclusion: the patients with moderate CKD with unstable angina pectoris are more likely to occur CIN after CAG or non emergency PCI, even if the preventive use of hydration and isotonic contrast agents, the incidence is still high. It is safe and effective, its effect is better than hydration therapy. Moreover, Rh BNP can also reduce the degree of renal function damage, and shorten the time of renal function recovery. The effect of.Rh BNP on the prevention of CIN may be achieved by inhibiting the mechanism of inflammatory reaction and RAAS.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R692

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