Persistent Renal Damage After Contrast-Induced Acute Kidney Injury Incidence, Evolution, Risk Factors, and Prognosis

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1 Persistent Renal Damage After Contrast-Induced Acute Kidney Injury Incidence, Evolution, Risk Factors, and Prognosis Mauro Maioli, MD; Anna Toso, MD; Mario Leoncini, MD; Michela Gallopin, MD; Nicola Musilli, MD; Francesco Bellandi, MD Background The temporal evolution of renal function in patients with acute kidney injury after contrast medium (CI-AKI) is not well known. The aim of this observational study was to evaluate the incidence, risk factors, and prognostic implications of persistent renal damage (RD) in patients with preexistent moderate-to-severe renal dysfunction. Methods and Results From June 2003 to March 2008, 3986 patients underwent coronary angiography at our institution; 1490 of 3986 had an estimated creatinine clearance of 60 ml/min and were enrolled. CI-AKI was defined as an absolute increase 0.5 mg/dl over baseline serum creatinine within 3 days after the administration of contrast medium (iodixanol). In patients who developed CI-AKI, persistent RD was defined as a relative decrease of creatinine clearance 25% over baseline at 3 months. Patients whose creatinine clearance returned to baseline (or nearly) were classified as transient RD. The overall incidence of CI-AKI was 12.1%, and persistent RD occurred in 18.6% of CI-AKI patients. At Cox regression analysis, nephropathy risk score 17, left ventricular ejection fraction 30%, and increased value of serum creatinine 1.5-fold from baseline within 5 days were found to be significant risk factors for persistent RD. At 5 years, the incidence of death was significantly higher in patients with persistent RD than in both patients with transient RD (P 0.015) and those without CI-AKI (P ). A similar trend was observed for the combined end point of death, dialysis and cardiovascular events. Conclusions These results suggest that CI-AKI is not always a transient, benign creatininopathy, but rather a direct cause of worsening renal function. The occurrence of CI-AKI can identify patients at increased risk of cardiovascular events. (Circulation. 2012;125: ) Key Words: angiography chronic kidney disease contrast-induced nephropathy acute kidney injury contrast media catheter based coronary intervention Acute kidney injury after exposure to iodinated contrast media (CI-AKI) increases morbidity, early mortality, and hospital stay. 1 5 Moreover, renal insufficiency is an independent risk factor for increased long-term mortality in the general population. 6 This is also true in patients with mild renal impairment. 7,8 Clinical Perspective on p 3107 Long-term evolution of CI-AKI in patients undergoing percutaneous coronary intervention who survive to hospital discharge is less clear. In particular, the evolution of renal function in the posthospitalization period is not well known, although there is evidence for a cause-and-effect relationship between CI-AKI and increased mortality and cardiovascular events during long-term follow-up. 1,9 11 These associations are particularly relevant because preexisting kidney disease is common in patients with cardiovascular disease and among patients who develop CI-AKI. Aims of this observational study are to evaluate the evolution of creatinine values in the posthospitalization period and to define incidence, risk factors, and prognostic implications of persistent renal damage (RD) after coronary angiography and percutaneous coronary intervention in a high-volume cardiovascular referral practice with basal moderate-to-severe renal dysfunction. Methods Population and Study Protocol From June 2003 to March 2008, 3986 patients underwent coronary angiographic procedures at our institution; 1490 of 3986 patients (37.3%) had moderate-to-severe renal dysfunction (defined as estimated creatinine clearance 60 ml/min) and were selected for the present study. Patients with ST-segment elevation acute myocardial infarction or end-stage renal failure requiring dialysis were excluded. The present population includes patient groups already published in 3 previous articles, 1 observational study with consecutive enrolment 12 and 2 randomized studies. 13,14 We identified 3 groups of Received December 6, 2011; accepted May 2, From the Division of Cardiology, Misericordia e Dolce Hospital, Prato, Italy. The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Mauro Maioli, MD, Via Arcipressi 3, 50143, Florence, Italy. mauro.maioli@fastwebnet.it 2012 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 3100 Circulation June 26, 2012 Figure 1. The enrollment criteria and the study flow. PCI indicates percutaneous coronary intervention; CI-AKI, absolute increase 0.5 mg/dl over baseline serum creatinine within 3 days after the administration of the contrast medium; Persistent renal damage, residual impairment of renal function indicated by a reduction of creatinine clearance 25% at 3 months in comparison with baseline; Transient renal damage, creatinine clearance returned to baseline or nearly (creatinine clearance reduction 25%) at 3 months. patients in our cohort: NO CI-AKI, CI-AKI patients with persistent RD (creatinine clearance 25% above baseline at 3 months), and CI-AKI patients with transient RD (creatinine clearance returned to baseline or nearly at 3 months). Figure 1 shows the enrolment criteria and the study flow. Creatinine clearance was calculated by applying the Cockroft- Gault formula to the baseline serum creatinine. 15 All patients underwent an intravenous hydration protocol with saline or bicarbonate solutions as previously reported N-Acetylcysteine was given orally at a dose of 600 mg twice daily, on the day before and on the day after the procedure. 16 Echocardiographic evaluation of left ventricular function was performed in all patients on admission; hydration volumes were halved when left ventricular ejection fraction was 40%. In all cases iodixanol (Visipaque, GE Healthcare Ltd, Amersham, United Kingdom), a nonionic, dimeric iso-osmolar contrast medium was used. Serum creatinine concentration (isotope dilution mass spectrometry traceable method) was assessed the day before angiography (baseline, prehydration), immediately preprocedural on day 0 (preangiography, posthydration), and on days 1, 2, 3, 5, 10, and 30 after the procedure. Serum creatinine was measured again at 3 months for all CI-AKI patients and 930 of 1310 (71%) of the NO CI-AKI group. All tests, even after discharge, were done in our hospital laboratory with consistent methodology. Demographic, clinical, and procedural data were prospectively recorded for all patients in a dedicated database. Hospital ethics committee approved the protocol, and all patients gave informed consent. End Point, Clinical Definitions, and Follow-Up CI-AKI was defined as an absolute increase of at least 0.5 mg/dl over baseline serum creatinine within 3 days after the administration of the contrast medium, without an alternative etiology. 17 Persistent RD was defined as a residual impairment of renal function indicated by a reduction of creatinine clearance 25% at 3 months in comparison with baseline. 18,19 Transient RD was defined as a complete regression or persistent minimal reduction of renal function (creatinine clearance reduction 25% at 3 months in comparison with baseline). The short- and long-term clinical end points were death and the combined end point of death, dialysis, and major adverse cardiovascular events (stroke, non ST-segment elevation myocardial infarction, and ST-segment elevation myocardial infarction). The follow up events were carefully monitored and recorded by trained nursing personnel with office visits, telephone interviews, and access to hospital and demographic databases. Renal function was categorized according to the stages set by the National Kidney Foundation (USA), with creatinine clearance 59 to 30 ml/min considered moderately impaired and 30 ml/min severely impaired. 20 Advanced congestive heart failure was defined according New York Heart Association class III and IV. Anemia was defined using World Health Organization criteria: baseline hematocrit value 39% for men and 36% for women. 21 Periprocedural hypotension and the nephropathy risk score were defined as specified by Mehran et al. 2 The volume contrast medium-to-creatinine clearance ratio was calculated according Laskey et al. 22

3 Maioli et al Persistent Renal Damage After Coronary Angiography 3101 Statistical Analysis Categorical variables were summarized as frequencies with percentages and were compared by Pearson 2 analysis or Fisher exact test. Normal distribution of continuous data was tested by use of the Kolmogorov-Smirnov test. One-way ANOVA test and the Kruskal- Wallis test were used to determine differences between normal and nonnormally distributed continuous variables, respectively. Multiplicity issues resulting from the pairwise comparisons were approached with the Bonferroni adjustment (yielding a significance threshold of 0.015). Comparisons of the time course of creatinine values between groups were based on variance analysis for repeated measures. Univariate odds ratio was calculated for significant clinical factors; individual risk factors that were significant were entered into stepwise Cox regression model to identify independent predictors of persistent RD and long-term outcome and to estimate odds ratios. Other variables were excluded as not significant at the univariate analysis or because of colinearity. The optimal cutoff values for continuous variables were calculated by receiver-operating characteristic curve analysis. Continuous variables were included in the multivariable analysis as categorical variables by use of the cutoff values obtained by the receiver-operating characteristic curve analysis. Survival curves were generated with the Kaplan-Meier method, and the differences between groups were assessed by log-rank test. Multivariable Cox proportional hazard regression models were used to assess hazard ratios (HRs) with 95% CI for comparing NO CI-AKI patients with CI-AKI transient RD and CI-AKI persistent RD. All analyses were performed with SPSS statistical software, version 19.0 (SPSS Inc, Chicago, IL). All tests were 2-tailed, and statistical significance was defined as a P Results Clinical Characteristics and CI-AKI Incidence Baseline clinical, biochemical, and procedural characteristics of the enrolled patients are reported in Table 1. CI-AKI occurred in 180 of 1490 patients (12.1%) with baseline estimated creatinine clearance of 60 ml/min. We note that the relatively low incidence of CI-AKI in our population may be due to the high prevalence (69% of cases) of low-tomoderate contrast nephropathy risk score ( 11) (Table 1). As expected, patients developing CI-AKI showed a higher incidence of relevant comorbidities (diabetes mellitus, hypertension, left ventricular dysfunction, or advanced heart failure), and a worse baseline renal function, as well. Moreover, these patients also had more unfavorable procedural issues, such as higher contrast volume-to-clearance creatinine ratio or acute periprocedural hypotension. The sum of all these factors yielded a high nephropathy risk score. CI-AKI and Persistent RD Of the 180 CI-AKI patients, 167 were still alive at 3 months and 31 of these (18.6%) presented persistent RD. The remaining 136 CI-AKI patients (81.4%) had experienced transient RD and had returned to baseline (or nearly) creatinine clearance. Figure 2 shows the time course of creatinine values in all 3 groups. The peak of renal injury occurred days (peak value) after contrast exposure in both CI-AKI groups (transient RD and persistent RD); afterward, renal function progressively improved with a substantial recovery of the mean creatinine values at 3 months and with a mean loss of filtration rate of 5% (Table 2). Patients with persistent RD showed a mean reduction of glomerular filtration rate of 30% (Table 3), regardless of the baseline degree of renal impairment (moderate or severe). However, patients with a severe reduction in renal function at baseline showed a higher risk of developing a persistent RD after contrast medium administration when compared with those patients with a moderate baseline renal impairment: 10 patients (32.3%) versus 21 patients (15.4%) (P 0.03; odds ratio 2.6, interquartile range ). Risk Factor Analysis for Persistent RD When considering base variables only, Cox regression analysis in 1097 patients who presented creatinine analysis at 3 months revealed nephropathy risk score 17 (very high risk group) and left ventricular ejection fraction 30% as significant risk factors for persistent RD (Table 4). When postprocedural parameters were included in the analysis, the increase of creatinine 1.5-fold within 5 days from base value also was significantly related to the development of persistent RD (Table 4). Short-Term Clinical Outcome There were 13 (0.9%) in-hospital deaths in the entire series of 1490 patients: 10 were in the CI-AKI group (5.6%) and 3 in the other group (0.2%; P 0.001). Only 3 patients in the CI-AKI group were treated with temporary hemofiltration. In the first 3 months of follow-up there were 18 other deaths, 3 patients (1.8%) in the CI-AKI group and 15 patients (1.2%) in the NO CI-AKI group (P 0.75 after exclusion of in-hospital deaths; P including in-hospital deaths). Long-Term Clinical Outcome The median follow-up period was 3.8 years (interquartile range, years) and was available for 1252 of the 1477 patients who survived to discharge. We note that all patients lost to follow-up were NO CI-AKI (online-only Data Supplement Table I). At Kaplan-Meier analysis, patients with CI-AKI persistent RD presented a worse survival rate at 5 years than both CI-AKI transient RD (P 0.021) and NO CI-AKI patients (P ); the relationship between CI- AKI transient RD and NO CI-AKI patients was significant (P ) (Figure 3, A). At Cox proportional hazard regression analysis, the risk of death was higher in CI-AKI persistent RD patients than CI-AKI transient RD (HR, 2.38; 95% CI, ; P ) and NO CI-AKI patients (HR, 4.84; 95% CI, ; P ). The combined end point of death, dialysis, and/or major cardiovascular events (stroke, non ST-segment elevation myocardial infarction, and ST-segment elevation myocardial infarction) at 5 years follow-up was statistically significant for CI-AKI patients with persistent RD in comparison with both CI-AKI transient RD (P 0.018) and NO CI-AKI (P ) and for CI-AKI transient RD in comparison with NO CI-AKI (P ) (Figure 3B). At Cox proportional hazard regression analysis, the risk of combined clinical end points was higher in CI-AKI persistent RD patients in comparison with CI-AKI transient RD (HR, 2.62; 95% CI, ; P ) and with NO CI-AKI patients (HR, 5.0; 95% CI, ; P ). Adverse clinical events occurred at follow-up that may have contributed to the deterioration of renal function toward end-stage renal disease are reported in the online-only Data Supplement Table II.

4 3102 Circulation June 26, 2012 Table 1. Demographic, Clinical, and Procedural Data in the 3 Groups NO CI-AKI (n 1310) CI-AKI With Transient RD (n 136) CI-AKI With Persistent RD (n 31) P Age, y 73 8* 76 8* Age 75 y, n (%) 635 (48.5)* 86 (63.2)* 20 (64.5) Female sex, n (%) 447 (34.1) 48 (35.3) 14 (45.2) 0.28 Body mass index, kg/m Diabetes mellitus, n (%) 292 (22.3)* 48 (35.3)* 10 (32.3) Hypertension, n. (%) 768 (58.6) 83 (61) 26 (83.9) 0.02 Anemia, n (%) 122 (9.3) 21(15.4) 7 (22.6) Multivessel disease, n (%) 723 (55.2) 90 (66.2) 23 (74.2) 0.03 Advanced congestive heart failure, n (%) 56 (4.3)* 12 (8.8)* 8 (25.8) Diuretic therapy, n (%) 397 (30.3)* 71 (52.2)* 24 (77.4) Unstable angina, n (%) 382 (29.2)* 82 (60.3)* 22 (71.0) Percutaneous coronary intervention, n (%) 714 (54.5) 73 (53.7) 22 (71.0) 0.18 Left ventricular EF, % 47 11* 42 11* Left ventricular EF 30%, n (%) 158 (12.1) 24 (17.6) 13 (41.9) Periprocedural hypotension, n (%) 23 (1.8) 3 (2.2) 3 (9.7) 0.02 Intra-aortic balloon pump, n (%) 26 (2.0) 3 (2.2) 1 (3.2) 0.65 Proteinuria, mg/dl 9 31* 23 52* Serum creatinine, mg/dl * * Serum creatinine 2.0 mg/dl, n (%) 32 (2.4)* 16 (11.8)* 4 (12.9) Maximal increase serum creatinine, mg/dl * * Creatinine increase 1.5-fold within 5 d 0 (0)* 53 (39.0)* 18 (58.1) from baseline, n (%) Mean creatinine clearance, ml/min 46 10* 41 12* Creatinine clearance 30 ml/min 94 (7.2)* 21 (15.4)* 10 (32.3) Contrast volume, ml ml 276 (21.1) 38 (29.9) 4 (12.9) ml 652 (49.8) 57 (41.9) 12 (38.7) ml 268 (20.5) 27 (19.9) 11 (35.5) 300 ml 114 (8.7) 14 (10.3) 4 (12.9) Contrast volume-to-creatinine clearance ratio * * Contrast nephropathy risk score * * Score (20.5) 12 (8.8) 1 (3.2) Score (52.1) 53 (39.0) 10 (32.3) Score (25.3) 68 (50.0) 16 (51.6) Score (2.1) 3 (2.2) 4 (12.9) Data are presented as mean value SD, or n (%) of patients. RD indicates renal damage; EF, ejection fraction; CI-AKI, acute kidney injury after contrast medium. *NO CI-AKI versus CI-AKI with transient RD group, P (Bonferroni correction). NO CI-AKI versus CI-AKI with persistent RD group, P (Bonferroni correction). CI-AKI with transient RD versus CI-AKI with persistent RD group, P (Bonferroni correction). Predictors of Long-Term Mortality, Dialysis, and Major Cardiovascular Events At the Cox regression analysis in 1252 patients with longterm follow-up (Table 5), CI-AKI persistent RD was shown to be an independent predictor of 5-year outcome. Table 5 shows a 2.5-fold increase in the risk of mortality, dialysis, and/or major cardiovascular events in persistent RD subjects and a 1.6-fold increase in CI-AKI transient RD over NO CI-AKI patients (P 0.001). Additional covariates, identified as independent predictors of long-term outcome in multivariable analysis, were age 75 years, ejection fraction 40%, and baseline creatinine clearance 45 ml/min (Table 5). Discussion Contrast-induced nephropathy occurs in 2% to 25% to 30% of patients undergoing diagnostic and therapeutic radiographic procedures. 2,3 This wide range depends on the cohort studied, and on the definition used to identify kidney injury, as well. 4 In recent years, there has been a growing interest in this acute adverse event, and a cause-and-effect relationship has been

5 Maioli et al Persistent Renal Damage After Coronary Angiography 3103 Figure 2. The time course of mean creatinine values. The time course of mean creatinine values in NO CI-AKI patients (F), CI-AKI patients with transient renal damage (f), and CI-AKI patients with persistent renal damage (Œ) (analysis of variance for repeated measures between groups, P 0.011). The bars give SD for each measurement. CI-AKI indicates acute kidney injury after contrast medium; RD, renal damage. identified between CI-AKI and long-term cardiovascular outcome. 1,9 11 However, evolution of renal function in patients after hospital discharge has not been studied. The results of this observational study showed that persistent RD, defined as a decrease of creatinine clearance by 25% over baseline at 3 months after contrast medium administration, occurs in only 2% of all patients with moderate-tosevere renal impairment at baseline. This rate rises to 18.6% in the subgroup of patients with moderate-to-severe baseline renal impairment who developed CI-AKI and survived to discharge. These relative figures can be relevant in terms of absolute numbers when considering the increasing volumes of diagnostic and therapeutic procedures requiring contrast Table 2. Variations of Renal Function in CI-AKI Patients at 3 Months Baseline (180 Pts) medium in high-risk patients. Moreover, the present study confirms that patients developing CI-AKI have a worse long-term outcome, particularly when their renal function remains permanently even more impaired. CI-AKI and Short-Term Outcome It is known that patients with CI-AKI have a higher shortterm risk of adverse events in comparison with patients without CI-AKI. 1,3,4 In particular, patients with CI-AKI showed up to 5-fold higher risk of death in the short term, 6,7 and CI-AKI was found to be an independent predictor of 1-year mortality. 23 The negative prognostic impact of CI-AKI is certainly related to some risk markers such as baseline Peak (180 Pts) 1mo (170 Pts) 3mo (167 Pts) Serum creatinine Serum creatinine, mg/dl Serum creatinine 2.0 mg/dl 23 (12.8) 92 (54.1) 35 (20.6) 31 (18.6) Creatinine absolute variation, mg/dl Creatinine clearance Creatinine clearance, ml/min Creatinine clearance 30 ml/min 35 (19.4) 110 (64.7) 45 (26.5) 38 (22.8) Decreased creatinine clearance 25% (22.9) 31 (18.6) Creatinine clearance relative change, % Data are presented as mean value SD or n (%) of patients. Pts indicates patients; CI-AKI, acute kidney injury after contrast medium.

6 3104 Circulation June 26, 2012 Table 3. Basal and 3-Month Mean Creatinine Clearance in CI-AKI Patients Baseline 3 mo Variation, % P Creatinine clearance ml/min group All patients, n Persistent RD group, n 21 Creatinine clearance 30 ml/min group All patients, n Persistent RD group, n Data are presented as mean value SD. RD indicates renal damage; CI-AKI, acute kidney injury after contrast medium. renal function, diabetes, hypertension, low ejection fraction, hemodynamic instability, or heart failure that are individually strong predictors of adverse cardiovascular events in the general population, and in patients with a previous coronary event, as well. The results of this study confirm and further support previously published data, showing a higher shortterm mortality rate in CI-AKI than in NO CI-AKI patients. Persistent RD After CI-AKI The results of the present study show that in the majority of cases CI-AKI is transient, and a complete or near-complete recovery of baseline renal function occurs within 3 months, in agreement with a previous article. 18 However, some patients with CI-AKI ( 20% of our population) experience persistent and clinically relevant reduction of renal function associated with a worse prognosis. Only 0.9% of patients without CI-AKI showed worsening of renal impairment at 3 months, an expression of disease progression independent of contrast medium renal toxicity. Consistent with these results, the Alberta registry showed that patients who develop AKI following coronary angiography are at increased risk for progressive long-term loss of kidney function. 24 In this large registry, persistent RD at 3 months after angiography, defined as an increase in serum creatinine 50% or 0.3 mg/dl above baseline, occurred in 33.2% of patients with CI-AKI (defined as above). When applying this definition to the population of the present study, Table 4. Multivariable Cox Regression Model of Predictors of 3-Month Persistent Renal Damage Significant Variables Hazard Ratio 95% CI P Model 1: baseline parameters Contrast nephropathy risk score Left ventricular ejection fraction 30 % Model 2: baseline and hospital course parameters Contrast nephropathy risk score Left ventricular ejection fraction 30 % Increase of serum creatinine 1.5-fold within 5 d from baseline value the incidence of persistent RD at 3 months is 17.1%. This difference can be explained by considering that populations were selected according to different criteria, because the Alberta registry included patients with better baseline renal function (estimated glomerular filtration rate 90 ml/min). Moreover, enrolment in the registry was not consecutive and included only those patients with creatinine assessed both pre- and postangiography; this probably led to an overestimation of the group of patients with renal derangement, because low-risk patients did not undergo postangiographic creatinine dosage. A number of mechanisms may be involved in the association between CI-AKI and progressive loss of kidney function following coronary angiography and/or percutaneous coronary intervention. First, the association may be due to the impact of numerous comorbidities (hypertension, diabetes mellitus, proteinuria, reduced left ventricular function/congestive heart failure, or later stages of chronic kidney disease). Second, patients who develop CI-AKI may be more vulnerable to other processes that lead to progressive kidney disease, such as atheroemboli or persistent microvascular RD after an acute episode of ischemic tubular injury. 25 Moreover, during the course of care, these same patients can experience repeated bouts of AKI (for recurrent exposures to contrast media or recurrent acute clinical events) that may contribute to the deterioration of renal function toward end-stage renal disease The results of the present study are clinically relevant because they point to the importance of early identification of those patients more likely to develop persistent renal impairment after angiography. In the present study, nephropathy risk score 17 (very high risk group), left ventricular ejection fraction 30%, and relative increase of serum creatinine 1.5-fold within 5 days from basal value were predictors of chronic RD. Patients sharing these features need to be more closely followed and might benefit from more aggressive renoprotective therapies with drugs (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins) known to slow down the progression of chronic kidney disease. 29 CI-AKI and Long-Term Outcome It has been assumed by many authors that CI-AKI identifies patients with a greater burden of comorbidity and that the association with increased mortality and long-term adverse outcome in patients who develop CI-AKI reflects that burden. 5 Moreover, chronic kidney disease by itself is a strong risk factor for long-term cardiovascular events. 3 A previously published meta-analysis described an exponential relation between the severity of renal dysfunction and the risk for all-cause mortality. 30 Accordingly, it is conceivable that a stable reduction of glomerular filtration can be one of the factors contributing to the worse prognosis seen in patients who develop CI-AKI. Recent prospective randomized trials in which an intervention reduces both the incidence of CI-AKI and long-term adverse outcomes suggest that CI-AKI may directly contribute to an increased risk of cardiovascular and renal adverse events. 10,31 Moreover, episodes of acute kidney injury predis-

7 Maioli et al Persistent Renal Damage After Coronary Angiography 3105 Figure 3. A, Survival curves (Kaplan-Meier analysis) for mortality at 5 years; the end point of death was statistically significant between patients with NO CI-AKI versus CI-AKI transient RD (P ) and versus CI-AKI persistent RD (P ) and between CI-AKI transient versus persistent RD (P 0.021). B, Survival curves (Kaplan-Meier analysis) for combined end points (mortality, dialysis, and/or major adverse cardiovascular event [stroke, ST-segment elevation myocardial infarction, and non ST-segment elevation myocardial infarction]); the end point was statistically significant between patients with NO CI-AKI versus CI-AKI transient RD (P ) and versus CI-AKI persistent RD (P ) and between CI-AKI transient versus persistent RD (P 0.018). CI-AKI indicates acute kidney injury after contrast medium; RD, renal damage. pose patients to long-term loss of kidney function. 32 Longterm follow-up of patients who develop CI-AKI confirms that they experience a greater fall in glomerular filtration rate in comparison with individuals who do not experience CI-AKI. 33 In the Alberta registry, 11 the retrospective study cohort included a large number of patients who received coronary angiography who were followed for up to 39 months. CI-AKI was independently associated with a 2-fold increase in the risk of death, 4-fold increase in the risk of progression to end-stage renal disease, 1.5-fold increase in the risk of hospitalization for heart failure, and 2-fold increase in the risk of hospitalization with acute renal failure. Furthermore, the risk of these outcomes increased in a graded manner with increasing severity of AKI. As in our study, these results demonstrate that the occurrence of AKI identifies patients at higher risk for subsequent adverse cardiovascular and renal events and suggest that targeting these patients for careful outpatient management after coronary angiography may lead to improved long-term outcome. Persistent RD After CI-AKI and Long-Term Outcome The present study confirms that small decrements in renal function in CI-AKI patients, even if transient, are associated with increased mortality. Moreover, the subgroup of patients with persistent RD showed an even worse prognosis. It is possible that the development of reversible CI-AKI may be a marker of a limited cardiorenal reserve in patients with chronic kidney disease who often have other comorbidities, possibly leading to an increased risk for subsequent long-term mortality. In the subgroup of CI-AKI patients with persistent renal impairment after contrast administration, the further reduction in glomerular filtration rate might amplify the risk of long-term adverse events. Study Limitations The main limitation of the present study is the relatively small sample size. In fact, the low rate of persistent RD after contrast medium implies the need for a large population to

8 3106 Circulation June 26, 2012 Table 5. Multivariable Cox Regression Model of Predictors of 5-Year Outcome Significant Variables Hazard Ratio 95% CI P Mortality Left ventricular ejection fraction 40 % Persistent RD Baseline creatinine clearance ml/min Age 75 y Transient RD Mortality, dialysis, and major cardiovascular events Persistent RD Left ventricular ejection fraction 40 % Transient RD Baseline creatinine clearance ml/min Age 75 y RD indicates renal damage. assess its short- and long-term prognostic implications. However, our population is consecutive and well representative of everyday practice, so that it contributes to shedding some light on the epidemiology and time course of contrastinduced chronic RD. Another limitation is the lack of creatinine values at 3 months in 29% of patients who did not develop CI-AKI (18 certified deaths and 362 who did not present). However, baseline clinical characteristics and procedural data of these patients were not significantly different from those of patients regularly followed over time. Finally, we do not know the pharmacological treatments (ie, diuretics, angiotensin-converting enzyme inhibitors) at the time of final clinical follow-up. Conclusion The results of the present article confirm that, in patients with moderate-to-severe renal dysfunction, CI-AKI is not simply a transient, benign creatininopathy, but rather a direct cause of worsening chronic renal function, and it identifies a subgroup of patients with an increased risk of cardiovascular events. These data suggest that caution should be placed on the selection of patients with chronic kidney disease for diagnostic/therapeutic procedures that involve contrast exposure. After appropriate assessment of clinical indications for contrast-based procedures, it is important to identify those patients at higher risk by use of appropriate scores, to implement all possible preventive measures (such as hydration, statins, lowest contrast dose possible), and to adopt a careful postprocedural follow-up of renal function. Moreover, after CI-AKI, recurrent exposures to contrast media should be avoided wherever possible and drugs possibly helpful in slowing down the progression of renal disease should be started. Last, institutions should start to consider prevention of CI-AKI a quality improvement goal. Acknowledgments We thank Luisa Toschi, RN, and Carlo Micheletti, RN, Division of Cardiology, Misericordia e Dolce Hospital, Prato, Italy (neither of whom was compensated for their help), for their careful monitoring and recording of data.. None. Disclosures References 1. 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