J CARDIOVASC PHARMACOL THER-2015-Bei-1074248415590197

Original ArticleRemote Ischemic Conditioning forPreventing Contrast-Induced AcuteKidney Injury in Patients UndergoingPercutaneous Coronary Interventions/Coronary Angiography:A Meta-Analysisof Randomized Controlled TrialsWei-jie Bei,MD1,Chong-yang Duan,MD2,Ji-yan Chen,MD,FACC,FESC1,Kun Wang,MD1,Yuan-hui Liu,MD1,*,Yong Liu,MD1,*,and Ning Tan,MD1,*AbstractBackground:It is uncertain whether remote ischemic conditioning(RIC)has a protective effect on contrast-induced acute kidney injury(CI-AKI)after percutaneous coronary intervention(PCI)/coronary artery angiography(CAG).We performed a meta-analysis of randomized controlled trials(RCTs)to assess the effect of RIC on CI-AKI in such patients.Methods:PubMed, MEDLINE,EMBASE,,and the Cochrane Central Register of Controlled Trials databases were searched for RCTs that assessed the effect of RIC on CI-AKI in patients undergoing PCI/CAG.Results:Ten RCTs with1389patients (RIC group,757and control,632)were included.The RIC group significantly exerted a lower risk of CI-AKI compared to the controls(odds ratio[OR]¼0.52,95%confidence interval[CI]¼0.34-0.77,P¼.001),and they had the similar effect on major adverse cardiovascular events within1year(OR¼0.36,95%CI¼0.20-0.66,P<.001).The RIC reduced the rates of death within 30days,but this was not significant(OR¼0.16,95%CI¼0.02-1.34,P¼.091).The RIC was associated with a significantly lower incidence of CI-AKI in patients following elective PCI/CAG(OR¼0.54,95%CI¼0.33-0.87,P¼.011).The RIC before not after the intervention was effective in reducing the occurrence of CI-AKI(OR:0.37vs1.05,P¼.022).The RIC of the upper arm has statistically significant effect on protecting CI-AKI but not that of the lower limb(OR:0.41vs1.41,P¼.004).The effect of RIC on CI-AKI was similar between patients with a mean estimated glomerular filtration rate<60mL/min/1.73m2and those with mean rates 60(OR:0.23vs0.41,P¼.333).Conclusion:The RIC reduced the incidence of CI-AKI in those receiving PCI/CAG.And RIC of the upper arm significantly reduced the risk of CI-AKI but not RIC of the lower limb in patients undergoing PCI/CAG. Keywordsremote ischemic conditioning,contrast-induced acute kidney injury,meta-analysis,percutaneous coronary interventions, coronary angiographyIntroductionContrast-induced acute kidney injury(CI-AKI)is a common complication of percutaneous coronary intervention(PCI)/cor-onary artery angiography(CAG),and it is associated with poor short-and long-term cardiovascular and renal outcomes.1,2The incidence of CI-AKI varies from2%in the general population to 50%in high-risk groups.3However,apart from periproce-dural hydration and limiting the amount of contrast medium (CM),few strategies have been approved as effective for pre-venting CI-AKI.Therefore,an increasing number of studies have been performed to determine timely and successful strate-gies for preventing and treating CI-AKI.*The authors are considered equally as corresponding authors1Department of Cardiology,Guangdong Cardiovascular Institute,Guangdong General Hospital,Guangdong Academy of Medical Sciences,Guangzhou, Guangdong,China2Department of Biostatistics,School of Public Health and Tropical Medicine, Southern Medical University,Guangzhou Guangdong,ChinaManuscript submitted:February26,2015;accepted:April26,2015.Corresponding Author:Ning Tan,Department of Cardiology,Guangdong Cardiovascular Institute, Guangdong General Hospital,Guangdong Academy of Medical Sciences, Guangzhou510100,China.Emails:tanning100@;lyh0718@Journal of CardiovascularPharmacology and Therapeutics1-11ªThe Author(s)2015Reprints and permission:/journalsPermissions.navDOI:10.1177/1074248415590197at UNIV OF VIRGINIA on June 28, 2015 Downloaded fromRemote ischemic conditioning(RIC),including remote ischemic preconditioning(RIPC)and remote ischemic post-conditioning(RIPost),is a method that applies brief nonlethal episodes of ischemia and reperfusion to an organ or tissue that is remote from the target organ or tissue.4It has been proven to provide protection,particularly against experimental ischemic–reperfusion injuries of the heart,kidney,brain,and skeletal muscle,5-7and it has a cardiac protective effect in patients undergoing cardiac and vascular surgery.8,9Unfortunately, although a number of well-designed and large-scale rando-mized controlled trials(RCTs)have been performed to assess the protective effect of RIC against CI-AKI,the findings remain controversial and contradictory.10-19Yang et al20 demonstrated that RIPC may be beneficial for preventing AKI after cardiac and vascular interventions.In contrast,Li et al21 reported that they could not draw conclusions on the protective effect of RIPC against AKI.These meta-analyses focused on the inconsistent inclusion of patients who were treated with dif-ferent interventions,such as cardiac surgery,vascular surgery, PCI,and so on.Although the precise pathophysiology of CI-AKI and postoperative AKI are not yet completely clear,it has been reported that2scenarios of AKI are somewhat differ-ent.22However,presently,few meta-analyses have evaluated the renoprotective effect of RIC in patients after CM exposure. Therefore,we aimed to perform a meta-analysis of RCTs on RIC against CI-AKI in patients undergoing PCI/CAG. MethodsLiterature Search StrategyAll studies relevant to RIC in patients undergoing PCI/CAG were identified by searching PubMed(1998through December, 2014),MEDLINE,EMBASE(1998through December,2014), ,and the Cochrane Central Register of Controlled Trials databases.According to optimal search stra-tegies,we used terms such as remote ischemic conditioning or remote conditioning or remote ischaemic conditioning or remote preconditioning or remote ischemic preconditioning or remote ischaemic preconditioning or remote postcondition-ing or remote ischemic postconditioning or remote ischaemic postconditioning or RIC.Abstracts presented at the American Heart Association,American College of Cardiology,and European Society of Congress from2009to2014(if available online)were also searched for additional unpublished data. The language was restricted to English.Study SelectionTwo reviewers(YH-L and WJ-B)independently scanned the selected studies based on their titles and abstracts.The full text of an article was reviewed carefully for inclusion if the topic was unclear after screening its title and abstract.20Any dis-agreements between the investigators were resolved through rereview and discussion with a third reviewer(K-W).Eligible trials were included if they met the following criteria:(1)RCTs of patients undergoing PCI/CAG;(2)RCTs with a control group as a comparison(without RIC),and the treatment method was RIC noninvasively before or after the interventions regardless of whether it involved the upper arms or lower limbs;and(3)RCTs that reported on the incidence of CI-AKI after interventional procedures in both the groups. Trials that did not report on the target populations or outcomes, nonrandomized studies,and duplicate articles were excluded. Moreover,if there were duplicate articles,we chose the article that included complete data.The primary outcome was CI-AKI,which was defined as an absolute increase in the serum creatinine(SCr) 0.5mg/dL or an increase of 25%from baseline to within2to5days after CM exposure.23The secondary outcomes were death within 30days and major adverse cardiac events(MACEs)within1year. Data Extraction and Assessment of the Risk of Bias Two reviewers(YH-L and WJ-B)independently extracted data from the identified studies.The authors of the articles were contacted if any additional data were needed.The extracted data included the patients’demographic characteristics(ie,the number of patients,mean age,and proportion of females and diabetes mellitus),inclusion criteria,contrast dose,protocol for RIC,baseline SCr levels,SCr and estimate glomerular filtra-tion rate(eGFR)after the interventions,definition and inci-dence of CI-AKI,incidence of death within30days,and MACEs within1year.The identified studies were independently evaluated for methodological quality by using the Jadad scoring system,24 and a quality assessment was judged on the concealment of treatment allocation,similarity of study groups at baseline, eligibility criteria,any blinding procedures used,reporting on those lost to follow-up,and intention-to-treat analysis.25Dis-agreements were resolved by the third reviewer or by reaching a consensus.Statistical AnalysisData analysis was performed using R statistical software, version.3.1.2(R Foundation for Statistical Computing, Vienna),26and the meta27package was used to perform the meta-analysis.The mean difference and95%confidence intervals(CIs)were calculated for continuous outcome data, and the odds ratios(ORs)and95%CIs were calculated and analyzed for dichotomous outcome data.The fixed effect model and the random effects model were used to pool stud-ies.The Q test and I2were used to evaluate statistical hetero-geneity.I2values of25%,50%,and75%were considered as evidence for low,moderate,and severe statistical heterogene-ity,respectively.28If the I2value was>50%or the P value was <.1,we considered it heterogeneous and a random effects model was used for data synthesis.Otherwise,a fixed effect model was used.Additionally,a subgroup analysis was per-formed based on the types of conditioning(preconditioning or postconditioning),types of PCI(primary or elective),and2Journal of Cardiovascular Pharmacology and Therapeuticsat UNIV OF VIRGINIA on June 28, 2015Downloaded fromdefinitions of CI-AKI.All the tests were 2tailed,and a P value <.05was considered statistically significant in the meta-analysis.ResultsCharacteristics of the Included Studies and InterventionsWe initially generated 739relevant articles (Figure 1).After excluding 358duplicates and 339clearly irrelevant articles,42articles remained.The clearly irrelevant articles included nonrandomized studies,and no target outcomes or interven-tion procedures were described after carefully reading the titles and abstracts.Full-text assessment of the 42potentially relevant articles finally identified 9eligible trials.Conse-quently,9RCTs involving 1389participants who had under-gone PCI/CAG met the inclusion criteria and were included in the meta-analysis.All the included studies reported on the incidence of CI-AKI in 1389patients who underwent intervention proce-dures.The RIC method was performed in 757patients (treat-ment group)and 632patients (control group).The RIC group used an inflatable tourniquet around the upper or lower limbs to result in intermittent ischemia or reperfusion through sev-eral cycles of inflations or deflations,while the control group used the same tourniquets but did not inflate to induce ische-mia and reperfusion.Of all the studies,7performed RIC before the interventions (RIPC),while the other 2performed after the interventions (RIPost).Elective PCI/CAG was per-formed in 7studies,and primary PCI was performed in theother 2studies.Moreover,2studies included all patients with diabetes mellitus 14,18and 1study included with moderate chronic kidney disease.13Several studies did not mention the details of the hydration protocols before or after CM expo-sure.10,14,16,17The mean baseline SCr level ranged from 0.82to 1.63mg/dL,and the mean CM dose ranged from 91.8to 309mL (Table 1).The criteria used to define CI-AKI varied among the indi-vidual studies.Two trials defined CI-AKI as a relative increase of >25%from baseline,10,172trials used the definition of an absolute increase in the SCr of >0.5mg/dL (44.2mmol/L)or a relative increase of >25%from baseline to within 16hours after CM exposure,12,141trial employed the same within 24hours,11,14and 3trials within 48hours.11,13,15Additionally,1trial defined CI-AKI as a 30%increase or an increase of 0.3mg/dL in the SCr level.18Assessment of the Study Quality and Publication BiasThe quality of the included studies was assessed by 2reviewers (YH-L and WJ-B)independently using the Jadad score criteria (Table 2).Only 5studies provided the con-cealment of allocation,while the other 4studies did not describe this in detail.Adequate blinding was performed in 7studies.However,the other 2studies did not mention it well.Almost all of the studies included patients with sim-ilar baseline characteristics,and they provided details about the eligibility criteria and completeness of follow-up and the intention-to-treat analysis.The details of the funnel plot are shown in Figure2.Figure 1.Flow diagram of the study selection.Bei et al 3at UNIV OF VIRGINIA on June 28, 2015 Downloaded fromT a b l e 1.P a t i e n t s ’B a s e l i n e C h a r a c t e r i s t i c a n d t h e I n t e r v e n t i o n s o f I n c l u d e d S t u d i e s .A u t h o r (Y e a r )N o .o f P a t i e n t s ,R I C /C o n t r o l I n c l u s i o n C r i t e r i aR I C P r o t o c o lA g e (y e a r s ),R I P C /C o n t r o l F e m a l e (%),R I P C /C o n t r o l S c r ,m g /d L ,R I C /C o n t r o l D M (%),R I P C /c o n t r o l C o n t r a s t D o s e ,m L ,R I P C /C o n t r o l D e f i n i t i o n o f C I -A K IH o o l e e t a l (2009)10104/98E l e c t i v e P C IP r e :3c y c l e s o f a l t e r n a t i n g 5m i n i n f l a t i o n a n d 5i n d e f l a t i o n o f a s t a n d a r d u p p e r a r m b l o o d p r e s s u r e c u f f t o 200m m H g 63.2/61.820(19)/24(24)N A 24(23)/20(20)196.7/187.5S c r >25%i n c r e a s e f r o m b a s e l i n e a t 24h E r e t a l (2012)1150/50E l e c t i v e c o r o n a r y a n g i o g r a p h y P r e :4c y c l e s o f a l t e r n a t i n g 5m i n i n f l a t i o n a n d 5m i n d e f l a t i o n o f a s t a n d a r d u p p e r a r m b l o o d p r e s s u r e c u f f73.2/72.734(68)/37(74)1.63/1.6232(64)/32(64)124/103S c r 25%o r 0.5m g /d L i n c r e a s e f r o m b a s e l i n e a t 48h a f t e r C M e x p o s u r e L u o e t a l (2013)12101/104E l e c t i v e c o r o n a r y a n g i o g r a p h y o r P C I P r e :3c y c l e s o f a l t e r n a t i n g 5m i n i n f l a t i o n a n d 5m i n d e f l a t i o n o f a s t a n d a r d u p p e r a r m b l o o d p r e s s u r e c u f f t o 200m m H g 59.2/59.323(23)/26(25)N A 26(26)/31(30)154/145S c r >25%o r m o r e t h a n 44.2m m o l /L i n c r e a s e f r o m b a s e l i n e w i t h i n 16hI g a r a s h i e t a l (2013)1330/30E l e c t i v e c o r o n a r y a n g i o g r a p h y P r e :4c y c l e s o f a l t e r n a t i n g 5m i n i n f l a t i o n a n d 5m i n d e f l a t i o n o f a s t a n d a r d u p p e r a r m b l o o d p r e s s u r e c u f f t o 200m m H g71.3/70.810(33.3)/7(23.3)1.15/1.1211(36.7)/9(30.0)92.9/91.8A n i n c r e a s e i n s e r u m c r e a t i n i n e >25%f r o m b a s e l i n e o r a n a b s o l u t e i n c r e a s e 0.5m g /d L w i t h i n 48h L a v i e t a l(2014)16228/109E l e c t i v e c o r o n a r y a n g i o g r a p h y o r P C I P o s t :3c y c l e s o f a l t e r n a t i n g 5m i n i n f l a t i o n a n d 5m i n d e f l a t i o n o f a s t a n d a r d u p p e r a r m o r l o w e r l i m b b l o o d p r e s s u r e c u f f t o 200m m H g 64.2/63.767(29.4)/30(27.5)N A75(32.9)/37(33.9)190/185S c r 25%o r >44m m o l /L i n c r e a s e f r o m b a s e l i n e w i t h i n 24hC r i m i e t a l (2014)1747/48P r i m a r y P C I P o s t :3c y c l e s o f a l t e r n a t i n g 5m i n i n f l a t i o n a n d 5m i n d e f l a t i o n t h r o u g h t h e l o w e r l i m b 61.0/56.05(10.6)/6(12.5)N A4(8.5)/7(14.6)211/229S c r 25%i n c r e a s e f r o m b a s e l i n e X u e t a l (2014)14102/98E l e c t i v e c o r o n a r y a n g i o g r a p h y P r e :3c y c l e s o f a l t e r n a t i n g 5m i n i n f l a t i o n a n d 5m i n d e f l a t i o n o f a s t a n d a r d u p p e r a r m b l o o d p r e s s u r e c u f f t o 200m m H g 69.1/68.934(33.3)/30(30.6)0.88/0.84102(100)/98(100)171.8/163.3>25%o r >44.2m m o l /L i n c r e a s e i n s e r u m c r e a t i n i n e a t 16h a f t e r P C I Y a m a n a k a e t a l (2015)1547/47P r i m a r y P C I P r e :3c y c l e s o f a l t e r n a t i n g 5m i n i n f l a t i o n a n d 5m i n d e f l a t i o n o f a s t a n d a r d u p p e r a r m b l o o d p r e s s u r e c u f f t o 200m m H g 67.0/67.013(24)/11(24)0.82/0.8714(31)/17(37)177/199A n i n c r e a s e i n s e r u m c r e a t i n i n e >0.5m g /d L o r >25%o v e r t h e b a s e l i n e v a l u e a f t e r 48-72h S a v a j e t a l (2014)1848/48E l e c t i v e c o r o n a r y a n g i o g r a p h y P r e :3c y c l e s o f a l t e r n a t i n g 5m i n i n f l a t i o n a n d 5m i n d e f l a t i o n o f a s t a n d a r d u p p e r a r m b l o o d p r e s s u r e c u f f t o 200m m H g63.0/60.931(64.6)/34(70.8)1.3/1.148(100)/48(100)126.6/123.8a >30%r i s e o r >0.3m g /d L i n c r e a s e i n s e r u m c r e a t i n i n e l e v e lA b b r e v i a t i o n s :R P I C ,r e m o t e i s c h e m i c p r e c o n d i t i o n i n g ;p r e ,r e m o t e i s c h e m i c p r e c o n d i t i o n i n g ;p o s t ,r e m o t e i s c h e m i c p o s t c o n d i t i o n i n g ;S C r ,s e r u m c r e a t i n i n e ;e G F R ,e s t i m a t e g l o m e r u l a r f i l t r a t i o n r a t e ;P C I ,p e r c u t a n e o u sc o r o n a r y i n t e r v e n t i o n ;D M ,d i a be t e s m e l l i t u s ;C I -A K I ,c o n t r a s t i n d u c e d a c u t e k i d n e y i n j u r y .4at UNIV OF VIRGINIA on June 28, 2015 Downloaded fromStudy OutcomesIncidence of CI-AKI.Almost all of the studies provided informa-tion on the incidence of CI-AKI.Although Igarashi et al 13did not provide an accurate incidence of CI-AKI based on the SCr levels between the 2groups,we contacted the author to request the results.In the overall population,RIC significantly reduced the risk of CI-AKI compared to the control group based on the fixed effect model (OR ¼0.52,95%CI ¼0.34-0.77,P ¼.001).The statistical heterogeneity among the included trials was rel-atively moderate (I 2¼38.9%,P ¼.109;Figure 3A).Death within 30days and major adverse cardiovascular events within 1year.There were only 2trials 11,15that reported on the incidence of death within 30days and 5patients died within 30days.There was no significant difference between the 2groups (OR ¼0.16,95%CI ¼0.02-1.34,P ¼.091;Figure 3B).The incidence of MACEs was available in 4trials,10,11,15,19and there were 18(7.26%)patients in the RIC group and 42(17.28%)in the control group who developed MACEs within 1year.The RIC significantly decreased the incidence of MACEs according to the fixed effect model (OR ¼0.36,95%CI ¼0.20-0.66,P <.001;Figure 3C).Subgroup AnalysisWe identified 7trials that represented elective PCI/CAG,while the other 2studies represented primary PCI.15,17According to a fixed effect model,the subgroup analysis demonstrated that RIC may statistically reduce the risk of CI-AKI in patients undergoing elective PCI/CAG (OR ¼0.54,95%CI ¼0.33-0.87,P ¼.011).Because of the small sample size (47/48and 47/47patients),there was not enough power to draw conclu-sions about the effect of RIC on primary PCI.In addition,since different types of remote conditioning may independently influence kidney function,we classified the trials according to whether they performed the measurements before or after the interventions.Among 9studies,7used RIPC,while 2used RIPost.16,17The RIPC effectively reduced incidence of CI-AKI,while RIPost was ineffective (OR ¼0.37vs 1.05,respectively,P ¼.022;Figure 4).Moreover,patients who received RIPC had a 63%lower risk of CI-AKI compared to patients in the control group (OR ¼0.37,95%CI ¼0.22-0.61;P <.001).Furthermore,2studies involved the lower limbs,and we divided Lavi et als trial,16which included 3arms (upper,lower,and control),into 2studies (Lavi I and Lavi II)according to the different conditioning protocols.The RIC of the upper arm sig-nificantly prevented CI-AKI (OR ¼0.41,95%CI ¼0.26-0.64,P <.001;Figure 5);however,RIC of the lower-limb in patients treated with PCI/CAG did not have the same effect (OR ¼1.41,95%CI ¼0.70-2.86,P ¼.338).Six trials reported the mean baseline eGFR,and we per-formed another subgroup analysis according to whether the mean eGFR was 60mL/min/1.73m 2.The result indicated that the effect of RIC on CI-AKI was similar between patients with a mean eGFR <60and those with eGFR 60mL/min/1.73m 2(OR:0.23vs 0.41,P ¼.333).Ultimately,we evaluated the effect of RIC on CI-AKI using different definitions.Six studies defined CI-AKI asTable 2.Quality of the Included Randomized Controlled Trials.a Author Year Jadad Score Randomization Allocation Concealment Similarity of Baseline Characteristics EligibilityCriteria Blinding Completeness of Follow-Up ITT AnalysisHoole et al 1020094Yes Yes Yes Yes Single blind Yes No Er et al 1120124Yes*Yes Yes Yes Double blind Yes Yes Luo et al 1220133Yes*No Yes Yes Single blind Yes Yes Igarashi et al 1320133Yes Yes Yes Yes NoYes Yes Lavi et al 1620144Yes Yes Yes Yes Single blind Yes Yes Crimi et al 1720144Yes Yes Yes Yes Single blind Yes Yes Xu et al 1420143Yes*No Yes Yes Single blind No Yes Yamanaka et al 1520154Yes No Yes Yes Single blind Yes Yes Savaj et al 1820141YesNoYesYesNoNoYesAbbreviation:ITT,intention-to-treat.aYes*:1score.Figure 2.Funnel plot for the subjective assessment of bias among the included studies.Bei et al5at UNIV OF VIRGINIA on June 28, 2015 Downloaded froman absolute increase in the SCr level of >0.5mg/dL or a rela-tive increase of >25%from baseline to within 48to 72hours.Two other studies defined CI-AKI as a relative increase of >25%from baseline to within 48to 72hours.The risk of CI-AKI incidence was not significantly different under the different definitions of CI-AKI (OR:0.53vs 0.78,respec-tively,P ¼.523).Sensitivity AnalysisA leave-one-out sensitivity analysis was performed and revealed that our results were sufficiently robust.The OR and95%CI regarding the effect of RIC on CI-AKI prevention were still similar to the results obtained before excluding the low-quality studies (Jadad score <3)and removing the studies with-out an intention-to-treat analysis based on the fixed effect model (Figure 6).DiscussionThe present meta-analysis demonstrated that patients treated with RIC may have a significantly lower risk of CI-AKI than control participants in the entire cohort treated with PCI/CAG and in patients undergoing elective PCI.In addition,RICFigure 3.Forest plot of odds ratio (OR)and 95%confidence interval (CI)for contrast-induced acute kidney injury (A),death within 30days (B),and major adverse cardiovascular events within 1year (C)among patients assigned to the remote ischemic conditioning compared to the con-trol group.6Journal of Cardiovascular Pharmacology and Therapeuticsat UNIV OF VIRGINIA on June 28, 2015 Downloaded fromsignificantly reduced the risk of MACEs within 1year but not that of death within 30days in patients undergoing PCI/CAG.Furthermore,the subgroup analysis indicated that RIPC effec-tively reduced the risk of CI-AKI.Additionally,RIC of the upper arm had significantly reduced the risk of CI-AKI,but RIC of the lower limb in patients undergoing PCI/CAG did not have the same effect.The protective effect of RIC on CI-AKI was similar between patients with mean eGFR <60and those with eGFR 60mL/min/1.73m 2.Moreover,the risk of CI-AKI occurrence was not significantly different according to the different definitions of CI-AKI.The mechanisms of CI-AKI are still unclear.Mechanisms underlying CI-AKI included renal hemodynamics,damage to the tubular epithelial cells and vascular endothelium,medul-lary vasoconstriction,regional hypoxia,and the production of oxygen radicals,which scavenge nitric oxide (NO)and blunt NO activity.29The RIC was considered to play an important role in improving postischemic blood flow.30In addition,Gassanov et al showed that RIC may protect and prompt endothelial oxide synthase to enhance the production of NO,31which may be one of the medullary vasodilatory factors that reduce the incidence of regional hypoxia.Moreover,RIC may result in fewer productions of reactive oxygen species (ROS),which is an important factor in the late phase of reper-fusion,as it reduces damage to the tubular epithelial cells and vascular endothelium.7However,low blood flow,less NO,and increased ROS have been proven to be important contributors of CI-AKI development.Therefore,researchers have hypothesized that RIC may reduce the risk of CI-AKI through the aforementioned mechanisms.The RIC is an emerging treatment that provides intermittent stimulus on an organ (mostly a limb)to increase ischemic tol-erance of a distant organ to the subsequent ischemic insult.32Previous studies have used different types of ischemic condi-tioning,which is performed by intermittently reinflating the stent balloon immediately after reperfusion during cardiac intervention.33After considering a more simple translation of RIC for clinical setting,we finally chose RCTs that used an applicable,harmess,cost-effective,and noninvasive procedure that simply involved inflating and deflating a blood pressure cuff placed on the upper arm or lower limb.Although an increasing number of clinical trials have eval-uated the effect of RIC on AKI in patients undergoing cardiac and vascular interventions or surgery,the findings are still conflicting and controversial.The precise pathophysiology of CI-AKI and postoperative AKI are not completely similar,and no meta-analysis has specially evaluated the more tar-geted renoprotection of RIC in patients undergoing PCI/CAG.Therefore,the present meta-analysis may be the first to systematically evaluate the effect of RIC in patients under-going PCI/CAG.The findings showed that RIC,especially RIPC,significantly reduced the risk of CI-AKI in patients compared to that in the control group after CM exposure.Although Alreja et al 34and Yang et al 20performedmeta-Figure 4.Subgroup analysis of the forest plot of odds ratio (OR)and 95%confidence interval (CI)for contrast-induced acute kidney injury among patients assigned to the remote ischemic conditioning compared to the control according to the conditioning types (preconditioning vs postconditioning).Bei et al 7at UNIV OF VIRGINIA on June 28, 2015 Downloaded fromanalyses of RCTs to confirm the protective effect of RIPC on renal injury following cardiac and vascular interventions,other studies have revealed the contradictory.The meta-analyses by Li et al 21and Haji et al 35indicated that RIPC had no protective effect on CI-AKI.However,these meta-analyses included participants who had undergone different interventions,such as cardiac and vascular surgery,complex valvular heart surgery,complex congenital heart diseasesurgery,or PCI.This may have resulted in the significant confounding factors and have greatly influenced the findings of the effect of RIC on AKI;thus,these findings should be discussed further.Previous meta-analyses have shown similar findings regarding the effect of RIC on mortality rates 21,36but not on the incidences of MACEs.36In addition,some previous studies have also been performed to evaluate the effect of RIC on MACEs in patients undergoing cardiac surgery.However,studies by Hausenloy 37and Brevoord et al 36failed to demon-strate statistically significant protective effect of RIC on MACEs within 1year.This may be because high-risk patients having diabetes and hypertension,different causes of injury during surgery (coronary microembolization and inflamma-tion),and perioperative myocardial injury were included in those studies.However,our present meta-analysis demon-strated that compared to the control group,the group receiv-ing RIC showed a reduced risk of MACEs within 1year,which was different from the findings of previous studies.The previous meta-analyses included such a broad population that underwent different interventions,instead of a small RCT (1study),and high-risk patients were excluded,which weakened the reliability of the main findings.Conversely,our findings were sufficiently robust as these problems are notpresent.Figure 6.Leave-one-out sensitivityanalysis.Figure 5.Subgroup analysis of the forest plot of odds ratio (OR)and 95%confidence interval (CI)for contrast-induced acute kidney injury among patients assigned to the remote ischemic conditioning group compared to the control according to the different limbs (lower limbs vs upper arms).8Journal of Cardiovascular Pharmacology and Therapeuticsat UNIV OF VIRGINIA on June 28, 2015 Downloaded from。