| BackgroundContrast medium is widely used as the economy grows and healthcare improves rapidly. Contrast induced nephropathy (CIN) is a common complication after coronary angiography (CAG) or percutaneous coronary intervention (PCI) and is the third leading cause of hospital acquired acute kidney injury, associating with increased in-hospital and long-term clinical events and mortality, as well as prolonged hospital stay and raised healthcare costs. There was a 9.7% to 14% increase in mortality after developing CIN according to previous studies.Chronic kidney disease (CKD) has been proved to be an independent risk factor for CIN. Patients with severe renal insufficiency are at especially high risk of developing CIN with an incidence of over 50%. However, the mechanism of CIN is still not fully understood. As a result, the effective treatment options are still not available, and efforts to control CIN have been focusing on prevention. Nevertheless, the effective preventive strategy for CIN is also limited. Avoiding and eliminating risk factors such as potential nephrotoxic drugs, limiting contrast medium volume and hydrating sufficiently with normal saline during periprocedural periodare the most fundamental preventive strategies for CIN.There was an important role of the activated renin-angiotensin-aldosterone system (RAAS) in contrast-induced intrarenal vasoconstriction and renal tubular cell apoptosis.Experimental data suggested that the levels of plasma renin, angiotensin-Ⅱ and aldosterone were significantly increased after exposure to contrast media.and The blockade of angiotensin-II decreased the duration of renal vasoconstriction and renal tissue injury following contrast medium exposure. However, the role of periprocedural use of Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB), both of which are RASS blockers, in the pathophysiology of CIN after CAD or PCI remains controversial, as the available literature is conflicting and inconclusive.Some studies regarding perioprocedural use of ACEI/ARB on CIN reported reduced CIN incidence and speculated that ACEI/ARB protect against CIN by counteracting afferent arteriolar vasoconstriction and subsequent medullary ischemia secondary to RAAS activation after contrast medium administration. European Society of Cardiology guidelines on myocardial revascularization had ever recommended that as a prevention strategy of CIN for CKD patients (Class I, Level A). However, there were a certain amount of research indicated that ACEI/ARB increased the risk of CIN especially in patients with preexisted renal dysfunction, proposing that ACEI/ARB preferentially dilated the efferent arteriole and therefore decreased the renal medullary blood flow and glomerular filtration rate, and recommend holding these drugs prior to contrast administration. The clinical practice guideline of CIN established by European Society of Radiology Contrast Agent Security Council pointed out that the effect of periprocedural use of ACEI/ARB on CIN risk cannot be definitely concluded, and whether to withhold these drugs during the periprocedural period need further investigation. Thus, paradoxical opinions exist among clinicians as to whether or not the administration of ACEI/ARB should be held prior to coronary catheterization.Similar to ACEI/ARB, sufficient hydration with isotonic saline, which is a well proved and widely accepted preventive strategies for CIN, has a significant effect of inhibiting RAAS activation by volume expansion and sodium load. However, sufficient saline hydration presented continuous renal protective effect almost in all studies concerning CIN. Compared to ACEI/ARB, sufficient saline hydration not only decreases the release of vasoconstrictors and reactive oxygen species production by inhibiting RAAS activation, but also decreases the direct toxic effects of contrast medium to renal tubules by diluting it and promoting excretion. Additionally, the effects of isotonic saline hydration on renal hemodynamics may prevent against the deleterious effect of ACEI/ARB on glomerular filtration rate and further increase renal blood flow through volume expansion. Therefore, the effect of ACEI/ARB on CIN may also be affected by saline hydration. However, none of the studies mentioned above investigated the effect of ACEI/ARB on CIN in different situations of hydration.ObjectiveThis study is to prospectively evaluate the potential effect of hydration intensity on the role of ACEI/ARB in CIN risk in patients with CKD.Study population and MethodsStudy populationThis prospective observational study reviewed all consecutive patients who underwent coronary catheterization between January 2010 and October 2012 at the Guangdong Cardiovascular Institute of the Guangdong General Hospital, Guangdong Academy of Medical Sciences. The eligibility criteria was≥18 years of age with creatinine clearance rate (CrCl) raged from 15 mL/min to less than 60 mL/min who agreed to stay in the hospital for at least 2 days after coronary catheterization. The exclusion criteria included pregnancy, lactation, contrast medium or ACEI/ARB allergy, bilateral renal artery stenosis, angioedema, baseline serum potassium>5.5 mmol/L, baseline systolic blood pressure (SBP)<90 mmHg, and severe aortic stenosis or aortic regurgitation, severe mitral insufficiency, hypertrophic obstructive cardiomyopathy, constrictive pericarditis, older smoker with peripheral vascular murmur, severe heart failure (New York Heart Association [NYHA] class≥Ⅲ or Killip class≥Ⅱ), other disease need therapy by surgery, renal replacement, use of drugs with potential effects on renal function (sodium bicarbonate, non-steroid anti-inflammatory drugs, aminoglycosides, cyclosporin, and cisplatin) within 48h before and 72h after the proceduure, contrast medium exposure or acute infections within 7 days before or 3 days after the procedure, malignancy, life expectancy<1 year, death during procedure, withdraw ACEI/ARB during follow-up, no use of low-osmolar contrast mediums, no use of isotonic saline for hydration, and deletion of serum creatine (SCr).Treatment and proceduresCoronary catheterization was performed by experienced interventional cardiologists according to standard clinical practice via the femoral or radial approach, using standard devices. All patients received nonionic, low-osmolarity contrast agents (either Iopamiron or iopromide, both 370 mg I/mL).The contrast dose was based on the need for procedure. Pharmacotherapy and behavioral interventions were administrated at the decision of clinicians following the clinical practice guidelines. Isotonic saline hydration were administrated at a rate of 1 mL/kg per hour (0.5 mL/kg per hour in case of left ventricular ejection fraction<35% or severe congestive heart failure) for at least 2 to 12 h before and 6 to 24 h after the procedure. Serum creatinine concentrations were measured in all patients at admission and on the 1,2, and 3 days after the procedure. The CrCl was calculated using the Cockcroft-Gault formula. Hydration volume of isotonic saline during 12 h before and 24 h after the procedure were recorded, and hydration volume to weight (HV/W) ratio were calculated to indicate the adjusted intensity of hydration. Patients were followed up at 1,6,12, and 24 months in an outpatient clinic or by a telephone interview.EndpointsThe primary endpoint was the occurrence of CIN, which was defined as an absolute increase in SCr by≥0.5 mg/dL (44.2 mmol/L) from the baseline value within 48-72 h of contrast medium exposure. Other endpoint were:in-hospital all-cause death and combined major adverse clinical events (MACE) including all-cause death, nonfatal recurrent myocardial infarction, target vessel revascularization, acute heart failure, arrhythmia, stroke, and renal replacement therapy; different definitions of CIN (CIN-0.5/25% was defined as an absolute increase by≥0.5 mg/dL or a relative increase in SCr of 25% from the baseline value within 48-72 h of contrast medium exposure; CIN-0.3/50% was defined as an absolute increase by≥0.3 mg/dL or a relative increase in SCr of 50% from the baseline value within 48-72 h of contrast medium exposure).Statistical analysisAll analyses were performed with SAS version 9.2 (SAS Institute, Cary, NC, USA), and statistical significance was considered if the P value was<0.05 (2-tailed). Continuous variables are described as means ± standard deviation or median (if not normally distributed); while categorical variables are presented as absolute values (percentages). Patients were stratified into 3 groups according to tertiles of baseline HV/W:<10.21 mL/kg,10.21 to<17.86 mL/kg, and≥17.86 mL/kg. To identify the differences of baseline characteristics between ACEI/ARB and no ACEI/ARB group, Student’s t-test or Wilcoxon rank sum test were used for continuous variables, and Pearson Chi-square test or Fisher’s exact test were applied to categorical variables, as appropriate. The association between ACEI/ARB treatment and CIN occurrence were assessed by using Logistic regression analysis adjusting for potential confounding variables; the included variables either exhibited a statistically significant difference from baseline or were considered to have an important effect on the endpoints based on findings from clinical practice or previous studies. The in-hospital and long-term clinical outcomes between groups were compared using the Log-Rank test and Kaplan-Meier survival method. Cox regression analysis was conducted to determine the risk factors for follow-up death and MACE.ResultsBaseline characteristicsOf all 1254 consecutive CKD patients (mean CrCl,45.1 ± 10.5) enrolled with an median follow-up period of 2.59 ± 0.91 years (interquartile range,1.84-3.44 years), 1094 were treated with ACEI/ARB during the perioprocedural period and the other 160 were nonusers. Compared to no ACEI/ARB group, ACEI/ARB group in the first tertile (HV/W<10.21 mL/kg,375 patients) seemed to have higher body weight, LVEF, contrast volume, proportion of hypertension, and lower HV/W ratio (P< 0.05); ACEI/ARB group in the second tertile(10.21≤HV/W<17.86 mL/kg,369 patients) appeared to have less patients older than 75 years(P<0.05), higher SBP and diastolic blood pressure (P<0.05), and lower proportion of anemia (P<0.05); ACEI/ARB group in the third tertile (HV/W≥17.86 mL/kg,350 patients) were higher in SBP and DBP (P<0.05), and lower in Mehran risk score, HV/W ratio, baseline SCr, and proportion of CrCl<30 mL/min and chronic heart failure (CHF, P<0.05). The other demographic, laboratory, and procedural characteristics, such as gender, triglyceride, urine acid, stent number, were similar between the 2 groups in all tertiles.Analysis in all subjectsOverall, CIN occured in 84(6.7%) patients. The incidences of CIN were significantly lower in patients treated with perioprocedural ACEI/ARB (6.2% vs. 10.8%, P=0.029). Similar results were also obtained regarding the rate of in-hospital death (2.9% vs.7.5%, P=0.003) and arrhythmia (6.0% vs.11.9%, P=0.005). However, there were no significant differences between the two groups with regard to the rate of MACE (11.1% vs.16.3%, P=0.057) and other in-hospital adverse events such as renal replacement therapy (1.4% vs.3.1%, P=0.098).Multivariate logistic regression analysis indicated that perioprocedural ACEI/ARB administration had no significant effect on the risk of CIN after percutaneous coronary angiography or intervention in patients with CKD (odds ratio [OR]:0.89,95% confidence interval [CI]:0.46-1.73, P=0.735) after adjusting for potential confounding risk factors (age>75 years, CrCl<30 mL/min, CHF, contrast volume, anemia, SBP, DBP, HV/W). Age>75 years (P=0.045), CrCl<30 mL/min (P <0.001), and CHF (P<0.001),and contrast volume (P=0.021)were risk factors for CIN occurrence in this population.Effect of ACEI/ARB on CIN by HV/W tertilesPerioprocedural administration of ACEI/ARB significantly reduce the incidence of CIN in the second tertile (5.44% vs.13.21%, P=0.031). In addition, CIN incidence of patients treated with perioprocedural ACEI/ARB compared to nonusers indicated a nonsignificant trend toward higher in the first tertile (3.51% vs.2.38%, P =0.701), while lower in the third tertile (9.7% vs.14.75%, P=0.254).In consistent with the results mentioned above, multivariate logistic regression analysis revealed that perioprocedural administration of ACEI/ARB significantly reduce the risk of CIN after coronary catheterization in CKD patients only in the second tertile after adjusting for age>75 years, CrCl<30 mL/min, CHF, contrast volume, anemia, SBP, DBP, HV/W ratio (OR:0.26,95% CI:0.09-0.74, P=0.012).Kaplan-Meier survival analysis was performed to determine the relationship between the accumulated risk of adverse events and perioprocedural administration of ACEI/ARB. Patients treated with perioprocedural ACEI/ARB demonstrated a lower incidence of all-cause death in the second tertile (14.5% vs.26.2%, P=0.043) and MACE in the first (6.8% vs.16.7%, P=0.027) and second tertile (15.2% vs.28.6%, P=0.023).On multivariable Cox proportional hazard regression analysis, perioprocedural ACEI/ARB administration significantly reduce the risk of death (hazard ratio [HR]: 0.426,95% CI:0.207-0.877, P=0.02) and MACE (HR:0.43,95% CI:0.216-0.856, P=0.016) only in the second tertile after adjusting for age>75 years, DM, CrCl, CHF, SBP, HV/W ratio. In addition, age>75 years, DM, and CrCl were independent risk factors for long-term death and MACE after coronary catheterization in the second HV/W tertile (P<0.05).ConclusionsOur study indicated that in patients undergoing coronary angiography or intervention with CKD, the effect of perioprocedural administration of ACE/ARB on the risk of CIN varied according to isotonic saline hydration intensity. When a moderate intensity of saline hydration (HV/W:10.21 to<17.86 mL/kg) was administrated concomitantly during the perioprocedural period, ACE/ARB associated with significant reduction in CIN incidence and improvement in long-term outcomes. |
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