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Usefulness of Statin Pretreatment to Prevent Contrast-InducedNephropathy and to Improve Long-Term Outcome in Patients

Undergoing Percutaneous Coronary Intervention

Giuseppe Patti, MDa, Annunziata Nusca, MDa, Massimo Chello, MDa, Vincenzo Pasceri, MD, PhDb,Andrea D’Ambrosio, MDa, George W. Vetrovec, MDc, and Germano Di Sciascio, MDa,*

Contrast-induced nephropathy (CIN) is an important cause of mortality and morbidity inpatients undergoing angiography. This study investigated whether statins decrease inci-dence of CIN in the setting of percutaneous coronary intervention (PCI) and evaluated theinfluence of such potential benefit on long-term outcome. Four-hundred thirty-four patientsundergoing PCI were prospectively enrolled and followed up to 4 years. Patients werestratified according to preprocedural statin therapy (260 statin treated, 174 statin naive).CIN was defined as a postprocedural increase in serum creatinine of >0.5 mg/dl or >25%from baseline. Follow-up assessment included 4-year occurrence of major adverse cardiacevents. Statin-treated patients had a significantly lower incidence of CIN (3% vs 27%,p <0.0001; 90% risk decrease) and had better postprocedural creatinine clearance (80 � 20vs 65 � 16 ml/min, p <0.0001). Benefit of statin before treatment was observed in allsubgroups, except in patients with a pre-existing creatinine clearance <40 ml/min. Duringfollow-up, CIN was a predictor of poorer outcome; 4-year survival free of major adversecardiac events was highest in statin-treated patients without CIN (95%, p <0.015) andlowest in statin-naive patients with CIN (53%, p <0.018). In conclusion, patients receivingstatins before PCI have a significant decrease of CIN; this early protective effect translatesinto better long-term event-free survival. These results may lend further support to utili-zation of statins as adjuvant pharmacologic therapy before PCI. © 2008 Elsevier Inc. All

rights reserved. (Am J Cardiol 2008;101:279–285)

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retreatment with atorvastatin before percutaneous coro-ary intervention (PCI) has significantly decreased the oc-urrence of periprocedural myocardial infarction1,2 and de-reased postoperative atrial fibrillation after cardiacurgery,3 possibly through anti-inflammatory effects.4 In-ammatory mechanisms and oxidative stress may be also

nvolved in the pathogenesis of contrast-induced nephropa-hy (CIN)5,6; hence, the rationale for a prospective evalua-ion of statin benefit in this setting. A recent review of aarge insurance database has shown that statin therapy isssociated with a lower incidence of CIN after PCI,7 andimilar results were retrospectively observed after cardiacatheterization in patients with chronic renal impairment.8owever, no study has addressed the issue of whetherrevention of CIN with statins would improve long-termlinical outcome.

ethods

our-hundred eighty consecutive patients undergoing PCI atampus Bio-Medico University of Rome from June 1, 2000 to

aDepartment of Cardiovascular Sciences, Campus Bio-Medico Univer-ity of Rome, and bInterventional Cardiology, San Filippo Neri Hospital,ome, Italy; and cCardiology Division, Virginia Commonwealth Univer-

ity, Richmond, Virginia. Manuscript received July 7, 2007; revised manu-cript received and accepted August 9, 2007.

*Corresponding author: Tel: 39-06-2254-1523; fax: 39-06-2254-1336.

mE-mail address: g.disciascio@unicampus.it (G. Di Sciascio).

002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2007.08.030

une 1, 2001 were evaluated (Figure 1). Patients had signsnd/or symptoms of myocardial ischemia and angiographicvidence of significant coronary disease warranting PCI. Toinimize the potential role of hemodynamic instability as a

ause of postprocedural renal failure, 46 patients with ST-egment elevation acute myocardial infarction �48 hours, car-iogenic shock, or left ventricular ejection fraction �30%ere excluded. Thus, 434 patients giving informed consentere enrolled. The study population was prospectively divided

nto statin-treated patients (n � 260) and statin-naive patientsn � 174) at the time of intervention. PCI was performed withtandard technique. A nonionic, low-osmolar (915 mOsm/kg),odinated contrast agent (iobitridol, Xenetix, Guerbet, RoissydG Cedex, France) was used in all interventions. Patients

eceived aspirin (100 mg/day) and ticlopidine 250 mg 2 times/ay from the day before or clopidogrel 300 mg 6 hours beforehe procedure. All patients continued ticlopidine 250 mg 2imes/day or clopidogrel 75 mg/day for �1 month, and theyere discharged on long-term statin therapy, unless contrain-icated.

By study design, blood samples were drawn before and4 hours after PCI for measurement of serum creatinine;urther determinations of creatinine beyond 24 hours wereone if clinically indicated; in such cases, the peak postpro-edural value was used for the purpose of this study. Cre-tinine clearance was calculated by applying the Cockcroft-ault formula: creatinine clearance � ([140 � age] �eight/serum creatinine � 72) with female gender adjust-

ent (creatinine clearancefemale � creatinine clearance �

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.85). Patients with baseline renal failure (defined as pre-rocedural serum creatinine �1.5 mg/dl or creatinine clear-nce �70 ml/min) underwent intravenous hydration withormal saline at 1 ml/hour/kg body weight for �12 hoursefore and 24 hours after angioplasty. CIN was defined aspostprocedural increase in serum creatinine of �0.5g/dl or �25% from baseline9; postprocedural acute renal

ailure was defined as a rapid decrease in renal glomerularltration with �2 mg/dl creatinine increase from baseline.xceeding weight- and creatinine-adjusted maximum con-

rast doses were also calculated using the formula bodyeight (kilograms) � 5 ml/serum creatinine.10

PCI success was defined as a postprocedural Thrombolysisn Myocardial Infarction grade 3 flow and decrease of stenosiso �30% residual narrowing by quantitative analysis; inci-ence of major in-hospital complications (death, myocardialnfarction, urgent coronary revascularization) was also re-orded. Periprocedural myocardial infarction was defined as anncrease in creatine kinase-MB �5 times after intervention.11

atients were prospectively followed for 4 years by officeisits and/or telephone interviews or contact with a referringhysician at 1, 3, 6, and 12 months and yearly thereafter.ollow-up evaluation included occurrence of major adverseardiac events (MACEs; cardiac death, myocardial infarction,r repeat coronary revascularization) and verification of con-inued statin therapy. Clinical, procedural, and laboratory dataere prospectively entered in a computerized database and

etrospectively analyzed. The study was approved by the in-titutional review board of the university.

Results are expressed as mean � SD unless otherwisepecified. Continuous variables were compared by t test forormally distributed values; otherwise the Mann-Whitney U

Figure 1. D

est was used. Proportions were compared by Fisher’s exact a

est when the expected frequency was �5; otherwise chi-quare test (Yates corrected) was applied. Odds ratios (ORs)nd 95% confidence intervals (CIs) assessing the risk ofIN and the risk of MACEs on long-term follow-up ac-ording to potential confounding variables were assessed byogistic regression. The following parameters were evalu-ted first in a univariate model: age; gender; hyperlipidemia;ystemic hypertension; diabetes; cigarette smoking; bodyass index; clinical pattern (stable vs unstable coronary

yndrome); left ventricular ejection fraction; congestiveeart failure; previous myocardial infarction; previous cor-nary revascularization; therapy with statins, � blockers,ngiotensin-converting enzyme inhibitors, diuretics, andlycoprotein IIb/IIIa inhibitors; baseline renal failure; base-ine creatinine clearance and serum creatinine; maximalontrast volume; maximal allowable contrast dose; treatedoronary vessel (left anterior descending coronary artery vsot left anterior descending coronary artery); type of lesionA/B1 vs B2/C), multivessel coronary disease; multivesselntervention; stent implantation (vs balloon angioplasty);tent length; number and diameter of implanted stents; andse of direct stenting. Variables with a p value �0.15 werehen entered into a multivariable logistic regression analy-is. Event-free survival analysis was performed by theaplan-Meier method with log-rank test group comparison.p value �0.05 (2-tailed) was considered statistically sig-

ificant. Analysis was performed with GB-STAT 6 (Dy-amic Microsystems, Inc., Silver Springs, Maryland).

esults

n the statin-treated group, 153 patients (59%) were taking

the study.

torvastatin, 77 (30%) simvastatin, 19 (7%) rosuvastatin,

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281Coronary Artery Disease/Statins and CIN After PCI

nd 11 (4%) pravastatin; mean duration of statin pretreat-ent was 10.6 � 9.1 months. Clinical and procedural char-

cteristics are listed in Tables 1 and 2, respectively. Statin-reated patients were younger and had higher prevalences ofypercholesterolemia, acute coronary syndromes on presen-ation, previous coronary revascularization, more complexesions (B2 and C), and more multivessel coronary arteryisease. The 2 groups were similar with regard to other drugherapy, cardiovascular risk factors, and procedural fea-ures. Mean procedural contrast volume was not signifi-antly different, and neither was the proportion of patientsxceeding a maximal allowable contrast dose. Angiographicuccess was obtained in 257 of 260 patients (99%) in thetatin-treated group and in all 174 statin-naive patients100%, p � 0.41); postprocedural non–Q-wave myocardialnfarction occurred in 4 patients (1%) and 5 patients (3%),espectively (p � 0.54). There was no in-hospital death oreed for urgent revascularization.

Baseline serum creatinine and creatinine clearance wereimilar in the 2 groups, as was the prevalence of pre-existinghronic renal failure (Table 1). After the procedure, statin-

able 1aseline demographic and clinical features

ariable Statin Pretreatment pValue

Yes No(n � 260) (n � 174)

ge (yrs) 65 � 10 67 � 10 0.017omen 59 (23%) 28 (16%) 0.12

ystemic hypertension 190 (73%) 135 (76%) 0.34iabetes mellitus 97 (37%) 64 (37%) 0.99ypercholesterolemia(�200 mg/dl)

197 (76%) 106 (61%) 0.001

igarette smoking 152 (58%) 94 (54%) 0.42ody mass index (kg/m2)�25 60 (23%) 33 (19%) 0.3725–30 120 (46%) 92 (53%) 0.2030 80 (31%) 49(28%) 0.63linical presentationStable angina 111 (43%) 92 (53%) 0.047Non–ST-segment elevationacute coronary syndrome

149 (57%) 82 (47%) 0.047

revious myocardialinfarction

82 (32%) 58 (33%) 0.77

revious coronaryintervention

66 (25%) 24 (14%) 0.005

revious bypass surgery 26 (10%) 4 (2%) 0.004ow-density lipoproteincholesterol (mg/dl)

94 � 14 123 � 30 0.006

erum creatinine (mg/dl) 1.1 � 0.3 1.2 � 0.3 0.18reatinine clearance (ml/min)

84 � 23 83 � 19 0.87

hronic renal failure 34 (15%) 29 (17%) 0.37emoglobin (g/dl) 12.9 � 1.4 13.1 � 1.5 0.16reprocedural medicationsAngiotensin-convertingenzyme inhibitors

202 (78%) 125 (72%) 0.20

� Blockers 100 (38%) 59 (34%) 0.39Calcium channel blockers 125 (48%) 89 (51%) 0.60Diuretics 46 (18%) 36 (21%) 0.51Acetylcysteine 12 (5%) 8 (5%) 0.82

reated patients had a significantly lower incidence of CIN h

3% vs 27%, p � 0.0001; Figure 2); mean postproceduralerum creatinine was also lower in the statin group (1.2 �.4 vs 1.4 � 0.4 mg/dl, p �0.0001) and creatinine clearanceas significantly better (p �0.0001; Figure 2). Occurrencef postprocedural acute renal failure was rare and similar inhe 2 groups (1%, p � 0.99). In patients with CIN, thoseeceiving statins had significantly lower postprocedural cre-tinine peak levels (1.6 � 0.5 vs 2.3 � 1.4 mg/dl, p �.007). No patient with CIN required dialysis, and all wereischarged when renal function returned to baseline afterggressive hydration. Patients with low-density lipoproteinholesterol levels below the median (96 mg/dl) had 1 epi-ode of CIN versus 6 patients in the group with levels abovehe median (p � 0.13). Length of stay after intervention washorter in statin-treated than in statin-naive patients (2.2 �.5 vs 2.4 � 0.6, p � 0.01) and longer in patients with CIN2.7 � 0.9 vs 2.2 � 0.6 days, p � 0.001); as expected,ength of stay was shortest in statin-treated patients withoutIN (2.2 � 0.4 days, p �0.036).

Multivariable analysis (Figure 3) identified statin pre-reatment as strong predictor of decreased risk of CIN (OR.10, 95% CI 0.02 to 0.18, p � 0.0001); female gender,iabetes mellitus, previous myocardial infarction, increasedaseline serum creatinine level, decreased baseline creati-ine clearance, and amount of contrast load were indepen-ently associated with increased risk. In a subgroup analysisFigure 4) that included age, gender, presence of diabetesellitus, therapy with angiotensin-converting enzyme in-

able 2ngiographic and procedural characteristics

ariable Statin Pretreatment p Value

Yes No(n � 260) (n � 174)

ultivessel coronary disease 153 (59%) 77 (44%) 0.004eft ventricular ejectionfraction (%)

54 � 9 55 � 9 0.15

oronary vesselLeft main 1 (1%) 3 (2%) 0.36Left anterior descending 133 (44%) 90 (47%) 0.99Circumflex 79 (26%) 41 (22%) 0.15Right 76 (25%) 54 (28%) 0.77Saphenous vein graft 10 (4%) 2 (1%) 0.17esion type B2/C 146 (56%) 66 (38%) �0.001ultivessel intervention 39 (15%) 16 (9%) 0.10rgent PCI 149 (57%) 82 (47%) 0.047ype of procedureBalloon only 16 (6%) 11 (6%) 0.90Stent 244 (94%) 163 (94%) 0.90irect stenting 70 (27%) 59 (34%) 0.15o. of stents/patient 1.4 � 0.7 1.4 � 0.6 0.81se of drug-eluting stents 44 (17%) 21 (12%) 0.21tent diameter (mm) 3.1 � 0.5 3.1 � 0.5 0.20otal stent length (mm) 16 � 4 17 � 0.5 0.90lycoprotein IIb/IIIainhibitors

73 (28%) 45 (26%) 0.69

otal mean contrast volume(ml)

221 � 100 234 � 105 0.32

xceeding maximal allowablecontrast dose

36 (14%) 35 (20%) 0.10

ibitors, left ventricular ejection fraction, clinical presenta-

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ion, previous myocardial infarction, baseline renal func-ion, and extension of coronary artery disease, a significantenefit of statins was maintained in all subgroups, except foratients with a baseline creatinine clearance �40 ml/minOR 0.35, 95% CI 0.10 to 1.7, p � 0.18).

Four-year clinical follow-up was obtained in 430 of 434atients (99%). Incidence of late MACEs was significantlyower in patients receiving statins at the time of intervention6% vs 36%, p �0.0001), and this was driven by a decreasen cardiac death and repeat coronary intervention (Table 3).

ultivariable analysis (Table 4) demonstrated that statinherapy was independently associated with a lower risk of

ACEs during follow-up; CIN, older age, and impaired leftentricular ejection fraction were predictors of poorer out-ome. Event-free survival was higher in statin-treated pa-ients at 48 months (94% vs 66%, p �0.0001) and inatients without CIN (87% vs 61%, p �0.0001; Figure 5).ctuarial life-table analysis (Figure 6) showed that 4-year

igure 2. (A) Incidence of CIN in patients with (black bars) versus withouaseline (p � 0.87) and postprocedural (p �0.0001) creatinine clearance

Figure 3. Multiva

vent-free survival was best in statin-treated patients and no p

IN (95%, p �0.015 vs other groups) and worst in statin-aive patients with CIN (53%, p �0.018 vs other groups);urvival of statin-treated patients with CIN was similar tohat of statin-naive patients who did not develop CIN (72%s 71%).

iscussion

his study indicates that patients receiving statin treatmentefore PCI have a decreased incidence of postproceduralIN compared with patients not receiving statins; this ben-fit is associated with improved long-term clinical outcome,ncluding a significant decrease in cardiac death at 4 years.

Chronic renal failure worsens prognosis in patients withoronary artery disease and in those undergoing coronaryngioplasty,12,13 and development of CIN after PCI corre-ates with increased risk of early and late cardiovascularvents.14,15 Although the pathogenesis of CIN is not com-

bars) statin treatment at the time of intervention (p � 0.0001). (B) Meangroups of patients.

nalysis for CIN.

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283Coronary Artery Disease/Statins and CIN After PCI

er contrast exposure, there is a brief period of vasodilationollowed by renal vasoconstriction, and various moleculesi.e., angiotensin, vasopressin, and endothelin) appear toediate this decrease in renal blood flow.5,6 Because statins

nduce downregulation of angiotensin receptors and de-rease endothelin synthesis,16,17 these drugs may prevent

Figure 4. Subgroup analysis showing ben

able 3dverse events at four-year clinical follow-up

ariable Statin Pretreatment p Value

Yes No(n � 258) (n � 172)

ardiac death 3 (2%) 11 (8%) 0.01yocardial infarction 3 (2%) 5 (4%) 0.40linically driven repeatangiography

8 (4%) 30 (22%) �0.0001

estenosis with target lesionrevascularization

1 (1%) 11 (8%) 0.001

epeat PCI* 7 (4%) 27 (20%) �0.0001ypass surgery 4 (2%) 6 (4%) 0.38otal MACEs 12 (6%) 50 (36%) �0.0001

* Target plus nontarget vessel revascularization.

IN by decreasing the period of renal hypoperfusion and l

schemia. Another mechanism responsible for CIN is directamage to tubular cells mediated by oxygen-free radicals,roinflammatory cytokines, and complement activation,ith subsequent cytoplasmic vacuolization, necrosis, inter-

titial inflammation, and tubular obstruction by protein pre-ipitates.5,6,18 Statins may decrease inflammation and im-rove endothelial function by inhibiting nuclear factor �B,transcription factor that acts on genes encoding for proin-ammatory mediators,19 decreasing expression of endothe-

tatin therapy in different patient subsets.

able 4redictors of adverse events during follow-up (multivariable analysis)

ariable OR 95% CI p Value

tatin therapy 0.17 0.08–0.34 0.0001omen 1.4 0.68–3.0 0.34ge �65 yrs 2.1 1.2–3.7 0.01iabetes mellitus 1.9 0.95–3.9 0.07eft ventricular ejection fraction �40% 2.1 1.3–3.8 0.01IN 2.6 1.2–5.4 0.01alloon angioplasty 5.1 0.68–37 0.11tent length �15 mm 0.62 0.34–1.1 0.12tent diameter �3 mm 1.4 0.83–2.5 0.18

ial adhesion molecules,20,21 increasing nitric oxide bio-

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284 The American Journal of Cardiology (www.AJConline.org)

vailability,19,22 attenuating production of reactive oxygenpecies,23 and protecting against complement-mediated in-ury.24 In addition, experimental data have shown that sta-ins exert nephroprotective effects in a rat model of long-erm inhibition of nitric oxide synthesis by amelioration ofascular endothelial growth factor expression and decreasef RhoA activity.25 Thus, by all those actions, statins mayrovide protection against CIN.

In our study, patients treated with a variety of statinsndergoing PCI had a 90% risk decrease of CIN; this wasndependent of possible confounding factors and probablyot related to cholesterol lowering. This beneficial effectas observed despite a higher risk profile (i.e., higher prev-

lence of unstable syndromes, complex lesions, multivesseloronary disease, and previous coronary revascularization)resent in patients receiving statins. Thus, the “sickest”ardiac patients obtain the greatest benefit with statins.enal protection was observed even in patients more prone

o develop postprocedural renal failure, such as older pa-ients or diabetics, and it resulted in a significant decrease inength of stay. When patients developed CIN, their peakreatinine levels after PCI were significantly attenuated ifhey were taking statins. Patients with severely impairedaseline renal function (creatinine clearance �40 ml/min)ad less benefit, probably due to multiple nonreversibleathogenetic mechanisms involved in advanced renal fail-re.26

Importantly, prevention of CIN by statin therapy leads tosignificant long-term decrease of adverse events; statin-

igure 5. Event-free survival in patients (A) with (solid line) or without (dIN.

igure 6. Event-free survival according to statin pretreatment and CIN in gdotted line), C (no statin, no CIN) (solid line), and D (no statin, CIN) (d

reated patients without CIN had a 90% relative decrease of h

ACEs at 4 years compared with the worst scenario oftatin-naive patients who developed CIN. CIN was associ-ted with an excess mortality of 5% and an excess event ratef 25% at 4 years; similar results were obtained in a previ-us observational analysis in 7,586 patients.14 Accordingly,24% absolute decrease in the incidence of CIN, as ob-

erved in this study, would translate into 3 lives saved andrevention of 15 cardiac events per 1,000 patients treateder year.

Mechanisms underlying improved late outcome are notompletely clear. Vulnerability to contrast agents may be aarker of multisystem atherosclerosis responsible for late

ardiac complications, as suggested by the correlation be-ween cardiovascular risk (i.e., previous myocardial infarc-ion) and postprocedural renal impairment. Accordingly, theame CIN-protective mechanisms exerted by statins duringCI (i.e., anti-inflammatory effects and improvement ofndothelial function) may play a role in the decrease ofardiac events in the long term. In fact, thanks to statinherapy, the event-free survival curve of patients who de-eloped CIN was essentially equal to that of statin-naiveatients without CIN.

The present study presents limitations inherent to allonrandomized analyses. However, randomized, placebo-ontrolled trials using statins to prevent contrast-inducedenal impairment during cardiovascular procedures woulde difficult to design, due to the current widespread use oftatins in patients with coronary artery disease. Because aingle serum creatinine determination was obtained 24

ine) statin pretreatment and (B) with (dashed line) or without (solid line)

(statin pretreatment, no CIN) (dashed line), B (statin pretreatment, CIN)otted line).

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285Coronary Artery Disease/Statins and CIN After PCI

urements were performed only if clinically indicated (i.e.,vidence of worsening renal function), some patients with aate increase in serum creatinine could have been missednd the incidence of CIN underestimated; however, mostatients developing CIN present a �0.5 mg/dl increase inerum creatinine within 24 hours from contrast exposure,27

nd, in our study, the incidence of such complication wasimilar to other large observational series.7,28 Although inur cohort the mean duration of statin pretreatment was 10onths and atorvastatin was the drug most frequently used,e cannot establish specific correlations between durationf therapy or type of statin and protection against CIN.

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2. Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G,Montinaro A, Di Sciascio G. Atorvastatin pretreatment improves out-comes in patients with acute coronary syndromes undergoing earlypercutaneous coronary intervention: results of the ARMYDA-ACSrandomized trial. J Am Coll Cardiol 2007;49:1272–1278.

3. Patti G, Chello M, Candura D, Pasceri V, D’Ambrosio A, Covino E, DiSciascio G. A randomized trial of atorvastatin for reduction of post-operative atrial fibrillation in patients undergoing cardiac surgery. Resultsof the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhyth-mia After cardiac surgery) Study. Circulation 2006;114:1455–1461.

4. Patti G, Chello M, Pasceri V, Colonna D, Nusca A, Miglionico M,D’Ambrosio A, Covino E, Di Sciascio G. Protection from proceduralmyocardial injury by atorvastatin is associated with lower levels ofadhesion molecules after percutaneous coronary intervention. Resultsfrom the ARMYDA-CAMs (Atorvastatin for Reduction of MYocar-dial Damage during Angioplasty-Cell Adhesion Molecules) Substudy.J Am Coll Cardiol 2006;48:1560–1566.

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6. Tumlin J, Stacul F, Adam A, Becker CR, Davidson C, Lameire N,McCullough PA, on behalf of the CIN Consensus Working Panel.Pathophysiology of contrast-induced nephropathy. Am J Cardiol 2006;98(suppl):14K–20K.

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