Contrast-induced acute kidney injury: how should at-risk patients be identified and managed?

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1 THOROUGH CRITICAL APPRAISAL JNEPHROL 2010; 23( 04) : Contrast-induced acute kidney injury: how should at-risk patients be identified and managed? Maurice Laville, Laurent Juillard Department of Nephrology, Hôpital Edouard Herriot and Unité, Université de Lyon, Lyon - France Ab s t r a c t Contrast-induced acute kidney injury (CIAKI)* refers to a sudden deterioration in renal function associated with the use of iodinated contrast media. CIAKI can lead to increased morbidity and mortality. Risk of CIAKI is low in the general population but increased in patients with risk factors, which include chronic kidney disease (particularly secondary to diabetes mellitus) and advanced age. Screening for risk factors and implementation of prevention practices in at-risk patients is recommended. Patients at risk of CIAKI because of chronic kidney disease can be identified by serum creatinine measurement, although, preferably, this should be applied to estimate glomerular filtration rate; screening questionnaires or risk scoring can also identify at-risk patients. Current best practice calls for intravenous periprocedural volume expansion in at-risk patients, but this is not practical in all clinical settings. No pharmacological approach has been demonstrated to offer consistent protection. Volume/ dose of contrast agent should be the lowest needed to achieve a diagnostic result. The use of iso-osmolar contrast media is recommended for high-risk patients, because recent controlled clinical trials in coronary procedure settings have shown a lower nephrotoxicity of iodixanol, as compared with several low-osmolar contrast agents. However, additional studies involving a larger selection of iso- and low-osmolar contrast media are needed, particularly with intravenous use for computed tomography scans, if their use in this patient population is to be optimized. Key words: Computed tomography, Contrast-induced acute kidney injury, Contrast-induced nephropathy (CIN), Coronary angiography, Iodinated contrast agent, Percutaneous coronary intervention In t r o d u c t i o n Contrast-induced acute kidney injury (CIAKI), or contrastinduced nephropathy (CIN), refers to an abrupt deterioration in renal function associated with the administration of iodinated contrast media (CM). As proposed by the Acute Kidney Injury Network, CIAKI is characterized by an acute (within 48 hours) 26.5 μmol/l (0.3 mg/dl) or 50% increase in baseline serum creatinine (SCr), or a reduction in urine output of <0.5 ml/kg per hour for more than 6 hours (1). The most common definition of CIN is a 44.2 μmol/l (0.5 mg/dl) or 25% increase in baseline SCr within 3 days of intravascular CM exposure, in the absence of an alternative etiology (2). The SCr increase peaks between days 3 and 5, with levels usually returning to baseline within 1 to 3 weeks (3). Although transient in the majority of cases, persistent SCr elevation and the underlying renal impairment this reflects can lead to increased morbidity and even death in some patients with CIAKI. Technological advances in imaging modalities, expanding imaging applications and an aging world population are all responsible for increasing the exposure of patients to iodinated contrast agents and their attendant risk for CIA- KI. A broad spectrum of patient populations is affected, including cardiology patients undergoing invasive coronary angiography and/or percutaneous coronary intervention (PCI); interventional radiology patients undergoing, for example, image-guided oncological procedures; and * We use the term CIAKI throughout this report in keeping with recent recommendations that it replace CIN (see, e.g., Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med. 2007;33: ) 2010 Società Italiana di Nefrologia - ISSN

2 Laville and Juillard: Contrast-induced AKI (14) Fig. 1 - Intermediate risk (death/nfmi) NSTE- MI-ACS patient scheduled for coronary angiography/pci next day: flow chart illustrating management of CIAKI risk in the interventional cardiology setting. BP = blood pressure; CHF = congestive heart failure; CIAKI = contrastinduced acute kidney injury; CKD = chronic kidney disease; CM = contrast medium; DM = diabetes mellitus; ECG = electrocardiogram; egfr = estimated glomerular filtration rate; HCTZ = hydrochlorothiazides; HR = heart rate; MDRD = Modification of Diet in Renal Disease; MI = myocardial infarction; NFMI = nonfatal myocardial infarction; NSAIDs = nonsteroidal antiinflammatory drugs; NSTEMI-ACS = non- ST segment-elevation myocardial infarction acute coronary syndrome; PCI = percutaneous coronary intervention; SCr = serum creatinine. (15, 16, 17) (18, 19) patients from a variety of different specialties undergoing diagnostic computed tomography (CT). This exposure occurs in a range of clinical settings inpatient, critical care, outpatient and emergency department. The heterogeneity in CIAKI risk across these diverse populations and clinical settings suggests that a single algorithm for optimizing renal safety during CM-enhanced procedures would not be effective, as recently reviewed (4). CIAKI is associated with increased morbidity and mortality: longer hospital stays; higher rates of in-hospital events; and higher rates of in-hospital 1-year and 5-year mortality have all been reported (5, 6). CIAKI requiring dialysis carries a particularly poor prognosis, with in-hospital mortality and 2-year survival at 35.6% and 18.8%, respectively (7). In the interventional cardiology setting CIAKI is a recognized predictor of higher mortality (7, 8), and its incidence serves as a quality indicator for PCI outcomes (9). Related to this, recent findings indicate that CIAKI in the CT setting is also an independent risk factor for increased 30-day (odds ratio [OR] = 3.40; 95% confidence interval [95% CI], ; p<0.001) and overall mortality (hazard ratio [HR] = 1.57; 95% CI, ; p<0.001) (10). Given the poor prognostic implications of CIAKI, identifying individuals who are at increased risk becomes essential. In this way, the benefit to risk ratio of the CM-enhanced procedure can be evaluated, and appropriate preventive measures adopted, as needed. Awareness of the risk factors for CIAKI and their impact is highly variable among radiologists (11), and screening and prevention practices vary within and across clinical settings in which iodinated CM are administered (12, 13). This report focuses on CIAKI risk across the different clinical settings in which contrast-enhanced procedures are administered. Using 2 case studies for illustration (Figs. 1 and 2), it highlights the more recent literature on factors that influence risk and how to identify patients who are at risk, as well as the potential role of judicious CM selection in minimizing the occurrence of CIAKI. Wh o is a t r i s k f o r CIAKI? Patient risk factors The most important and well-established patient-related risk factors for CIAKI are chronic kidney disease (CKD), particularly CKD combined with diabetes mellitus (DM), 388

3 JNEPHROL 2010; 23( 04) : (20) (20) Fig. 2 - Patient referred for outpatient diagnostic computed tomography (CT) to rule out deep infection responsible for chronic fever: flow chart illustrating management of CIAKI risk in the outpatient setting. C&G = Cockcroft-Gault; CKD = chronic kidney disease; CM = contrast medium; DM = diabetes mellitus; egfr = estimated glomerular filtration rate; MDRD = Modification of Diet in Renal Disease; NSAID = nonsteroidal antiinflammatory drug; SCr = serum creatinine. [21] [22] and advanced age (2, 23, 24). These factors have become increasingly prevalent worldwide (25-27). For patients in high-risk clinical scenarios, CIAKI incidences as high as 50% have been reported (28). In addition to the traditional risk factors CKD with or without DM, and age several potential new markers of CIAKI risk have been identified in patients undergoing coronary intervention. These include metabolic syndrome, prediabetes, hyperuricemia, hypertriglyceridemia and impaired fasting glucose (24). The sex of the patient may also be a significant factor based on recent findings demonstrating that women 65 years of age are at greater risk of CIAKI following coronary angiography than their male counterparts (29). From these data, it appears that a large proportion of patients undergoing cardiovascular imaging procedures have either impaired renal function or characterized risk factors for CIAKI, or both. Procedural (non-cm) risk factors The risk of CIAKI may also vary according to the particular contrast-enhanced procedure involved. This recognizes that limited comparisons can be made between different clinical settings, where patient populations differ in their degree of CIAKI risk, where the length of contrastenhanced procedures and the volume of CM administered vary according to application, and where implementation of preventive measures may or may not be feasible. The route of CM administration intra-arterial versus intravenous is a procedure-dependent parameter that may significantly impact a patient s risk of CIAKI. Compared with contrast-enhanced procedures requiring intra-arterial administration, intravenous CM administration as part of a CT procedure appears to carry a low risk of CIAKI, even in patients with CKD. In 1 registry study involving 400 outpatients (SCr μmol/l; mg/dl) who underwent iodixanol-enhanced multidetector CT angiography according to a standardized protocol that included prophylactic use of intravenous volume expansion and N-acetylcysteine, only 7 patients (1.75%) experienced CIAKI (defined as an SCr increase 44.2 μmol/l; 0.5 mg/dl); of these, 5 were elderly (>80 years) with DM (30). In this study, a combination of preventive measures including volume expansion, pharmacological prophylaxis and use of the iso-osmolar CM iodixanol was associated with a low incidence of CIAKI in at-risk 389

4 Laville and Juillard: Contrast-induced AKI patients administered intravenous contrast in the outpatient CT setting. This study notwithstanding, routine administration of preventive intravenous fluids is generally considered impractical in most outpatient CT settings because of high throughput as well as limited space and health care resources/personnel. The relative safety of intravenous CM administration for outpatient CT procedures conducted without the benefit of prophylactic volume expansion is suggested by findings from another recent study, where 86% of patients were administered iodixanol and 14% received the low-osmolar CM (LOCM) iohexol. Among outpatients with mild-to-moderate CKD (egfr >45-59 ml/ min per 1.73 m 2 ), the incidence of CIAKI following CT was <1% (SCr increase 44.2 μmol/l; 0.5 mg/dl); this low incidence occurred without the benefit of preventive volume expansion, since 94% of this patient subpopulation received no preprocedure and postprocedure intravenous fluid. The incidence of CIAKI was higher, however, among outpatients with more severe CKD and among hospitalized patients with mild CKD (31). These findings suggest that the use of less nephrotoxic (i.e., low- or iso-osmolar) CM among outpatients with only mildly reduced kidney function may reduce the risk of CIAKI following CT so that volume expansion under these particular circumstances could be less critical (31). Finally, it is worth noting that although the risk of CIAKI associated with intravenous CM administration may be lower than with intra-arterial administration (32), additional findings in a study already referred to suggest that CIAKI-related mortality may be higher after intravenous than after intra-arterial administration (10). Identifying patients at risk for CIAKI How should renal impairment be measured for risk factor assessment? Although SCr concentration is commonly used as an indicator of renal impairment (12), estimated glomerular filtration rate (egfr) provides the best indication of renal function. Serum creatinine level alone should not be used to evaluate the extent of baseline renal damage and therefore CIAKI risk, since this measure is affected by a variety of physiological factors independent of the GFR (22). Measurement of GFR using radionuclide tracer clearance over a 24-hour urine collection is impractical in most clinical settings, but GFR can be estimated (egfr) from SCr using prediction equations. The Cockcroft- Gault equation provides an estimate of creatinine clearance (CrCl) from SCr with corrections for age, weight and sex (21), while the Modification of Diet in Renal Disease (MDRD) study equation gives egfr, additionally taking ethnicity into account (22). Several comparative evaluations of these equations against reference methods for GFR measurement suggest that the MDRD equation provides a more accurate estimation of GFR in elderly and obese patients (33). These equations identify patients with impaired renal function at risk of CIAKI who would be missed using a simple SCr cutoff value (34, 35). For example, as demonstrated for a cohort of emergency department patients with acute abdominal pain warranting a CT scan, the commonly used 133 μmol/l (1.5 mg/ dl) SCr cutoff threshold failed to identify 40% of patients at risk of CIAKI (34). Cystatin C has been identified as a promising marker of kidney function that is independent of sex and body mass index and, compared with SCr, is less influenced by extrarenal factors (36). Cystatin C may be a more sensitive measure of mild decreases in GFR and appears to be a more accurate marker of early CKD than SCr or SCrbased egfr in patients with DM (36, 37). In a study of patients undergoing cardiac catheterization, cystatin C was the most useful predictor of CIAKI, with a cutoff of >1.2 mg/l detecting CIAKI with 95% sensitivity and 84% sensitivity (38). A variety of other novel serum and urinary biomarkers of renal function (including neutrophil gelatinase-associated lipocalin [NGAL], interleukin-18 and glutathione-s-transferase) have been proposed, but these still require validation in general and, specifically, as markers of CIAKI risk (39). Related to this, urinary proteomic analysis has recently shown promise as a technique for identifying novel biomarkers of renal function predictive of CIAKI (40). What do guidelines say about who is at risk and how to identify them? Guidelines on CIAKI and identifying patients at risk have been issued by various national and international medical organizations. The European Society of Urogenital Radiology (ESUR) guidelines on CM recommend that egfr be measured in selected patients 7 days preceding CM administration to identify those at risk (egfr <60 ml/min per 1.73 m 2 ). The patients specified are those with a known egfr <60 ml/min per 1.73 m 2 or with an elevated SCr; diabetic patients taking metformin; patients scheduled to receive intra-arterial CM; and those with a history suggesting the possibility of 390

5 JNEPHROL 2010; 23( 04) : reduced GFR. In the case of emergency settings, if it is not possible to defer the procedure until an egfr is obtained, a patient should be assumed to be at risk and treated appropriately (2). The American College of Radiology (ACR) guidelines recommend measurement of SCr before intra-arterial administration of CM in patients with a history (or a family history) of kidney disease; DM; paraproteinemia syndromes; collagen vascular disease; prior renal surgery or patients on certain medications (metformin, nonsteroidal antiinflammatory drugs or nephrotoxic antibiotics) (14). Using risk scores to identify patients at risk Risk scores incorporating the multiple factors that increase risk of CIAKI and their relative weights may be of clinical utility in evaluating risk in individual patients. Risk scores have been developed for patients undergoing coronary intervention, but the correlation between risk factors and CIAKI incidence established for the interventional cardiology setting has not yet been shown for CT (41-44). Risk scores can be applied to characterize study populations in clinical trials of CIAKI, facilitate interpretation of the results and permit comparison between study population risks across clinical trials (45-47). In the outpatient CT setting, simple screening questionnaires that focus on renal disorders and additional risk factors serve to identify patients at increased risk of CIAKI and may reduce the need for SCr measurement prior to administration of CM (20, 48). One study found that a screening questionnaire identified 99% of patients with SCr less than or equal to the value used as a cutoff for CM administration in the institution, suggesting such questionnaires could safely be used in place of SCr determination (20). This, of course, raises the question of whether procedures should be postponed pending egfr determination in patients screening positive, a decision in which the risk of delay must be balanced against the risk of renal damage (4). Practical considerations: how we do it In our institution, providing SCr measurements is mandatory to obtain a CT appointment. Our radiologists use the MDRD formula that does not include weight, as this information is often omitted from the clinician s request. If decreased egfr is detected late in at-risk patients, the benefit of CM injection is challenged, and volume expansion is started, even if reduced in time (3 hours) and with limited volume (500 ml). Minimizing r e n a l i n j u r y in h i g h-r i s k p a t i e n t s In patients at high risk of CIAKI, an alternative imaging method not involving iodinated CM should be considered (2). Nephrotoxic drugs and diuretics should be stopped at least 24 hours before CM administration (2). Despite numerous clinical trials and meta-analyses, the utility of the often-used antioxidant N-acetylcysteine in CIAKI prophylaxis remains unclear, not least because the statistical design of many the relevant studies has been criticized (49, 50). Similarly, there is little consensus from trials evaluating other pharmacological agents for CIAKI prophylaxis, and, to date, none can be recommended. While CM can be removed by dialysis there is no evidence that this protects patients with preexisting renal impairment, from CIAKI (2). Most importantly, the involvement of a nephrologist in the preprocedure and postprocedure care of the high-risk patient is essential. Prophylactic volume expansion Periprocedural volume expansion has an established role in reducing the risk of CIAKI, the rationale being to preserve renal blood flow and minimize exposure of tubular epithelial cells to CM (50). However, adequate trials have yet to ascertain the most effective protocol (47). There is some evidence that sodium bicarbonate may be superior to normal saline but against a background of study heterogeneity and probable publication bias (51). The ESUR guidelines recommend intravenous infusion of normal saline at 1 ml/kg body weight for at least 6 hours before and after the procedure (2), a regimen that is unlikely to be practical in all clinical settings. Although intravenous volume expansion has been reported to be superior to bolus volume expansion during the procedure and to unrestricted oral fluid intake in prevention of CIAKI (52, 53), a prospective trial in at-risk patients (mean estimated CrCl 37 ml/min per 1.73 m 2 ) undergoing a variety of radiological procedures found that oral saline hydration was as effective as intravenous saline hydration (54). An oral volume expansion regimen is more convenient for patients, less costly, and may enable more procedures to be carried out under outpatient conditions (54). The impact of CM dose/volume CM volume and dose can affect the risk of CIAKI. For all patients, whether or not they are at increased risk of CIAKI, 391

6 Laville and Juillard: Contrast-induced AKI the lowest dose of CM consistent with a diagnostic result should be used. Volume should be limited to no more than 100 ml in patients with egfr <60 ml/min per 1.73 m 2, recognizing that a volume as small as 30 ml can cause CIAKI in patients at very high risk (28). As recently reported, the use of ultralow volumes (<50 ml) in patients with CKD undergoing coronary angiography was associated with a reduction in CIAKI, with each 20-mL increment leading to an incremental 2 increase in risk (55). Volume limits normalized to body weight and SCr or to CrCl may provide a more accurate indication of the threshold above which CIAKI risk is substantially increased (15, 16, 56). In a recent study involving patients who underwent primary PCI for ST-segment elevation myocardial infarction, those who received more than a maximum CM dose (ml) of 5 body weight (kg)/scr had a threefold higher incidence of CIAKI than patients receiving no more than the maximum dose (29% vs. 10%, p=0.001, for patients with normal renal function; 60% vs. 21%, p=0.001, for those with CKD) (17). A recent meta-analysis showed a very close relationship between the dose of iodine per ml of GFR, and the occurrence of CIN (57). Issues related to CM volume and CIAKI risk are not limited to the interventional cardiology setting. Advances in CT technology that have reduced radiation exposure through shorter scan times have undoubtedly contributed to the increased use of diagnostic and interventional CT procedures and the likelihood that an individual patient will undergo multiple CT scans in the course of his or her care. When these involve several contrast-enhanced CT scans over a short period of time, safety issues related to maximum CM volume become a legitimate concern. Th e c o n t r a s t in c o n t r a s t-i n d u c e d acute kidney injury CIAKI in the absence of CM Studies evaluating the influence of CM on CIAKI incidence rarely include control groups i.e., patients not receiving CM. It has been argued that SCr fluctuations may occur in selected patient subgroups in the absence of CM exposure or may be caused by an aspect of the imaging procedure other than enhancement so that CIAKI may be less frequent and severe than previously assumed (58, 59). This has recently been addressed in a large retrospective study (n>11,500) that compared the real world incidence of AKI in patients undergoing CT procedures with a contrast agent or unenhanced (control group); patients received either the iso-osmolar CM iodixanol or the LOCM iohexol for enhancement. The acute kidney injury incidence among control patients closely paralleled the use of iodixanol across the entire range of baseline SCr concentrations studied (53 to >177 μmol/l; 0.6 to >2.0 mg/dl) whereas it paralleled the use of iohexol only for baseline SCr values up to 159 μmol/l (1.8 mg/dl), above which CIAKI incidences with iohexol were higher (60). These findings not only support the view that background SCr fluctuation can contribute to the elevated SCr levels in patients with CIAKI, but they also suggest a benefit of iso-osmolar CM in high-risk patients undergoing a contrast-enhanced CT examination. Comparative CM nephrotoxicity: evidence from CIAKI trials ( ) Recently, the comparison of the renal safety of iso-osmolar CM iodixanol versus a variety of LOCMs has been addressed by several controlled trials (Tab. I). In patients at-risk of CIAKI who underwent coronary or aortofemoral angiography, the Nephrotoxicity in High- Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media (NEPHRIC) trial found that compared with iohexol, iodixanol was associated with a significantly smaller increase in SCr (the primary end point) and a significantly lower incidence of CIAKI (64). Similarly, in 2 other trials involving patients with CKD in the setting of coronary angiography, the incidence of CIAKI was significantly lower with iodixanol than with either ioxaglate (Renal Toxicity Evaluation and Comparison Between Visipaque and Hexabrix In Patients with Renal Insufficiency Undergoing Coronary Angiography [RECOVER] trial) (63) or iopromide (65) (Tab. I). Two trials failed to demonstrate any significant difference in CIAKI incidence between iodixanol and LOCM comparators in interventional cardiology settings (66, 67). The Cardiac Angiography in Renally Impaired Patients (CARE) Study (66) showed the lowest rates of CIAKI among the trial conducted in similar settings, likely from the use of bicarbonate for volume expansion in all patients: this lower-than-expected CIAKI incidence may have obscured potential differences between the CM. The Visipaque Angiography/Interventions with Laboratory Outcomes in Renal Insufficiency (VALOR) Trial (67) observed a lower nonsignificant (14.7% vs. 20.0%; p=0.06) peak creatinine change in patients receiving iodixanol, and a significant benefit in DM patients. Trials conducted in patients with normal or less impaired renal function did not show any difference between iso-osmolar CM and LOCM com- 392

7 JNEPHROL 2010; 23( 04) : TABLE I INCIDENCE OF CIAKI IN RANDOMIZED CONTROLLED TRIALS ( ) OF IODIXANOL (IOCM) VERSUS LOCM COMPARATORS Renal SCr measurement End point outcome LOCM function (inclusion criteria) DM (%) Primary end point Fixed Multiple time points Iodixanol LOCM p Value Coronary angiography/pci trials: normal renal function Hardiek et al, 2008 (61) (n=122) Iopamidol Normal SCr 177 μmol/l (2 mg/dl) % increase in SCr over days 1, 3 and 7 (days 1, 3 and 7) 13.0% 20.8% NS* Feldkamp et al, 2006 (62) (n=221) Iopromide Normal GFR >50 ml/min 38 25% increase in SCr at 48 hours No 8.6% 6.9% NS Coronary angiography/pci trials: CKD RECOVER Jo et al, 2006 (63) (n=300) Ioxaglate CrCl 60 ml/ min 35 Rise in SCr 25% or 44.2 μmol/l (0.5 mg/dl) within 2 days (days 1 and 2) 7.9% 17.0% NEPHRIC Aspelin et al, 2003 (64) (n=129) Iohexol SCr μmol/l ( mg/dl) or CrCl 60 ml/ min 100 Peak increase in SCr day 0 3 (days 2, 3 and 7) 0.13 mg/dl 0.55 mg/dl Rise in SCr Nie et al, 2008 (65) (n=208) Iopromide CrCl 60 ml/ min 27 25% or 44.2 μmol/l (0.5 mg/dl) within 72 (days 2 and 3) 5.7% 16.7% hours CARE Solomon et al, 2007 (66) (n=414) Iopamidol Moderate-severe CKD egfr ml/ min 41 >44.2 μmol/l (0.5 mg/dl) rise in SCr at hours No No 6.7% 4.4% NS to be continued 393

8 Laville and Juillard: Contrast-induced AKI TABLE I CONTINUED LOCM Renal function (inclusion criteria) DM (%) Primary end point SCr measurement Multiple Fixed time points End point outcome Iodixanol LOCM p Value VALOR Rudnick et al, 2008 (67) (n=337) Ioversol Stable CKD Men: SCr 150 μmol/l (1.7 mg/dl) Women: SCr 133 μmol/l (1.5 mg/dl) 52 >44.2 μmol/l (0.5 mg/dl) rise in SCr within 72 hours (24, 48 and 72 hours) 21.8% 23.8% NS CT trials: CKD PREDICT Kuhn et al, 2008 (68) (n=263) Iopamidol Moderate-severe CKD egfr ml/min per 1.73 m Rise in SCr 25% within hours No No 4.9% 5.6% NS ACTIVE Thomsen et al, 2008 (69) (n=148) Iomeprol Moderate-severe CKD SCr 133 μmol/l (1.5 mg/dl) or CrCl <60 ml/min) 20 Rise in SCr 44.2 μmol/l (0.5 mg/dl) at hours No No 6.9% 0% IMPACT Barrett et al, 2006 (70) (n=166) Iopamidol Moderate-severe CKD SCr 133 μmol/l (1.5 mg/dl) and/or CrCl 60 ml/min) 24 Rise in SCr 44.2 μmol/l (0.5 mg/dl) or 25% at hours No No 2.6% 3.9% 0% 3.9% NS NS Nguyen et al, 2008 (71) (n=117) Iopromide SCr 133 μmol/l (1.5 mg/dl) or GFR <60 ml/min 28 Peak rise in SCr days 1-3 (days 1, 2 and 3) μmol/l (-0.12 mg/dl) (day 1) 2.2 μmol/l (0.05 mg/dl) (day 1) Trials with a statistically significant outcome are shaded. CIAKI = contrast-induced acute kidney injury; CIN = contrast-induced nephropathy; CKD = chronic kidney disease; CrCl = creatinine clearance; CT = computed tomography; DM = diabetes mellitus; egfr = estimated glomerular filtration rate; GFR = glomerular filtration rate; IOCM = iso-osmolar contrast media; LOCM = low-osmolar contrast media; NS = not significant; PCI = percutaneous coronary intervention; SCr = serum creatinine. Trial acronyms: ACTIVE = Abdominal Computed Tomography: Iomeron 400 versus Visipaque 320 Enhancement; CARE = Cardiac Angiography in Renally Impaired Patients; IMPACT = Isovue-370 and Visipaque-320 in Renally Impaired Patients Undergoing Computed Tomography; NEPHRIC = Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media; PREDICT = Patients with Renal Impairment and Diabetes Undergoing Computed Tomography; RECOVER = Renal Toxicity Evaluation and Comparison Between Visipaque and Hexabrix In Patients with Renal Insufficiency Undergoing Coronary Angiography; VALOR = Visipaque Angiography/Interventions with Laboratory Outcomes in Renal Insufficiency. *Significantly higher CIAKI/CIN incidence ( 0.5 mg/dl increase in SCr) with iopamidol versus iodixanol at day 7 (8% vs. 0%, p=0.045). Significantly lower CIAKI/CIN incidence ( 0.5 mg/dl increase in SCr) with iodixanol versus ioxaglate (3.1% vs. 26.1%, p=0.002). Significantly smaller mean increase in SCr with iodixanol versus iopromide (0.02 ± 0.18 vs ± 0.29 mg/dl, p=0.02). Significantly lower mean post-scr increase with iopamidol versus iodixanol (0.07 ± 0.22 vs ± 0.23 mg/dl, p=0.032). In patients with DM, significantly lower mean peak % change in SCr with iodixanol versus ioversol (12.9% vs. 22.4%, p=0.01). Significantly lower proportion of patients with DM in iodixanol group (12.5%) versus iomeprol (27.6%), p=0.02. Significantly higher mean SCr change from baseline with iodixanol versus iomeprol (0.06 ± 0.27 vs ± 0.19 mg/dl, p=0.017). Significantly higher proportion of patients with DM in iodixanol group (37.7%) versus iopromide (17.9%), p= Significantly higher CIAKI/CIN incidence with iopromide versus iodixanol: 18.5% vs. 5.1%, p=0.037 ( 0.5 mg/dl increase in SCr); and 27.8% versus 8.5%, p=0.012 ( 25% increase in SCr). 394

9 JNEPHROL 2010; 23( 04) : parators (61, 72). Overall these results suggest a lower risk of CIAKI with iodixanol in high-risk patients undergoing CM-enhanced coronary interventions, as reflected in several cardiology and nephrology guidelines (18, 19, 73). Very recently, a 1-year follow-up analysis of a subset of patients from the CARE study observed an increased incidence of post-cin adverse events in patients who had received iodixanol (61). However, a different definition of CIN using cystatin C was used, and only the first adverse event was recorded for analysis, so a causality relationship is far from being demonstrated. Long-term prognosis of CIN especially regarding cardiovascular and renal outcomes is a very important issue which deserves further prospective investigations. In the CT setting, a recent clinical trial involving patients with CKD has demonstrated a benefit for iodixanol relative to iopromide in terms of renal safety, with iodixanol resulting in a significant decrease in SCr after the procedure, in addition to a significantly lower CIAKI incidence (71) (Tab. I). There was no significant difference in CIAKI between iodixanol and LOCM comparators in other CT settings (68, 70). One CT trial, Abdominal Computed Tomography: Iomeron 400 Versus Visipaque 320 Enhancement (ACTIVE), indicated a renal safety advantage of the LOCM iomeprol over iodixanol (69) (Tab. I). Although all patients in this trial had CKD, 4 of the 5 iodixanol patients who experienced CIAKI had a medical history that included chronic renal failure, and the extent to which this may have affected the outcome in these patients remains unclear. In addition, the ACTIVE trial, as well as the 2 inconclusive trials PREDICT (68) and IMPACT (70) used a single random measurement of SCr between 48 and 72 hours post-cm to determine the incidence of CIN. As recently reviewed in this journal, the disparity in findings across CIAKI trials may well be influenced by differences in clinical setting (coronary angiography/pci vs. CT), general and statistical features of study design, study population risk profiles (e.g., proportion of patients with CKD and DM), prophylaxis protocols (e.g., volume expansion and other prophylactic procedures), CM volume/dose and definition of CIAKI and its measurement (47). Issues such as statistical power related to study size or the extent to which preventive measures are used, are easily appreciated sources of inconsistent findings across different CIAKI trials. Other reasons are less intuitive. This is the case for variables related to the timing of postprocedure SCr measures, that is, when to test renal function to disclose CIAKI a question recently posed by others who have noted the wide variability in reported CIAKI incidences across studies (74). Co n c l u s i o n s Awareness of risk factors for CIAKI enables patients at increased risk to be identified by egfr assessment or through use of screening questionnaires addressing CKD and other known risk factors. Since most risk factors such as age, diabetes and previous renal impairment are not modifiable, attention should be given to minimize the risk in individual patients. This approach should be adapted to the patient s risk, to the specific risks of the procedure and to the clinical settings in which the procedure is performed. Stopping potentially nephrotoxic agents or those likely to aggravate CKD is always necessary, as is restoration of euvolemia. In highrisk patients, especially those submitted to intra-arterial CM injection for diagnostic/interventional vascular imaging procedures, active volume expansion and use of an iso-osmolar contrast agent should be associated with lowest possible CM volume and iodine dose. Such a patient- and procedure-adjusted combination of preventive measures offers maximal protection against CIAKI and its harmful consequences. Financial support: Editorial support was provided by Andy Brown, PhD, of PAREXEL International, with funding provided by GE Healthcare. Conflict of interest statement: M.L. received travel grants and consultant fees from GE Healthcare. L.J. had no conflict of interest to report. Address for correspondence: Prof. Maurice Laville Department of Nephrology Hôpital Edouard-Herriot EA INSERM ESPRI ERI 22 Université de Lyon Lyon, France laville@univ-lyon1.fr 395

10 Laville and Juillard: Contrast-induced AKI Re f e re n c e s 1. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11:R Thomsen HS. ESUR guidelines on contrast media, version 7.0. Heidelberg, Germany: European Society of Urogenital Radiology; Nikolsky E, Aymong ED, Dangas G, Mehran R. Radiocontrast nephropathy: identifying the high-risk patient and the implications of exacerbating renal function. Rev Cardiovasc Med. 2003;4(Suppl 1):S7-S Goldfarb S, McCullough PA, McDermott J, Gay SB. Contrastinduced acute kidney injury: specialty-specific protocols for interventional radiology, diagnostic computed tomography radiology, and interventional cardiology. Mayo Clin Proc. 2009;84: Dangas G, Iakovou I, Nikolsky E, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol. 2005;95: Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation. 2002;105: McCullough PA, Wolyn R, Rocher LL, Levin RN, O Neill WW. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med. 1997;103: Harjai K, Shenoy C, Raizada A, et al. Major adverse noncardiac events after PCI as predictors of long-term mortality. J Interv Cardiol. 2008;21: Moscucci M, Rogers EK, Montoye C, et al. Association of a continuous quality improvement initiative with practice and outcome variations of contemporary percutaneous coronary interventions. Circulation. 2006;113: From AM, Bartholmai BJ, Williams AW, Cha SS, McDonald FS. Mortality associated with nephropathy after radiographic contrast exposure. Mayo Clin Proc. 2008;83: Reddan D, Fishman EK. Radiologists knowledge and perceptions of the impact of contrast-induced nephropathy and its risk factors when performing computed tomography examinations: a survey of European radiologists. Eur J Radiol. 2007;66: Elicker BM, Cypel YS, Weinreb JC. IV contrast administration for CT: a survey of practices for the screening and prevention of contrast nephropathy. AJR Am J Roentgenol. 2006;186: Weisbord SD, Bruns FJ, Saul MI, Palevsky PM. Provider use of preventive strategies for radiocontrast nephropathy in high-risk patients. Nephron Clin Pract. 2004;96:c56-c Radiology. ACo. Manual on contrast media, version 6. Available at: Accessed April 9, Cigarroa RG, Lange RA, Williams RH, Hillis LD. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. Am J Med. 1989;86: Laskey WK, Jenkins C, Selzer F, et al. Volume-to-creatinine clearance ratio. J Am Coll Cardiol. 2007;50: Marenzi G, Assanelli E, Campodonico J, et al. Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality. Ann Intern Med. 2009;150: Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-st-elevation myocardial infarction: executive summary. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST- Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50: King SB III, Smith SC Jr, Hirshfeld JW Jr, et al focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation. 2008;117: Choyke PL, Cady J, DePollar SL, Austin H. Determination of serum creatinine prior to iodinated contrast media: is it necessary in all patients? Tech Urol. 1998;4: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16: Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. 2003;139: Detrenis S, Meschi M, Bertolini L, Savazzi G. Contrast medium administration in the elderly patient: is advancing age an independent risk factor for contrast nephropathy after angiographic procedures? J Vasc Interv Radiol. 2007;18: Toprak O. Conflicting and new risk factors for contrast-induced nephropathy. J Urol. 2007;178: World Health Organization. The world is growing fast: have we noticed? Available at: International Diabetes Federation. Diabetes facts and figures Available at: Lameire N, Jager K, Van Biesen W, de Bacquer D, Vanholder R. Chronic kidney disease: a European perspective. Kidney Int 396

11 JNEPHROL 2010; 23( 04) : Suppl. 2005;99:S30-S Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med. 1990;89: Sidhu RB, Brown JR, Robb JF, et al. Interaction of gender and age on post cardiac catheterization contrast-induced acute kidney injury. Am J Cardiol. 2008;102: El-Hajjar M, Bashir I, Khan M, Min J, Torosoff M, DeLago A. Incidence of contrast-induced nephropathy in patients with chronic renal insufficiency undergoing multidetector computed tomographic angiography treated with preventive measures. Am J Cardiol. 2008;102: Weisbord SD, Mor MK, Resnick AL, Hartwig KC, Palevsky PM, Fine MJ. Incidence and outcomes of contrast-induced AKI following computed tomography. Clin J Am Soc Nephrol. 2008;3: McCullough PA, Stacul F, Davidson C, et al. Overview. Am J Cardiol. 2006;98: Cirillo M, Anastasio P, De Santo NG. Relationship of gender, age, and body mass index to errors in predicted kidney function. Nephrol Dial Transplant. 2005;20: Band RA, Gaieski DF, Mills AM, et al. Discordance between serum creatinine and creatinine clearance for identification of ED patients with abdominal pain at risk for contrast-induced nephropathy. Am J Emerg Med. 2007;25: Herts BR, Schneider E, Poggio ED, Obuchowski NA, Baker ME. Identifying outpatients with renal insufficiency before contrast-enhanced CT by using estimated glomerular filtration rates versus serum creatinine levels. Radiology. 2008;248: Pucci L, Triscornia S, Lucchesi D, et al. Cystatin C and estimates of renal function: searching for a better measure of kidney function in diabetic patients. Clin Chem. 2007;53: Royakkers AA, van Suijlen JD, Hofstra LS, et al. Serum cystatin C: a useful endogenous marker of renal function in intensive care unit patients at risk for or with acute renal failure? Curr Med Chem. 2007;14: Kato K, Sato N, Yamamoto T, Iwasaki YK, Tanaka K, Mizuno K. Valuable markers for contrast-induced nephropathy in patients undergoing cardiac catheterization. Circ J. 2008;72: Coca SG, Yalavarthy R, Concato J, Parikh CR. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int. 2008;73: Bennett MR, Ravipati N, Ross G, et al. Using proteomics to identify preprocedural risk factors for contrast induced nephropathy. Proteomics Clin Appl. 2008;2: Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol. 2004;44: Bartholomew BA, Harjai KJ, Dukkipati S, et al. Impact of nephropathy after percutaneous coronary intervention and a method for risk stratification. Am J Cardiol. 2004;93: Skelding KA, Best PJ, Bartholomew BA, Lennon RJ, O Neill WW, Rihal CS. Validation of a predictive risk score for radiocontrast-induced nephropathy following percutaneous coronary intervention. J Invasive Cardiol. 2007;19: Brown JR, DeVries JT, Piper WD, et al. Serious renal dysfunction after percutaneous coronary interventions can be predicted. Am Heart J. 2008;155: Briguori C, Airoldi F, D Andrea D, et al. Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation. 2007;115: Ozcan EE, Guneri S, Akdeniz B, et al. Sodium bicarbonate, N- acetylcysteine, and saline for prevention of radiocontrastinduced nephropathy: a comparison of 3 regimens for protecting contrast-induced nephropathy in patients undergoing coronary procedures: a single-center prospective controlled trial. Am Heart J. 2007;154: Reddan D, Laville M, Garovic VD. Contrast-induced nephropathy (CIN) and its prevention: what do we really know from evidence-based findings? J Nephrol. 2009;22: Tippins RB, Torres WE, Baumgartner BR, Baumgarten DA. Are screening serum creatinine levels necessary prior to outpatient CT examinations? Radiology. 2000;216: Pannu N, Wiebe N, Tonelli M. Prophylaxis strategies for contrastinduced nephropathy. JAMA. 2006;295: McCullough PA. Multimodality prevention of contrast-induced acute kidney injury. Am J Kidney Dis. 2008;51: Hogan SE, L Allier P, Chetcuti S, et al. Current role of sodium bicarbonate-based preprocedural hydration for the prevention of contrast-induced acute kidney injury: a meta-analysis. Am Heart J. 2008;156: Bader BD, Berger ED, Heede MB, et al. What is the best hydration regimen to prevent contrast media-induced nephrotoxicity? Clin Nephrol. 2004;62:1-7. Trivedi HS, Moore H, Nasr S, et al. A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract. 2003;93:C29-C34. Dussol B, Morange S, Loundoun A, Auquier P, Berland Y. A randomized trial of saline hydration to prevent contrast nephropathy in chronic renal failure patients. Nephrol Dial Transplant. 2006;21: Kane GC, Doyle BJ, Lerman A, Barsness GW, Best PJ, Rihal CS. Ultra-low contrast volumes reduce rates of contrast-induced nephropathy in patients with chronic kidney disease undergoing coronary angiography. J Am Coll Cardiol. 2008;51: Nyman U, Björk J, Aspelin P, Marenzi G. Contrast medium doseto-gfr ratio: a measure of systemic exposure to predict contrast-induced nephropathy after percutaneous coronary intervention. Acta Radiol. 2008;49: Nyman U, Almen T, Aspelin P, Hellstrom M, Kristiansson M, Sterner G. Contrast-medium-induced nephropathy correlated to the ratio between dose in gram iodine and estimated GFR in ml/ min. Acta Radiol. 2005;46:

12 Laville and Juillard: Contrast-induced AKI Rao QA, Newhouse JH. Risk of nephropathy after intravenous administration of contrast material: a critical literature analysis. Radiology. 2006;239: Newhouse JH, Kho D, Rao QA, Starren J. Frequency of serum creatinine changes in the absence of iodinated contrast material: implications for studies of contrast nephrotoxicity. AJR Am J Roentgenol. 2008;191: Bruce RJ, Djamali A, Shinki K, Michel SJ, Fine JP, Pozniak MA. Background fluctuation of kidney function versus contrast-induced nephrotoxicity. AJR Am J Roentgenol. 2009;192: Hardiek KJ, Katholi RE, Robbs RS, Katholi CE. Renal effects of contrast media in diabetic patients undergoing diagnostic or interventional coronary angiography. J Diabetes Complications. 2008;22: Feldkamp T, Baumgart D, Elsner M, et al. Nephrotoxicity of isoosmolar versus low-osmolar contrast media is equal in low risk patients. Clin Nephrol. 2006;66: Jo SH, Youn TJ, Koo BK, et al. Renal toxicity evaluation and comparison between Visipaque (iodixanol) and Hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography: the RECOVER study: a randomized controlled trial. J Am Coll Cardiol. 2006;48: Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003;348: Nie B, Cheng WJ, Li YF, et al. A prospective, double-blind, randomized, controlled trial on the efficacy and cardiorenal safety of iodixanol vs. iopromide in patients with chronic kidney disease undergoing coronary angiography with or without percutaneous coronary intervention. Catheter Cardiovasc Interv. 2008;72: Solomon RJ, Natarajan MK, Doucet S, et al. Cardiac Angiography in Renally Impaired Patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease. Circulation. 2007;115: Rudnick MR, Davidson C, Laskey W, Stafford JL, Sherwin PF. Nephrotoxicity of iodixanol versus ioversol in patients with chronic kidney disease: the Visipaque Angiography/Interventions with Laboratory Outcomes in Renal Insufficiency (VAL- OR) Trial. Am Heart J. 2008;156: Kuhn MJ, Chen N, Sahani DV, et al. The PREDICT study: a randomized double-blind comparison of contrast-induced nephropathy after low- or isoosmolar contrast agent exposure. AJR Am J Roentgenol. 2008;191: Thomsen HS, Morcos SK, Erley CM, Grazioloi L, Bonomo L, Ni Z. The ACTIVE Trial: comparison of the effects on renal function of iomeprol-400 and idoixanol-320 in patients with chronic kidney disease undergoing abdominal computed tomography. Invest Radiol. 2008;43: Barrett BJ, Katzberg RW, Thomsen HS, et al. Contrast-induced nephropathy in patients with chronic kidney disease undergoing computed tomography: a double-blind comparison of iodixanol and iopamidol. Invest Radiol. 2006;41: Nguyen SA, Suranyi P, Ravenel JG, et al. Iso-osmolality versus low-osmolality iodinated contrast medium at intravenous contrast-enhanced CT: effect on kidney function. Radiology. 2008;248: Solomon RJ, Mehran R, Natarajan M, et al. Contrast-induced nephropathy and long-term adverse events: cause and effect? Clin J Am Soc Nephrol. 2009;4: National Kidney Foundation. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Available at: cvd/guide2.htm. Accessed January 2008, Aguiar-Souto P, Valero-Gonzalez S. When to test renal function to disclose contrast-induced nephropathy. Am J Cardiol. 2008;102:371. Received: July 22, 2009 Revised: August 22, 2009 Accepted: September 07,