Strategies for the prevention of contrast-induced acute kidney injury Steven D. Weisbord a,b and Paul M. Palevsky a,b

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1 Strategies for the prevention of contrast-induced acute kidney injury Steven D. Weisord a, and Paul M. Palevsky a, a Renal Section, VA Pittsurgh Healthcare System and Renal-Electrolyte Division, Department of Medicine, University of Pittsurgh School of Medicine, Pittsurgh, Pennsylvania, USA Correspondence to Paul M. Palevsky, MD, Room #7E123 (111F-U), VA Pittsurgh Healthcare System, University Drive Division, Pittsurgh, PA 15240, USA Tel: ; fax: ; palevsky@pitt.edu Current Opinion in Nephrology and Hypertension 2010, 19: Purpose of review The intravascular administration of iodinated contrast media for diagnostic imaging is a common cause of acute kidney injury and a leading cause of iatrogenic renal disease. The purpose of this review is to descrie the principal risk factors for contrast-induced acute kidney injury and to summarize recent data descriing the efficacy of various preventive interventions for this condition. Recent findings Whereas earlier studies suggested that certain low-osmolal contrast agents including iohexol and ioxaglate are more nephrotoxic than iso-osmolal iodixanol, recent clinical trials and meta-analyses comparing other low-osmolal contrast agents with iodixanol have found little difference in risk. The provision of prophylactic renal replacement therapy does not ameliorate the risk of contrast-induced acute kidney injury, and likely poses undue risk. Despite some research supporting a enefit of atrial natriuretic peptide, statins, and prostaglandin analogs, additional data from large, adequately powered studies are needed efore these agents can e recommended. N- Acetylcysteine and isotonic intravenous icaronate have een investigated intensely, yet the data on these interventions are conflicting due to methodological limitations in past studies. Summary Prevention of contrast-induced acute kidney injury involves the identification of high-risk patients, consideration of alternative imaging procedures that do not involve the administration of iodinated contrast, and integration of the cumulative data availale on preventive interventions in high-risk patients. Keywords contrast-induced acute kidney injury, prevention, risk factors Curr Opin Nephrol Hypertens 19: ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction The intravascular administration of iodinated contrast media remains a common cause of acute kidney injury (AKI) [1,2]. Past research has demonstrated that contrastinduced AKI (CIAKI) is associated with increased healthresource utilization, prolonged hospital stay, increased in-hospital and long-term mortality, and an acceleration in the rate of progression of chronic kidney disease (CKD) [3 9]. Three factors suggest that the incidence of CIAKI is likely to increase in the future. First, CKD, which is a principal risk factor for CIAKI, affects as many as 13 million Americans and is likely to continue to grow in prevalence [10]. Second, diaetes mellitus, which amplifies the risk for CIAKI in patients with underlying CKD, is also increasing in prevalence. Third, patients with advanced CKD have een shown to e at risk for nephrogenic systemic firosis, a potentially deilitating disorder that is associated with the administration of gadolinium-ased contrast agents [11]. As a result, many patients with CKD, who in the past years would have undergone contrast-enhanced magnetic resonance angiography, are now likely to undergo conventional angiography with iodinated contrast, increasing the numer of patients at risk for CIAKI. Multiple interventions have een investigated for their capacity to prevent CIAKI, yet few have conclusively demonstrated effectiveness. The following review discusses the principal risk factors for CIAKI and the current evidence asis related to interventions for the prevention of this iatrogenic condition with a focus on the most recent data. Risk factors for contrast-induced acute kidney injury Underlying kidney dysfunction is recognized as the most important risk factor for the development of CIAKI, with ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /MNH.0013e32833d42e3

2 540 Diagnostics and techniques increasing levels of renal impairment associated with escalating levels of risk [12]. The presence of diaetes mellitus sustantially amplifies the risk for CIAKI in patients with concomitant renal disease [7,12 14]. Patients with intravascular volume depletion are also susceptile to renal injury from iodinated radiocontrast, as are patients with advanced heart failure [12]. In oth clinical states, decreased effective circulating volume and reduced renal perfusion potentiate renal vasoconstriction following the administration of intravascular contrast. The risk of CIAKI is also related to the volume of contrast administered, with larger volumes associated with greater risk (Tale 1) [15,16]. In addition, the risk for CIAKI is greater following intraarterial contrast administration than intravenous administration. Recognition of these major risk factors has facilitated the identification of patients at increased risk for CIAKI and has helped inform research efforts to identify the effectiveness of interventions for the prevention of this condition. Prevention of contrast-induced acute kidney injury Whereas the treatment of estalished CIAKI is limited to supportive care and dialysis, the renal injury resulting from iodinated contrast exposure is potentially preventale. Procedures that utilize intravascular contrast, such as coronary and noncoronary angiograms, are commonly scheduled in advance, providing sufficient time to identify patients at increased risk and implement preventive measures. Efforts to find effective preventive interventions for CIAKI have focused on four principal strategies: administration of less nephrotoxic contrast agents; provision of preemptive renal replacement therapy to remove contrast from the circulation; utilization of pharmacologic agents to counteract the nephrotoxic effects of contrast media; and expansion of the intravascular space and enhanced diuresis with intravenous (i.v.) fluids. Type of contrast agent Iodinated contrast agents used for clinical imaging are categorized as either ionic or nonionic, and have variale osmolalities compared with plasma. The osmolality of conventional, high-osmolal contrast is in the range of mosm/kg. Low -osmolal agents were named Tale 1 Principal risk factors for contrast-induced acute kidney injury Patient-related factors Underlying renal insufficiency Diaetes mellitus a Intravascular volume depletion Congestive heart failure Procedure-related factors a Amplifies risk in the setting of renal insufficiency. Volume of contrast used Hyper-osmolal contrast media Intra-arterial contrast administration as such ecause their osmolalities are less than those of high-osmolal contrast agents. However, low-osmolal contrast agents are still hyperosmolal ( mosm/kg) compared with plasma. In a large randomized controlled trial of 1196 patients conducted over a decade ago, Rudnick et al. [13] demonstrated a reduction in the incidence of CIAKI with the use of iohexol, a low-osmolal agent, compared with diatrizoate, a high-osmolal contrast medium, in patients with pre-existent renal insufficiency, independent of the presence of diaetes mellitus. More recent studies have focused on the comparative nephrotoxicity of iodixanol, which is iso-osmolal (290 mosm/kg) to plasma, and various low-osmolal contrast media. Although a series of randomized trials over the past decade have suggested a lower incidence of CIAKI with iodixanol in high-risk patients, other clinical trials were unale to confirm the presence of such a enefit [17 22]. Meta-analyses and systematic reviews of these divergent results have also yielded conflicting findings on the relative nephrotoxicity of iodixanol and low-osmolal contrast agents [23 25]. Over the past 12 months, the results of at least four clinical trials that compared iodixanol to low-osmolal contrast agents have een pulished. Wessely et al. [26] randomized 324 patients with CKD undergoing coronary angiography with percutaneous coronary intervention (PCI) to receive either iodixanol or the lowosmolal agent iomeprol. The primary endpoint, which was defined as the maximal increase in serum creatinine (SCr) during the hospitalization, was not different in the two groups ( mg/dl with iodixanol vs mg/l with iomeprol; P ¼ 0.53). Similarly, rates of CIAKI were not different etween the two groups (22.2% with iodixanol vs. 27.8% with iomeprol; P ¼ 0.25). In a smaller study, Chuang and colleagues [27] randomized 50 patients undergoing intravenous pyelography to receive iodixanol or iohexol and found no difference in the incidence of CIAKI etween the two groups (4% in each). However, this study was limited y a very small numer of patients, many of whom had relatively preserved kidney function at aseline. Mehran et al. [28] reported the results of the ICON study a randomized, multicenter trial comparing iodixanol to ioxaglate in 146 patients with moderate CKD undergoing coronary angiography. The primary study endpoint, defined y the median peak increase in serum creatinine through day 3 following angiography, did not differ etween the two groups (0.09 mg/dl with iodixanol vs mg/dl with ioxaglate; P ¼ 0.07). Whereas there were slightly lower rates of CIAKI among patients who received iodixanol, these differences did not meet the level of statistical significance. Most recently, Laskey and colleagues [29] reported the results of a randomized clinical trial that compared iodixanol to iopamidol in 418 diaetic patients

3 Strategies for the prevention of CIAKI Weisord and Palevsky 541 with CKD undergoing coronary procedures. The proportion of patients who developed CIAKI was similar for oth contrast agents (11.2% with iodixanol vs. 9.8% with iopamidol; P ¼ 0.7). In the most recent meta-analysis, which included 16 trials encompassing 2763 patients, Reed and colleagues [30] compared iodixanol to several low-osmolal contrast agents. They found no difference in the incidence of CIAKI when they compared iodixanol to all low-osmolal contrast agents considered collectively. However, iodixanol was associated with a lower incidence of CIAKI compared with ioxaglate and iohexol, ut not when compared with other low-osmolal agents. Collectively, these past and most recent studies suggest a lower incidence of CIAKI with the use of iodixanol compared with specific low-osmolal agents, namely iohexol and possily ioxaglate, with no discernile difference when iodixanol is compared with iopamidol. However, the small numers of patients included in past trials, coupled with the lack of data on the relative effects of iso-osmolal and low-osmolal contrast agents on serious, adverse, patient-centered outcomes are important limitations to these studies. On the asis of these data, guidelines from the American College of Cardiology/American Heart Association recommend the use of iso-osmolal contrast or low-osmolal contrast other than iohexol and ioxaglate in patients with CKD undergoing angiography [31]. Renal replacement therapy The use of renal replacement therapy to prevent CIAKI is predicated on the premise that rapid removal of iodinated radiocontrast material from the circulation, limiting the filtered load at the glomerulus, will decrease the risk of renal injury. However, in a series of studies that have examined the use of conventional hemodialysis following the administration of radiocontrast, no eneficial outcomes were seen [32 36]. In addition, there was a trend toward an increased need for therapeutic hemodialysis as well as a higher incidence of renal failure in certain studies [32,34,35,37,38]. There have also een studies of continuous renal replacement therapies for prevention of CIAKI. Marenzi et al. [39] compared continuous hemofiltration initiated 4 8 h prior to and continued for h following coronary angiography to volume expansion with i.v. isotonic saline for the prevention of CIAKI, as defined y a more than 25% increase in the SCr during the hospitalization. Five per cent of the patients in the hemofiltration group demonstrated this change in SCr compared with 50% of the patients in the i.v. isotonic saline group (P < 0.001). However, ecause continuous hemofiltration directly lowers SCr, the use of changes in its concentration as the primary study endpoint, as a surrogate for measured change in kidney function, is of questionale validity. The oserved difference in the proportion of patients sustaining a more than 25% increase in SCr primarily reflects the direct decrease in SCr y the intervention in patients treated with hemofiltration. Cruz et al. [40] conducted a meta-analysis of lood purification therapies for the prevention of CIAKI. Considering data from eight clinical trials, six of which assessed hemodialysis and two of which assessed continuous renal replacement therapy, the authors found that renal replacement therapy did not reduce the incidence of CIAKI compared with routine preventive care [40]. Moreover, there was considerale intertrial heterogeneity. In sensitivity analyses that included only those studies of hemodialysis, intertrial heterogeneity was nonstatistically significant, yet there was a trend toward greater risk for CIAKI with hemodialysis compared with standard preventive care. In a recent trial, Holscher et al. [37] randomized 412 patients with aseline SCr values of mg/dl undergoing elective coronary angiography to periprocedural i.v. fluids, i.v. fluids with a one-time hemodialysis treatment immediately following angiography, or i.v. fluids with oral N-acetylcysteine (NAC). Despite the effect of hemodialysis on lowering SCr, patients randomized to receive i.v. fluids and hemodialysis experienced a higher incidence of CIAKI compared with patients who received i.v. fluids alone (16.4 vs. 7.2%), and compared with patients randomized to i.v. fluids and NAC (16.4 vs. 4.3%). Thus, it appears that the use of prophylactic hemodialysis is not only of no enefit, ut associated with potential harm. Whereas past studies have not demonstrated harm with prophylactic hemofiltration, this therapy is associated with known risks related to catheter insertion and infection, as well as significant costs. Therefore, we cannot recommend prophylactic renal replacement therapy for the prevention of CIAKI. Pharmacologic interventions Trials of pharmacologic interventions, including furosemide, dopamine, fenoldopam, calcium channel lockers, and mannitol, have failed to demonstrate significant enefit for the prevention of CIAKI and in some cases have een associated with harm [41 43]. Findings on the enefit of natriuretic peptides, aminophylline, theophylline, statins, ascoric acid, prostacyclin/prostaglandin analogs, and NAC are inconclusive. A series of recent trials provides additional data on the potential role of certain of these interventions. Atrial natriuretic peptide Morikawa and colleagues [44] recently reported the results of a single-center, unlinded, randomized clinical trial comparing the infusion of atrial natriuretic peptide (ANP) with i.v. fluids to an infusion of i.v. fluids alone among patients with CKD undergoing coronary angiography with or without angioplasty or stenting (PCI).

4 542 Diagnostics and techniques ANP was administered at a dose of mg/kg/min for 4 6 h prior to and 48 h following angiography. Of 254 patients who completed the study, decrements in estimated glomerular filtration rate (egfr) at 24 h, 48 h, 1 week, and 1 month following angiography were slightly less among patients who received ANP. Similarly, the incidence of CIAKI, defined y an increase in SCr of at least 25%, at least 0.5 mg/dl, or oth of these threshold changes was lower in patients who received ANP. Of note, ANP was also associated with a significant decrease in systolic lood pressure. There were no differences in the proportion of patients who required temporary dialysis or hospitalization for heart failure. The investigators posited that the lower dose and more sustained administration of ANP compared with prior negative trials of this agent accounted for the oserved enefit [45,46]. However, this study enrolled a relatively small numer of patients and lacked power to discern the effects of ANP on serious, adverse, patient-centered outcomes. Because of the cost and risks associated with ANP infusion, large trials that are adequately powered to assess the risks and potential enefits of ANP will e required efore this therapy can e recommended for routine use. Statins A series of studies have investigated the role of statins for the prevention of CIAKI ecause of their antioxidant and anti-inflammatory properties and effects on endothelial function [47 50]. Preliminary retrospective and prospective oservational studies suggested a enefit of statins in reducing the incidence of CIAKI. However, in a recent two-center clinical trial, Jo et al. [50] randomized 247 patients to receive four 40 mg doses of simvastatin or placeo, given every 12 h starting the evening efore coronary angiography, and failed to demonstrate a enefit associated with statin therapy. Similarly, in a singlecenter trial, Toso et al. [51] randomized 304 patients with CKD undergoing coronary angiography with or without PCI to receive 80 mg of atorvastatin or placeo daily for 2 days prior to and 2 days following the procedure. CIAKI, defined as an increase in SCr at least 0.5 mg/dl within 5 days, developed in 10% of atorvastatin-treated patients and 11% in placeo-treated patients (P ¼ 0.86). No differences were seen etween the groups in persistent renal injury at 30 days following angiography. Thus, data to date are insufficient to support the use of statins for the prevention of CIAKI. Prostaglandin/prostacyclin analogs A primary mechanism thought to e responsile for renal injury following intravascular iodinated contrast administration is vasoconstriction in the renal medulla [52,53]. Prostaglandins (PGI 2 and PGE 2 ) have vasodilatory actions in the kidney and may attenuate the vasoconstrictive effects of iodinated contrast. This forms the asis for recommendations to discontinue nonsteroidal antiinflammatory drugs (NSAIDs), which inhiit vasodilatory prostaglandins in the kidney, prior to contrast administration, and has led to investigation of the effect of vasodilatory prostaglandin analogs for the prevention of CIAKI. Studies in animal models suggest a potential eneficial role of prostaglandins for the prevention of nephrotoxicity caused y iodinated contrast [54,55]. Spargias and colleagues [56] conducted a randomized clinical trial in 208 patients with CKD who were undergoing coronary angiography, with or without PCI. Patients were randomized to receive iloprost, a PGI 2 analog, at a dose of 1 ng/kg per minute eginning min prior to angiography and continued for 4 h following angiography, or placeo. The primary study endpoint was the development of CIAKI, defined y an increase in SCr of at least 0.5 mg/dl or at least 25% within 2 5 days. The investigators found a lower incidence of CIAKI in patients randomized to iloprost as compared with patients who received placeo (8 vs. 22%; P ¼ 0.005), with few adverse events. Notwithstanding the reasonaly large reduction in the incidence of CIAKI, the results of this trial should e interpreted with caution. First, the study was powered ased on an assumed 70% reduction in the incidence of the primary outcome with iloprost. This clinically and iologically implausile effect size accounted for the small study population and increased the risk for a type 1 error. Second, effects of iloprost on longer-term adverse outcomes were not investigated. With the potential for adverse side effects with prostaglandin analogs such as iloprost, we cannot recommend the routine use of these agents for the prevention of CIAKI until definite enefit is demonstrated in large clinical trials. N-Acetylcysteine The rationale for the use of NAC for the prevention of CIAKI relates to its capacity to scavenge reactive oxygen species (ROS), reduce the depletion of glutathione, and stimulate the production of vasodilatory mediators, including nitric oxide. Tepel et al. [57] first descried the efficacy of NAC for the prevention of CIAKI in humans a decade ago. In this trial 83 patients undergoing computed tomography were randomized to receive 600 mg of NAC or placeo twice daily on the day prior to and the day of the procedure. Significantly fewer patients treated with NAC developed CIAKI compared with patients in the placeo arm (2 vs. 21%; P ¼ 0.01). Since the pulication of this initial study, a multitude of trials evaluating NAC for the prevention of CIAKI have een pulished in the peer-reviewed literature and yielded highly conflicting results (Tale 2) [57 82]. In an effort to reconcile the disparate clinical trial findings, multiple systematic reviews and meta-analyses have een performed to analyze the collective results of these studies. One of the largest and most rigorous of these analyses was performed y Kelly and colleagues [83] and

5 Strategies for the prevention of CIAKI Weisord and Palevsky 543 Tale 2 Randomized clinical trials comparing N-acetylcysteine and placeo to prevent contrast-induced acute kidney injury Authors NAC dose Numer of patients Definition 1 0 outcome % CIAKI NAC % CIAKI control Dialysis Death PRI/RH Positive studies Baker et al. [58] a 80 " SCr 25% % NR NR Balderramo et al. [59] 1200 mg po 2 61 " SCr 0.5 mg/dl NR NR NR 90% Diaz-Sandoval et al. [60] 600 mg po 4 54 " SCr25%/0.5 mg/dl 8 45 NR NR NR NR Drager et al. [61] 600 mg po 4 24 Mean D CrCl NR NR NR NR NR NR Kay et al. [62] 600 mg po " SCr 25% % 0% NR MacNeill et al. [63] 600 mg po 5 43 " SCr 25% 5 32 NR NR NR NR Marenzi et al. [64] c 352 " SCr 25% % 6% NR 50% Miner et al. [65] d 171 " SCr 25% % 5.5% 9.4% 50% Ochoa et al. [66] 1000 mg po 2 80 " SCr 25%/0.5 mg/dl 8 25 NR NR NR Shyu et al. [67] 400 mg po " SCr 0.5 mg/dl % NR NR Tepel et al. [57] 600 mg po 4 83 " SCr 0.5 mg/dl % NR NR NR Negative studies Allaqaand et al. [68] 600 mg p.o " SCr 0.5 mg/dl NR NR NR NR Amini et al. [69] 600 mg p.o " SCr 25%/0.5 mg/dl NR NR NR 90% Azmus et al. [70] 600 mg p.o " SCr 25%/#eGFR 50% % NR NR 65% Briguori et al. [71] 600 mg p.o " SCr 25% % NR NR NR Caronell et al. [72] 600 mg i.v " SCr 25%/0.5 mg/dl % 3.7% NR NR Coyle et al. [73] 600 mg p.o mean D SCr NR NR NR NR NR Durham et al. [74] 1200 mg p.o " SCr 0.5 mg/dl % NR NR NR Fung et al. [75] 400 mg p.o " SCr 25%/#eGFR 50% % NR NR 90% Goldenerg et al. [76] 600 mg p.o " SCr 0.5 mg/dl % 0% NR 90% Gomes et al. [77] 600 mg p.o " SCr 0.5 mg/dl 10.4% % 4.5% NR 50% Kefer et al. [78] 1200 mg i.v " SCr 25%/0.5 mg/dl % NR NR NR Oldemeyer et al. [79] 1500 mg p.o " SCr 25%/0.5 mg/dl % NR NR NR Rashid et al. [80] 1000 mg i.v " SCr 25%/0.5 mg/dl NR NR NR 90% Sandhu et al. [81] 600 mg p.o " SCr 0.5 mg/dl NR NR NR NR We et al. [82] 500 mg i.v # CrCl >5 ml/min % 2.5% NR 50% Assumed effect size NAC CIAKI, contrast-induced acute kidney injury; CrCl, creatinine clearance; egfr, estimated glomerular filtration rate; NAC, N-acetylcysteine; NR, not reported; PRI, persistent renal injury; RH, re-hospitalization; SCr, serum creatinine. a 150 mg/kg i.v. 1 h preangiography and 50 mg/kg i.v. 4 h postangiography. Effect size ased on difference in mean change of SCr. c Two NAC groups: standard dose ¼ 600 mg i.v. and 600 mg p.o. 4; high dose 1200 mg i.v. and 1200 mg p.o. 4. d 2000 mg p.o. either 2 or3. included 26 trials, encompassing 3393 patients. On the asis of the pooled data, these investigators calculated a 38% reduction in the risk of CIAKI associated with NAC [relative risk (RR) ¼ 0.62; 95% confidence interval (CI) ]. Although the investigators identified study heterogeneity, they did not identify evidence of pulication ias. In another recent meta-analysis of 22 trials, encompassing 2746 patients, Gonzales et al. [84] also found significant heterogeneity among the trials ut were ale to segregate the trials into two clusters that demonstrated minimal heterogeneity. One cluster included trials in which NAC was found to e protective, and was defined y an oserved decline in SCr following contrast administration in the patients treated with NAC. In the studies included in the other cluster, there was no fall in SCr in the NAC-treated patients and no overall enefit for the prevention of CIAKI. The investigators concluded that NAC was not actually effective for the prevention of CIAKI and that the apparent enefit represented an artifactual effect on serum concentration independent of actual kidney function. Most recently, Trivedi and colleagues [85] conducted a meta-analysis of trials that utilized high-dose NAC, defined as a daily dose of more than 1200 mg or one dose of more than 600 mg within 4 h of contrast administration. Compared with controls, high-dose NAC was associated with a lower risk of CIAKI using either a fixed-effects [odds ratio (OR) 0.46, 95% CI ] or a random-effects model. Their analysis found no significant heterogeneity or pulication ias. At the current time, no definitive conclusions on the effectiveness of NAC for the prevention of CIAKI can e drawn. If a eneficial effect exists, it may e related to the use of higher doses of NAC. Large clinical trials that are ased on clinically plausile effect sizes and that examine serious, adverse, patient-centered outcomes are needed to etter define the clinical utility of this agent. However, given the minimal cost and relative safety associated with NAC, its use in conjunction with appropriate fluid administration is not inappropriate. Intravenous fluids Intravascular volume expansion with i.v. fluids is elieved to protect against the development of CIAKI via two mechanisms. First, expansion of the intravascular space is thought to lunt the vasoconstrictive effect of contrast on the renal medulla due to the suppression of vasopressin secretion, inhiition of the renin angiotensin axis, and increased synthesis of vasodilatory renal

6 544 Diagnostics and techniques prostaglandins [86]. Second, i.v. fluids are elieved to attenuate the direct toxic effect of contrast agents on tuular epithelial cells y decreasing the concentration and viscosity of contrast media in the tuular lumen as the result of volume-mediated inhiition of proximal tuular salt and water reasorption and y decreasing contact time from the associated increase in tuular flow [86]. Several small randomized clinical trials estalished the current evidence asis for the use of i.v. fluids for the prevention of CIAKI, and provide preliminary data on the effects of i.v. fluid composition. In 1994, Solomon et al. [42] pulished the results of a clinical trial that examined the prophylactic effect of i.v. fluid alone or in comination with i.v. mannitol or furosemide. Patients with CKD undergoing coronary angiography were randomized to receive 0.45% (half-isotonic) saline alone prior to and following angiography or in comination with either 25 g of i.v. mannitol or 80 mg of i.v. furosemide prior to contrast administration. Among patients who received only i.v. fluids, 11% developed CIAKI, compared with 28% in the i.v. fluid and mannitol group, and 40% who received furosemide in addition to i.v. fluids (P ¼ 0.02 for comparison with i.v. fluid alone). Whereas this trial did not include a control group of patients who did not receive i.v. fluid, Trivedi et al. [87] susequently confirmed the enefit of i.v. fluid in a small clinical trial of patients undergoing nonemergent coronary angiography. Participants in this study were randomized to receive either i.v. isotonic saline for 12 h prior to and 12 h following angiography or unrestricted oral fluids. The study was stopped at an interim analysis after 53 of 160 potential participants had een enrolled when the rate of CIAKI was found to e nearly 10-fold higher in the oral fluid group compared with the i.v. saline group (34.6 vs. 3.7%; P ¼ 0.005). The effect of tonicity of i.v. fluids on the development of CIAKI was assessed in a trial conducted y Mueller and colleagues [88] in which low-risk patients who were undergoing coronary angiography were randomized to peri-procedural i.v. volume expansion with either 0.45% (half-isotonic) saline or 0.9% (isotonic) saline. The overall rate of CIAKI was greater in patients who received half-isotonic saline compared with those who were administered isotonic saline (2 vs. 0.7%; P ¼ 0.04). On the asis of this study, it has generally een accepted that isotonic saline is superior to hypotonic saline for the prevention of CIAKI. More recently, studies evaluating fluid administration for the prevention of CIAKI have focused on comparisons etween isotonic sodium icaronate (icaronate) and isotonic sodium chloride (saline). The generation of ROS in the kidney following contrast administration is thought to e an important mediator of CIAKI. Moreover, chronic kidney disease, diaetes, intravascular volume depletion, and heart failure, all of which are important clinical risk factors for CIAKI, are themselves associated with enhanced ROS formation [89 91]. Intravenous sodium icaronate administration is hypothesized to mitigate generation of ROS following contrast administration as the result of urinary alkalinization. Over the past 5 years, 10 clinical trials comparing the development of CIAKI following the administration of either isotonic icaronate or isotonic saline have een pulished in the peerreviewed literature, 6 demonstrating a lower incidence of CIAKI with icaronate administration, whereas 4 showed no significant enefit (Tale 3) [19,92 100]. The disparate results of these 10 clinical trials led to a proliferation of systematic reviews and meta-analyses comparing the effectiveness of icaronate and saline, 11 of which have now een pulished [ ]. Among Tale 3 Clinical trials comparing i.v. isotonic icaronate and i.v. isotonic saline to prevent contrast-induced acute kidney injury Authors Numer of patients Diaetes Baseline SCr (mg/dl) Definition of 1 0 outcome Frequency of CIAKI icaronate Frequency of CIAKI saline Dialysis Death PRI/RH Assumed effect size of icaronate Positive studies Briguori et al. [92] % 2.0 "SCr 25% 1.9% 9.9% 1% NA NA 86% Masuda et al. [93] 59 31% 1.3 "SCr 0.5 mg/dl or 25% 6.6% 34.5% 7% 3% NA 85% Merten et al. [94] % "SCr 25% 1.7% 13.6% 0% NA NA 66% Ozcan et al. [95] % 1.4 "SCr 0.5 mg/dl or 25% 4.2% 16.6% 1% NA NA NR Pakfetrat et al. [96] % % 12.5% NA NA NA NR Recio-Mayoral et al % 1.0 "SCr 0.5 mg/dl 1.8% 21.8% 4% 4.5% NA 85% [97] Negative studies Adolph et al. [19] % "SCr 0.5 mg/dl or 25% 4.2% 2.7% 0% NA NA 87% Brar et al. [98] % 1.5 #egfr 25% 13.3% 14.6% 2% 2% a 19% a 66% Maioli et al. [99] % 1.2 "SCr 0.5 mg/dl 10% 11.5% < 1% 1% NA 50% Vasheghani et al. c [100] % "SCr 0.5 mg/dl or 25% 7.4% 5.9% NA NA NA 71% CIAKI, contrast-induced acute kidney injury; egfr, estimated glomerular filtration rate; NA, not assessed; NR, not reported; PRI, persistent renal injury; RH, re-hospitalization; SCr, serum creatinine. a Outcomes assessed 2 weeks to 6 months following angiography. Three definitions of CIAKI assessed; differences etween icaronate and saline ased on "SCr 0.3 mg/dl. c Bicaronate administered as 75 ml of 8.4% sodium icaronate added to 1 l isotonic saline (i.e. hypertonic icaronate).

7 Strategies for the prevention of CIAKI Weisord and Palevsky 545 the most recent, Zoungas et al. [101] pooled the results of 23 pulished and unpulished trials that contained data on over 3500 patients. They found an overall relative risk of CIAKI of 0.62 (95% CI ) with icaronate therapy as compared with saline. However, the strength of this finding must e tempered y evidence of oth study heterogeneity and pulication ias. When they limited the analysis to only pulished studies they oserved an even lower relative risk of CIAKI with icaronate (RR 0.43, 95% CI ), whereas analyses of the unpulished trials failed to demonstrate such a enefit (RR 0.78, 95% CI ). As a result, the authors concluded that the effectiveness of i.v. isotonic icaronate compared with saline remains uncertain. In an even more recent meta-analysis, Kunadian et al. [110] included data from 7 pulished trials and documented a lower risk of CIAKI with i.v. isotonic icaronate compared with i.v. isotonic saline (OR 0.33, 95% CI ). However, once again these results need to e regarded with caution as the investigators also identified significant heterogeneity and evidence of pulication ias. At this time, data on the comparative effectiveness of icaronate and saline for the prevention of CIAKI are insufficient to warrant a recommendation for the routine use of a specific isotonic i.v. fluid. A large clinical trial that is appropriately powered to detect potentially sutle ut clinically significant differences etween these i.v. fluids in preventing not only CIAKI ut also serious, adverse patient-centered outcomes is needed. Methodological limitations to past research on the prevention of contrast-induced acute kidney injury There are common themes to the limitations of the vast majority of trials evaluating the efficacy of interventions for the prevention of CIAKI. First, all pulished trials to date have een relatively small. For example, the largest study comparing icaronate to saline enrolled only 502 patients, whereas the largest study of NAC enrolled just 487 patients. These small sample sizes mean that the clinical effects of the interventions that the individual studies are ale to detect are not likely to e iologically plausile. The risk of failing to detect smaller, yet clinically meaningful enefit is therefore sustantial. Second, nearly all past studies were designed with small, shortterm changes in SCr as their primary endpoint. Whereas these changes in SCr have een used to define CIAKI, and are associated with mortality and other adverse clinical outcomes such as dialysis or persistent change in kidney function, it has not een demonstrated that prevention of these small changes in SCr results in improved patient outcomes. None of the trials to date has een designed with sufficient statistical power to detect differences in these clinically meaningful, patient-centered outcomes. Finally, many of the studies enrolled patients who were at relatively low risk for the development of CIAKI, further diminishing the likelihood that a relatively small study could detect a meaningful clinical enefit. It is with these limitations in mind that we propose recommendations for the prevention of CIAKI and serious, adverse sequelae of contrastenhanced imaging procedures (Tale 4). Recommendations for prevention of contrastinduced acute kidney injury The first step in the prevention of CIAKI is identifying patients at increased risk. For the majority of patients, who have no identifiale risk factors, the risk of developing CIAKI is very low and no additional periprocedural precautions are warranted. This is in contradistinction to high-risk patients, particularly those with underlying chronic kidney disease. In these patients, prophylactic interventions should e instituted to reduce the risk of renal injury. The most effective approach to prevent CIAKI is avoidance of iodinated contrast media. The use of ultrasonography and unenhanced computed tomography may Tale 4 Preventive interventions for contrast-induced acute kidney injury Category of intervention Identification of high-risk patients Consider alternative imaging procedures Intravenous fluids N-Acetylcysteine Medication discontinuation Contrast agent Follow-up assessment of kidney function Specific strategies Identify patients with known risk factors Consider ultrasound, nuclear imaging, noncontrast computed tomography Consider use of CO 2 for select angiographic procedures Intravenous isotonic saline or intravenous isotonic sodium icaronate Hospitalized patients: 1 ml/kg per h for 12 h prior to and 12 h following the procedure Outpatients/urgent procedures: 3 ml/kg per h for 1 h prior to the procedure and ml/kg per h for 4 6 h following the procedure 1200 mg orally twice daily on the day prior to and the day of the procedure Discontinue selective and nonselective nonsteroidal anti-inflammatory medications on day prior to procedure and hold for 2 4 days following procedure Discontinue metformin at time of procedure and restart once postprocedure renal function deemed stale a Use iso-osmolal or low-osmolal contrast other than iohexol or ioxaglate Utilize lowest necessary dose of contrast Check serum creatinine h following procedure a Metformin is not nephrotoxic ut should not e used in the presence of kidney dysfunction.

8 546 Diagnostics and techniques oviate the need for contrast-enhanced radiographic studies. Whereas magnetic resonance angiography had previously een considered a well tolerated alternative to conventional angiography in patients with CKD, the risk for nephrogenic systemic firosis needs to e considered in those with advanced levels of renal impairment. Caron dioxide may e used as a non-nephrotoxic contrast agent for certain angiographic procedures. Specific modifiale risks for the development of CIAKI should e addressed. Overt volume depletion should e corrected in all patients prior to the administration of iodinated radiocontrast. In addition, nonselective nonsteroidal anti-inflammatory medications and selective cyclooxygenase-2 inhiitors, which inhiit vasodilatory prostaglandins, should e discontinued at least 24 h in advance of the planned procedure and avoided for h following the procedure. The dose of contrast should e limited to the minimum volume required to provide adequate clinical information. In addition, iso-osmolal or a nonionic, low osmolality contrast medium other than iohexol or ioxaglate should e employed. Intravenous isotonic saline or sodium icaronate should e administered prior to and following the administration of contrast. Although the administration of isotonic saline at a dose of 1 ml/kg/h for 12 h preceding and 12 h following the administration of iodinated contrast has een most rigorously validated, this dosing is not practical for outpatient procedures. For high-risk patients undergoing elective outpatient procedures, similar total volumes of isotonic fluid composed of either saline or sodium icaronate, administered over shorter intervals may provide a more practical alternative, although this approach has not een formally tested against more prolonged durations of i.v. fluid administration. Further research into the optimal dose and timing of i.v. fluid administration, particularly for outpatients, is clearly needed. Intravenous fluid administration should not e eschewed in patients with a history of congestive heart failure. Rather, careful volume expansion should e accompanied y close vigilance for signs or symptoms of pulmonary compromise. Although the enefit associated with NAC remains deatale, this agent has minimal toxicity and is inexpensive. Therefore, we recommend the use of oral NAC at a dose of 1200 mg twice daily on the day prior to and day of contrast administration. The use of NAC should not, however, provide a false sense of protection, and should not oviate good judgment in the decision to proceed with procedures that utilize intravascular radiocontrast. Nor should this medication e used in lieu of proven preventive interventions such as isotonic i.v. fluids. Agents that have een shown to e ineffective, and in some cases appear to e deleterious, such as mannitol, dopamine and fenoldopam, should not e utilized. Until large clinical trials shed further light on the role of atrial natriuretic peptide, statins, and prostaglandin analogs, we do not recommend their use. Similarly, we elieve there is currently no role for prophylactic renal replacement therapy for the prevention of CIAKI. Monitoring of renal function following the administration of iodinated radiocontrast is also important. We recommend that at a follow-up SCr should e otained h following the contrast administration in all high-risk patients. Conclusion Contrast-induced acute kidney injury is a common, yet potentially preventale iatrogenic condition. 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