Multimodality Prevention of Contrast-Induced Acute Kidney Injury

Abstract

Commentary on 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 115:1211-1217, 2007Contrast-induced acute kidney injury (AKI) is an important complication following the use of iodinated contrast media, accounts for a significant number of cases of hospital-acquired AKI, and is associated with long-term morbidity, mortality, and increased healthcare costs.1McCullough P.A. Soman S.S. Contrast-induced nephropathy.Crit Care Clin. 2005; 21: 261-280Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 2Gleeson T.G. Bulugahapitiya S. Contrast-induced nephropathy.AJR Am J Roentgenol. 2004; 183: 1673-1689Crossref PubMed Scopus (317) Google Scholar, 3Nash K. Hafeez A. Hou S. Hospital-acquired renal insufficiency.Am J Kidney Dis. 2002; 39: 930-936Abstract Full Text Full Text PDF PubMed Scopus (1533) Google Scholar Contrast-induced AKI has been defined as an acute decline in glomerular filtration rate (GFR), manifest by an increase in serum creatinine occurring within the first 24 hours after contrast exposure, and peaking up to 5 days afterwards. In most instances, the rise in serum creatinine is expressed either in absolute terms (0.5-1.0 mg/dL [44-88 μmol/L]) or as a proportional rise of 25% to 50% above the baseline value. The Acute Kidney Injury Network (AKIN) definition of AKI is a rise in serum creatinine of 0.3 mg/dL (27 μmol/L) or more, with or without oliguria, which is compatible with previous definitions and may be a new standard to follow.4Mehta R.L. Kellum J.A. Shah S.V. et al.Acute Kidney Injury Network (AKIN): report of an initiative to improve outcomes in acute kidney injury.Critical Care. 2007; 11: R31Crossref PubMed Scopus (5112) Google Scholar Chronic kidney disease (CKD) appears to be both necessary and sufficient for the development of contrast-induced AKI. This is a relatively new understanding based on the observed rates of AKI stratified by baseline estimated GFR (eGFR) in prospective trials.5McCullough P.A. Adam A. Becker C.R. et al.Risk Prediction of Contrast-Induced Nephropathy.Am J Cardiol. 2006; 98: 27-36Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar There are negligible rates of AKI in those with normal eGFR, and as eGFR falls, there is a curvilinear increase in the frequency of AKI below an eGFR of 60 mL/min/1.73 m2 (1 mL/s/1.73 m2). In these patients with CKD, there is a considerable loss of functioning nephron units and those remaining are vulnerable to injury. Thus, the pathophysiology of contrast-induced AKI in CKD assumes baseline reduced nephron number, with superimposed acute vasoconstriction caused by the release of adenosine, endothelin, and other renal vasoconstrictors triggered by iodinated contrast.1McCullough P.A. Soman S.S. Contrast-induced nephropathy.Crit Care Clin. 2005; 21: 261-280Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar After a very brief increase in renal blood flow, via the above mechanisms, there is an overall (approximately 50%) sustained reduction in renal blood flow lasting for several hours. There is concentration of iodinated contrast in the renal tubules and collecting ducts, resulting in a persistent nephrogram on fluoroscopy. This stasis of contrast in the kidney allows for direct renal tubular epithelial cell injury and death. The degree of cytotoxicity to renal tubular epithelial cells is directly related to the length of exposure of cells to iodinated contrast, hence, the importance of high urinary flow rates before, during, and after contrast procedures. The sustained reduction in renal blood flow to the outer medulla leads to medullary hypoxia, ischemic injury, and death of renal tubular epithelial cells. Through these 2 triggering mechanisms, oxidative stress and inflammation might further play a role in kidney injury. Thus, the use of intravenous fluids (in the form of normal saline or sodium bicarbonate), N-acetylcysteine (NAC), and ascorbic acid, collectively, are reasonable strategies aimed at preserving renal blood flow, reducing renal stasis of contrast, while at the same time reducing oxidative injury to renal tubular epithelial cells.What did This Important Study Show?The Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL) was a randomized trial comparing 3 strategies for the prevention of contrast-induced AKI in patients with CKD (as defined by a serum creatinine ≥ 2.0 mg/dL [177 μmol/L] or eGFR < 40 mL/min/1.73 m2 [0.67 mL/s/1.73 m2]) undergoing coronary or peripheral angiography and/or angioplasty.6Briguori 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: 1211-1217PubMed Google Scholar Patient were randomly assigned to prophylactic administration of either (1) intravenous 0.9% normal saline (1 mL/kg/h for 12 hours before and 12 hours after the procedure) plus NAC (1,200 mg orally twice daily before and after) (n = 111); (2) intravenous sodium bicarbonate (154 mEq/L [154 mmol/L] in dextrose and H2O, 3 mL/kg bolus for 1 hour before and 1 mL/kg/h for 6 hours after the procedure) plus NAC (as above) (n = 108); or (3) normal saline (as above) plus ascorbic acid (3 g intravenously before and 2 g intravenously for 2 doses afterwards) plus NAC (as above) (n = 107). This was a two-center trial with no blinding of treatment allocation or analysis. All patients received iso-osmolar iodixanol contrast media (mean dose of approximately 173 mL). The sample size was determined based on a very optimistic 87% relative risk reduction (from 15% to 2%) in the bicarbonate plus NAC or ascorbic acid groups compared to normal saline plus NAC. The very high and unconventional expected risk reduction suggests that this trial might not have had a formal estimate of sample size during the planning stage, and that the effect size was chosen to harmonize with the sample size obtained. The primary end point was an increase of at least 25% in the serum creatinine 48 hours after the procedure. Based on this definition, AKI developed in 11 of 111 patients (9.9%) in the saline plus NAC group, in 2 of 108 (1.9%) in the bicarbonate plus NAC group (P = 0.02 v saline plus NAC), and in 11 of 107 (10.3%) in the saline plus ascorbic acid plus NAC group (P = 1.00 v saline plus NAC group). This was not an intent-to-treat analysis because 23 patients did not have follow-up serum creatinine measurements and could not be included for the creatinine endpoint. Thus, because there are only 9 patients with events that constitute the largest differential between any 2 groups, and the P value of interest is less than 0.025 (adjusted for multiple comparisons), the conclusions of this trial favoring bicarbonate plus NAC are based on 1 event. This means that if an endpoint occurred by random chance in 1 or more of the 23 patients lost to follow-up, and this changed the event difference to 8 or less, the overall results of the trial would have been null. Thus, the major conclusion of this trial is extremely tenuous and assumes that the unmeasured results in the patients lost to follow-up would not have changed the outcome.How does This Study Compare to Prior Studies?There are limited data on the most appropriate choice of intravenous fluid, but the evidence indicates that isotonic crystalloid (in the form of saline or bicarbonate solution) is probably more effective than half-normal saline.7Mueller C. Buerkle G. Buettner H.J. et al.Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty.Arch Intern Med. 2002; 162: 329-336Crossref PubMed Scopus (725) Google Scholar However, the largest trial to date (n = 353, event rate 13.6% with bicarbonate) showed no benefit of sodium bicarbonate over normal saline.8Brar S: A randomized controlled trial for the prevention of contrast induced nephropathy with sodium bicarbonate vs. sodium chloride in persons undergoing coronary angiography (the MEENA trial). Abstract 209-9. Presentation at the 56th Annual Scientific Session of the American College of Cardiology, New Orleans, LA, USA, 24-27 March 2007Google Scholar Ascorbic acid has been tested in a multicenter, blinded, placebo-controlled trial (n = 231), and been shown to reduce rates of contrast-induced AKI. The dose of ascorbic acid used in this trial was 3 g orally the night before and 2 g orally twice daily after the procedure.9Spargias K. Alexopoulos E. Kyrzopoulos S. et al.Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention.Circulation. 2004; 110: 2837-2842Crossref PubMed Scopus (272) Google Scholar Although popular, NAC has not been consistently shown to be effective. Nine published meta-analyses have been published,10Stacul F. Adam A. Becker C.R. et al.Strategies to reduce the risk of contrast-induced nephropathy.Am J Cardiol. 2006; 98: 59K-77KAbstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar all documenting the significant heterogeneity between studies and pooled odds ratios for NAC approaching unity. Importantly, only in those trials where NAC reduced serum creatinine below baseline values did AKI rates appear to be reduced. In healthy human volunteers, NAC has been shown to reduce serum creatinine levels, possibly by decreasing generation by muscle or interfering in the assay, thereby increasing eGFR. Thus, NAC might falsely lower serum creatinine, rather than protect against AKI.11Hoffmann U. Fischereder M. Kruger B. et al.The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable.J Am Soc Nephrol. 2004; 15: 407-410Crossref PubMed Scopus (282) Google Scholar However, NAC as an antioxidant has been shown to lower rates of AKI and mortality after primary percutaneous coronary intervention in 1 trial.12Marenzi G. Assanelli E. Marana I. et al.N-acetylcysteine and contrast-induced nephropathy in primary angioplasty.N Engl J Med. 2006; 354: 2773-2782Crossref PubMed Scopus (520) Google Scholar Thus the findings in REMEDIAL either reflect a dramatic beneficial interaction between bicarbonate and NAC or the play of chance. The lack of supporting data in previous studies and the sparseness of the endpoints in REMEDIAL argue strongly for the latter interpretation.What Should Clinicians and Researchers do?Clinicians are currently advised to follow good clinical practice, and consensus-based recommendations as summarized in Table 1. Until definitive trials have been completed, this is the most reasonable strategy.Table 1Consensus statements, adapted from McCullough et al, 2006.15McCullough P.A. Stacul F. Becker C.R. et al.Contrast-Induced Nephropathy (CIN) Consensus Working Panel: Executive Summary.Rev Cardiovasc Med. 2006; 7: 177-197PubMed Google ScholarConsensus Statement 1Patients and clinicians should be aware that contrast-induced AKI is a common and potentially serious complication following the administration of contrast media in patients at risk for AKI.Consensus Statement 2The risk of contrast-induced AKI is elevated and of clinical importance in patients with CKD (particularly when diabetes is also present), recognized by an eGFR of less than 60 mL/min/1.73 m2.Consensus Statement 3When serum creatinine or estimated glomerular filtration rate is unavailable, then a medical history (inquiring about risk factors for CKD) may be used to identify patients at higher risk for contrast-induced AKI than the general population.Consensus Statement 4In the setting of emergency procedures, where the benefit of very early imaging outweighs the risk of waiting, the procedure can be performed without knowledge of serum creatinine or eGFR.Consensus Statement 5Clinicians should recognize the presence of multiple contrast-induced AKI risk factors in the same patient or high-risk clinical scenarios can create a very high risk (approximately 50%) for contrast-induced AKI and (approximately 15%) for need for dialysis after contrast exposure.Consensus Statement 6In patients at increased risk for contrast-induced AKI undergoing intra-arterial administration of contrast, nonionic, iso-osmolar contrast (iodixanol) is associated with the lowest risk of contrast-induced AKI.Consensus Statement 7Iodinated contrast volumes should be minimized. Higher contrast volumes (>100 mL) are associated with higher rates of contrast-induced AKI in patients at risk. However, even small (approximately 30 mL) volumes of iodinated contrast in very high-risk patients can cause contrast-induced AKI and need for dialysis, suggesting the absence of a threshold effect.Consensus Statement 8Intra-arterial administration of iodinated contrast appears to pose a greater risk of contrast-induced AKI above that with intravenous administration, thus when possible, intravenous studies are preferred.Consensus Statement 9Adequate intravenous volume expansion with isotonic crystalloid (1.0-1.5 mL/kg/h) for 3 to 12 hours before the procedure and continued for 6 to 24 hours afterwards can lessen the probability of contrast-induced AKI in patients at risk.Consensus Statement 10No adjunctive medical or mechanical treatment has been proven to be effective in reducing the risk of AKI after exposure to iodinated contrast. Hence use of a prophylactic agent is at the discretion of the treating physician. Prophylactic hemodialysis or hemofiltration has not been validated as an effective strategy.Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. Open table in a new tab Researchers have recognized that better markers of kidney damage and function are needed to move this field forward. Thus, there is considerable interest in developing blood and urine biomarkers for AKI analogous to troponin for acute myocardial infarction. Neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin family, is readily excreted and detected in urine, due to its small molecular size (25 kDa) and resistance to degradation. NGAL is highly accumulated in the human kidney cortical tubules, blood, and urine after nephrotoxic and ischemic injuries such as exposure to iodinated contrast.13Bachorzewska-Gajewska H. Malyszko J. Sitniewska E. et al.Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.Am J Nephrol. 2006; 26: 287-292Crossref PubMed Scopus (219) Google Scholar Thus, whole-blood NGAL might represent an early, sensitive biomarker for kidney damage in AKI for point-of-care use in the catheterization laboratory.13Bachorzewska-Gajewska H. Malyszko J. Sitniewska E. et al.Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.Am J Nephrol. 2006; 26: 287-292Crossref PubMed Scopus (219) Google Scholar, 14Mishra J. Dent C. Tarabishi R. et al.Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery.Lancet. 2005; 365: 1231-1238Abstract Full Text Full Text PDF PubMed Scopus (1915) Google Scholar Cystatin C is a serum protein that is a glomerular filtration marker that serves as a measure of kidney function. Cystatin C is thought to be steadily produced by nucleated cells, and its low molecular mass allows it to be freely filtered by the glomerulus. Its concentration in blood correlates with GFR. Cystatin C levels are independent of weight and height, muscle mass, age, and sex. Measurements can be made and interpreted from a single random sample. Thus, cystatin C may be a better marker of kidney function than creatinine, and has been cleared for use by the US Food and Drug Administration. It is expected that this marker may replace serum creatinine in the future, and it should be used in clinical trials now.Contrast-induced AKI is one of the most amenable forms of AKI for clinical trials. Future approaches that are underway include large planned studies of more potent antioxidants (eg, deferiprone), intrarenal infusions of renal vasodilators using flow-directed catheters, forced hydration with marked elevations of urine output to reduce the transit time of iodinated contrast in the renal tubules, systemic cooling, and novel, hopefully less toxic forms of radio-opaque contrast agents. If cardiovascular procedures could be performed with no risk of AKI, it is expected that major adverse cardiac and medical complications could be appreciably reduced. This is exactly the hypothesis that is encouraged in future, large-scale outcome trials of contrast-induced AKI prevention.In conclusion, the REMEDIAL study reminds us that the results of small, unblinded clinical trials of popular treatment strategies may reflect random error and are not sufficient to change clinical practice. Instead, we should cultivate an expectation for multicenter, large-scale randomized trials of preventive strategies. Future, nontoxic imaging agents are needed to manage the ever-increasing numbers of vulnerable patients undergoing contrast procedures. Commentary on 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 115:1211-1217, 2007 Commentary on 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 115:1211-1217, 2007 Commentary on 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 115:1211-1217, 2007 Contrast-induced acute kidney injury (AKI) is an important complication following the use of iodinated contrast media, accounts for a significant number of cases of hospital-acquired AKI, and is associated with long-term morbidity, mortality, and increased healthcare costs.1McCullough P.A. Soman S.S. Contrast-induced nephropathy.Crit Care Clin. 2005; 21: 261-280Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 2Gleeson T.G. Bulugahapitiya S. Contrast-induced nephropathy.AJR Am J Roentgenol. 2004; 183: 1673-1689Crossref PubMed Scopus (317) Google Scholar, 3Nash K. Hafeez A. Hou S. Hospital-acquired renal insufficiency.Am J Kidney Dis. 2002; 39: 930-936Abstract Full Text Full Text PDF PubMed Scopus (1533) Google Scholar Contrast-induced AKI has been defined as an acute decline in glomerular filtration rate (GFR), manifest by an increase in serum creatinine occurring within the first 24 hours after contrast exposure, and peaking up to 5 days afterwards. In most instances, the rise in serum creatinine is expressed either in absolute terms (0.5-1.0 mg/dL [44-88 μmol/L]) or as a proportional rise of 25% to 50% above the baseline value. The Acute Kidney Injury Network (AKIN) definition of AKI is a rise in serum creatinine of 0.3 mg/dL (27 μmol/L) or more, with or without oliguria, which is compatible with previous definitions and may be a new standard to follow.4Mehta R.L. Kellum J.A. Shah S.V. et al.Acute Kidney Injury Network (AKIN): report of an initiative to improve outcomes in acute kidney injury.Critical Care. 2007; 11: R31Crossref PubMed Scopus (5112) Google Scholar Chronic kidney disease (CKD) appears to be both necessary and sufficient for the development of contrast-induced AKI. This is a relatively new understanding based on the observed rates of AKI stratified by baseline estimated GFR (eGFR) in prospective trials.5McCullough P.A. Adam A. Becker C.R. et al.Risk Prediction of Contrast-Induced Nephropathy.Am J Cardiol. 2006; 98: 27-36Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar There are negligible rates of AKI in those with normal eGFR, and as eGFR falls, there is a curvilinear increase in the frequency of AKI below an eGFR of 60 mL/min/1.73 m2 (1 mL/s/1.73 m2). In these patients with CKD, there is a considerable loss of functioning nephron units and those remaining are vulnerable to injury. Thus, the pathophysiology of contrast-induced AKI in CKD assumes baseline reduced nephron number, with superimposed acute vasoconstriction caused by the release of adenosine, endothelin, and other renal vasoconstrictors triggered by iodinated contrast.1McCullough P.A. Soman S.S. Contrast-induced nephropathy.Crit Care Clin. 2005; 21: 261-280Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar After a very brief increase in renal blood flow, via the above mechanisms, there is an overall (approximately 50%) sustained reduction in renal blood flow lasting for several hours. There is concentration of iodinated contrast in the renal tubules and collecting ducts, resulting in a persistent nephrogram on fluoroscopy. This stasis of contrast in the kidney allows for direct renal tubular epithelial cell injury and death. The degree of cytotoxicity to renal tubular epithelial cells is directly related to the length of exposure of cells to iodinated contrast, hence, the importance of high urinary flow rates before, during, and after contrast procedures. The sustained reduction in renal blood flow to the outer medulla leads to medullary hypoxia, ischemic injury, and death of renal tubular epithelial cells. Through these 2 triggering mechanisms, oxidative stress and inflammation might further play a role in kidney injury. Thus, the use of intravenous fluids (in the form of normal saline or sodium bicarbonate), N-acetylcysteine (NAC), and ascorbic acid, collectively, are reasonable strategies aimed at preserving renal blood flow, reducing renal stasis of contrast, while at the same time reducing oxidative injury to renal tubular epithelial cells. What did This Important Study Show?The Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL) was a randomized trial comparing 3 strategies for the prevention of contrast-induced AKI in patients with CKD (as defined by a serum creatinine ≥ 2.0 mg/dL [177 μmol/L] or eGFR < 40 mL/min/1.73 m2 [0.67 mL/s/1.73 m2]) undergoing coronary or peripheral angiography and/or angioplasty.6Briguori 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: 1211-1217PubMed Google Scholar Patient were randomly assigned to prophylactic administration of either (1) intravenous 0.9% normal saline (1 mL/kg/h for 12 hours before and 12 hours after the procedure) plus NAC (1,200 mg orally twice daily before and after) (n = 111); (2) intravenous sodium bicarbonate (154 mEq/L [154 mmol/L] in dextrose and H2O, 3 mL/kg bolus for 1 hour before and 1 mL/kg/h for 6 hours after the procedure) plus NAC (as above) (n = 108); or (3) normal saline (as above) plus ascorbic acid (3 g intravenously before and 2 g intravenously for 2 doses afterwards) plus NAC (as above) (n = 107). This was a two-center trial with no blinding of treatment allocation or analysis. All patients received iso-osmolar iodixanol contrast media (mean dose of approximately 173 mL). The sample size was determined based on a very optimistic 87% relative risk reduction (from 15% to 2%) in the bicarbonate plus NAC or ascorbic acid groups compared to normal saline plus NAC. The very high and unconventional expected risk reduction suggests that this trial might not have had a formal estimate of sample size during the planning stage, and that the effect size was chosen to harmonize with the sample size obtained. The primary end point was an increase of at least 25% in the serum creatinine 48 hours after the procedure. Based on this definition, AKI developed in 11 of 111 patients (9.9%) in the saline plus NAC group, in 2 of 108 (1.9%) in the bicarbonate plus NAC group (P = 0.02 v saline plus NAC), and in 11 of 107 (10.3%) in the saline plus ascorbic acid plus NAC group (P = 1.00 v saline plus NAC group). This was not an intent-to-treat analysis because 23 patients did not have follow-up serum creatinine measurements and could not be included for the creatinine endpoint. Thus, because there are only 9 patients with events that constitute the largest differential between any 2 groups, and the P value of interest is less than 0.025 (adjusted for multiple comparisons), the conclusions of this trial favoring bicarbonate plus NAC are based on 1 event. This means that if an endpoint occurred by random chance in 1 or more of the 23 patients lost to follow-up, and this changed the event difference to 8 or less, the overall results of the trial would have been null. Thus, the major conclusion of this trial is extremely tenuous and assumes that the unmeasured results in the patients lost to follow-up would not have changed the outcome. The Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL) was a randomized trial comparing 3 strategies for the prevention of contrast-induced AKI in patients with CKD (as defined by a serum creatinine ≥ 2.0 mg/dL [177 μmol/L] or eGFR < 40 mL/min/1.73 m2 [0.67 mL/s/1.73 m2]) undergoing coronary or peripheral angiography and/or angioplasty.6Briguori 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: 1211-1217PubMed Google Scholar Patient were randomly assigned to prophylactic administration of either (1) intravenous 0.9% normal saline (1 mL/kg/h for 12 hours before and 12 hours after the procedure) plus NAC (1,200 mg orally twice daily before and after) (n = 111); (2) intravenous sodium bicarbonate (154 mEq/L [154 mmol/L] in dextrose and H2O, 3 mL/kg bolus for 1 hour before and 1 mL/kg/h for 6 hours after the procedure) plus NAC (as above) (n = 108); or (3) normal saline (as above) plus ascorbic acid (3 g intravenously before and 2 g intravenously for 2 doses afterwards) plus NAC (as above) (n = 107). This was a two-center trial with no blinding of treatment allocation or analysis. All patients received iso-osmolar iodixanol contrast media (mean dose of approximately 173 mL). The sample size was determined based on a very optimistic 87% relative risk reduction (from 15% to 2%) in the bicarbonate plus NAC or ascorbic acid groups compared to normal saline plus NAC. The very high and unconventional expected risk reduction suggests that this trial might not have had a formal estimate of sample size during the planning stage, and that the effect size was chosen to harmonize with the sample size obtained. The primary end point was an increase of at least 25% in the serum creatinine 48 hours after the procedure. Based on this definition, AKI developed in 11 of 111 patients (9.9%) in the saline plus NAC group, in 2 of 108 (1.9%) in the bicarbonate plus NAC group (P = 0.02 v saline plus NAC), and in 11 of 107 (10.3%) in the saline plus ascorbic acid plus NAC group (P = 1.00 v saline plus NAC group). This was not an intent-to-treat analysis because 23 patients did not have follow-up serum creatinine measurements and could not be included for the creatinine endpoint. Thus, because there are only 9 patients with events that constitute the largest differential between any 2 groups, and the P value of interest is less than 0.025 (adjusted for multiple comparisons), the conclusions of this trial favoring bicarbonate plus NAC are based on 1 event. This means that if an endpoint occurred by random chance in 1 or more of the 23 patients lost to follow-up, and this changed the event difference to 8 or less, the overall results of the trial would have been null. Thus, the major conclusion of this trial is extremely tenuous and assumes that the unmeasured results in the patients lost to follow-up would not have changed the outcome. How does This Study Compare to Prior Studies?There are limited data on the most appropriate choice of intravenous fluid, but the evidence indicates that isotonic crystalloid (in the form of saline or bicarbonate solution) is probably more effective than half-normal saline.7Mueller C. Buerkle G. Buettner H.J. et al.Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty.Arch Intern Med. 2002; 162: 329-336Crossref PubMed Scopus (725) Google Scholar However, the largest trial to date (n = 353, event rate 13.6% with bicarbonate) showed no benefit of sodium bicarbonate over normal saline.8Brar S: A randomized controlled trial for the prevention of contrast induced nephropathy with sodium bicarbonate vs. sodium chloride in persons undergoing coronary angiography (the MEENA trial). Abstract 209-9. Presentation at the 56th Annual Scientific Session of the American College of Cardiology, New Orleans, LA, USA, 24-27 March 2007Google Scholar Ascorbic acid has been tested in a multicenter, blinded, placebo-controlled trial (n = 231), and been shown to reduce rates of contrast-induced AKI. The dose of ascorbic acid used in this trial was 3 g orally the night before and 2 g orally twice daily after the procedure.9Spargias K. Alexopoulos E. Kyrzopoulos S. et al.Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention.Circulation. 2004; 110: 2837-2842Crossref PubMed Scopus (272) Google Scholar Although popular, NAC has not been consistently shown to be effective. Nine published meta-analyses have been published,10Stacul F. Adam A. Becker C.R. et al.Strategies to reduce the risk of contrast-induced nephropathy.Am J Cardiol. 2006; 98: 59K-77KAbstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar all documenting the significant heterogeneity between studies and pooled odds ratios for NAC approaching unity. Importantly, only in those trials where NAC reduced serum creatinine below baseline values did AKI rates appear to be reduced. In healthy human volunteers, NAC has been shown to reduce serum creatinine levels, possibly by decreasing generation by muscle or interfering in the assay, thereby increasing eGFR. Thus, NAC might falsely lower serum creatinine, rather than protect against AKI.11Hoffmann U. Fischereder M. Kruger B. et al.The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable.J Am Soc Nephrol. 2004; 15: 407-410Crossref PubMed Scopus (282) Google Scholar However, NAC as an antioxidant has been shown to lower rates of AKI and mortality after primary percutaneous coronary intervention in 1 trial.12Marenzi G. Assanelli E. Marana I. et al.N-acetylcysteine and contrast-induced nephropathy in primary angioplasty.N Engl J Med. 2006; 354: 2773-2782Crossref PubMed Scopus (520) Google Scholar Thus the findings in REMEDIAL either reflect a dramatic beneficial interaction between bicarbonate and NAC or the play of chance. The lack of supporting data in previous studies and the sparseness of the endpoints in REMEDIAL argue strongly for the latter interpretation. There are limited data on the most appropriate choice of intravenous fluid, but the evidence indicates that isotonic crystalloid (in the form of saline or bicarbonate solution) is probably more effective than half-normal saline.7Mueller C. Buerkle G. Buettner H.J. et al.Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty.Arch Intern Med. 2002; 162: 329-336Crossref PubMed Scopus (725) Google Scholar However, the largest trial to date (n = 353, event rate 13.6% with bicarbonate) showed no benefit of sodium bicarbonate over normal saline.8Brar S: A randomized controlled trial for the prevention of contrast induced nephropathy with sodium bicarbonate vs. sodium chloride in persons undergoing coronary angiography (the MEENA trial). Abstract 209-9. Presentation at the 56th Annual Scientific Session of the American College of Cardiology, New Orleans, LA, USA, 24-27 March 2007Google Scholar Ascorbic acid has been tested in a multicenter, blinded, placebo-controlled trial (n = 231), and been shown to reduce rates of contrast-induced AKI. The dose of ascorbic acid used in this trial was 3 g orally the night before and 2 g orally twice daily after the procedure.9Spargias K. Alexopoulos E. Kyrzopoulos S. et al.Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention.Circulation. 2004; 110: 2837-2842Crossref PubMed Scopus (272) Google Scholar Although popular, NAC has not been consistently shown to be effective. Nine published meta-analyses have been published,10Stacul F. Adam A. Becker C.R. et al.Strategies to reduce the risk of contrast-induced nephropathy.Am J Cardiol. 2006; 98: 59K-77KAbstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar all documenting the significant heterogeneity between studies and pooled odds ratios for NAC approaching unity. Importantly, only in those trials where NAC reduced serum creatinine below baseline values did AKI rates appear to be reduced. In healthy human volunteers, NAC has been shown to reduce serum creatinine levels, possibly by decreasing generation by muscle or interfering in the assay, thereby increasing eGFR. Thus, NAC might falsely lower serum creatinine, rather than protect against AKI.11Hoffmann U. Fischereder M. Kruger B. et al.The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable.J Am Soc Nephrol. 2004; 15: 407-410Crossref PubMed Scopus (282) Google Scholar However, NAC as an antioxidant has been shown to lower rates of AKI and mortality after primary percutaneous coronary intervention in 1 trial.12Marenzi G. Assanelli E. Marana I. et al.N-acetylcysteine and contrast-induced nephropathy in primary angioplasty.N Engl J Med. 2006; 354: 2773-2782Crossref PubMed Scopus (520) Google Scholar Thus the findings in REMEDIAL either reflect a dramatic beneficial interaction between bicarbonate and NAC or the play of chance. The lack of supporting data in previous studies and the sparseness of the endpoints in REMEDIAL argue strongly for the latter interpretation. What Should Clinicians and Researchers do?Clinicians are currently advised to follow good clinical practice, and consensus-based recommendations as summarized in Table 1. Until definitive trials have been completed, this is the most reasonable strategy.Table 1Consensus statements, adapted from McCullough et al, 2006.15McCullough P.A. Stacul F. Becker C.R. et al.Contrast-Induced Nephropathy (CIN) Consensus Working Panel: Executive Summary.Rev Cardiovasc Med. 2006; 7: 177-197PubMed Google ScholarConsensus Statement 1Patients and clinicians should be aware that contrast-induced AKI is a common and potentially serious complication following the administration of contrast media in patients at risk for AKI.Consensus Statement 2The risk of contrast-induced AKI is elevated and of clinical importance in patients with CKD (particularly when diabetes is also present), recognized by an eGFR of less than 60 mL/min/1.73 m2.Consensus Statement 3When serum creatinine or estimated glomerular filtration rate is unavailable, then a medical history (inquiring about risk factors for CKD) may be used to identify patients at higher risk for contrast-induced AKI than the general population.Consensus Statement 4In the setting of emergency procedures, where the benefit of very early imaging outweighs the risk of waiting, the procedure can be performed without knowledge of serum creatinine or eGFR.Consensus Statement 5Clinicians should recognize the presence of multiple contrast-induced AKI risk factors in the same patient or high-risk clinical scenarios can create a very high risk (approximately 50%) for contrast-induced AKI and (approximately 15%) for need for dialysis after contrast exposure.Consensus Statement 6In patients at increased risk for contrast-induced AKI undergoing intra-arterial administration of contrast, nonionic, iso-osmolar contrast (iodixanol) is associated with the lowest risk of contrast-induced AKI.Consensus Statement 7Iodinated contrast volumes should be minimized. Higher contrast volumes (>100 mL) are associated with higher rates of contrast-induced AKI in patients at risk. However, even small (approximately 30 mL) volumes of iodinated contrast in very high-risk patients can cause contrast-induced AKI and need for dialysis, suggesting the absence of a threshold effect.Consensus Statement 8Intra-arterial administration of iodinated contrast appears to pose a greater risk of contrast-induced AKI above that with intravenous administration, thus when possible, intravenous studies are preferred.Consensus Statement 9Adequate intravenous volume expansion with isotonic crystalloid (1.0-1.5 mL/kg/h) for 3 to 12 hours before the procedure and continued for 6 to 24 hours afterwards can lessen the probability of contrast-induced AKI in patients at risk.Consensus Statement 10No adjunctive medical or mechanical treatment has been proven to be effective in reducing the risk of AKI after exposure to iodinated contrast. Hence use of a prophylactic agent is at the discretion of the treating physician. Prophylactic hemodialysis or hemofiltration has not been validated as an effective strategy.Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. Open table in a new tab Researchers have recognized that better markers of kidney damage and function are needed to move this field forward. Thus, there is considerable interest in developing blood and urine biomarkers for AKI analogous to troponin for acute myocardial infarction. Neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin family, is readily excreted and detected in urine, due to its small molecular size (25 kDa) and resistance to degradation. NGAL is highly accumulated in the human kidney cortical tubules, blood, and urine after nephrotoxic and ischemic injuries such as exposure to iodinated contrast.13Bachorzewska-Gajewska H. Malyszko J. Sitniewska E. et al.Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.Am J Nephrol. 2006; 26: 287-292Crossref PubMed Scopus (219) Google Scholar Thus, whole-blood NGAL might represent an early, sensitive biomarker for kidney damage in AKI for point-of-care use in the catheterization laboratory.13Bachorzewska-Gajewska H. Malyszko J. Sitniewska E. et al.Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.Am J Nephrol. 2006; 26: 287-292Crossref PubMed Scopus (219) Google Scholar, 14Mishra J. Dent C. Tarabishi R. et al.Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery.Lancet. 2005; 365: 1231-1238Abstract Full Text Full Text PDF PubMed Scopus (1915) Google Scholar Cystatin C is a serum protein that is a glomerular filtration marker that serves as a measure of kidney function. Cystatin C is thought to be steadily produced by nucleated cells, and its low molecular mass allows it to be freely filtered by the glomerulus. Its concentration in blood correlates with GFR. Cystatin C levels are independent of weight and height, muscle mass, age, and sex. Measurements can be made and interpreted from a single random sample. Thus, cystatin C may be a better marker of kidney function than creatinine, and has been cleared for use by the US Food and Drug Administration. It is expected that this marker may replace serum creatinine in the future, and it should be used in clinical trials now.Contrast-induced AKI is one of the most amenable forms of AKI for clinical trials. Future approaches that are underway include large planned studies of more potent antioxidants (eg, deferiprone), intrarenal infusions of renal vasodilators using flow-directed catheters, forced hydration with marked elevations of urine output to reduce the transit time of iodinated contrast in the renal tubules, systemic cooling, and novel, hopefully less toxic forms of radio-opaque contrast agents. If cardiovascular procedures could be performed with no risk of AKI, it is expected that major adverse cardiac and medical complications could be appreciably reduced. This is exactly the hypothesis that is encouraged in future, large-scale outcome trials of contrast-induced AKI prevention.In conclusion, the REMEDIAL study reminds us that the results of small, unblinded clinical trials of popular treatment strategies may reflect random error and are not sufficient to change clinical practice. Instead, we should cultivate an expectation for multicenter, large-scale randomized trials of preventive strategies. Future, nontoxic imaging agents are needed to manage the ever-increasing numbers of vulnerable patients undergoing contrast procedures. Clinicians are currently advised to follow good clinical practice, and consensus-based recommendations as summarized in Table 1. Until definitive trials have been completed, this is the most reasonable strategy. Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. Researchers have recognized that better markers of kidney damage and function are needed to move this field forward. Thus, there is considerable interest in developing blood and urine biomarkers for AKI analogous to troponin for acute myocardial infarction. Neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin family, is readily excreted and detected in urine, due to its small molecular size (25 kDa) and resistance to degradation. NGAL is highly accumulated in the human kidney cortical tubules, blood, and urine after nephrotoxic and ischemic injuries such as exposure to iodinated contrast.13Bachorzewska-Gajewska H. Malyszko J. Sitniewska E. et al.Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.Am J Nephrol. 2006; 26: 287-292Crossref PubMed Scopus (219) Google Scholar Thus, whole-blood NGAL might represent an early, sensitive biomarker for kidney damage in AKI for point-of-care use in the catheterization laboratory.13Bachorzewska-Gajewska H. Malyszko J. Sitniewska E. et al.Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions.Am J Nephrol. 2006; 26: 287-292Crossref PubMed Scopus (219) Google Scholar, 14Mishra J. Dent C. Tarabishi R. et al.Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery.Lancet. 2005; 365: 1231-1238Abstract Full Text Full Text PDF PubMed Scopus (1915) Google Scholar Cystatin C is a serum protein that is a glomerular filtration marker that serves as a measure of kidney function. Cystatin C is thought to be steadily produced by nucleated cells, and its low molecular mass allows it to be freely filtered by the glomerulus. Its concentration in blood correlates with GFR. Cystatin C levels are independent of weight and height, muscle mass, age, and sex. Measurements can be made and interpreted from a single random sample. Thus, cystatin C may be a better marker of kidney function than creatinine, and has been cleared for use by the US Food and Drug Administration. It is expected that this marker may replace serum creatinine in the future, and it should be used in clinical trials now. Contrast-induced AKI is one of the most amenable forms of AKI for clinical trials. Future approaches that are underway include large planned studies of more potent antioxidants (eg, deferiprone), intrarenal infusions of renal vasodilators using flow-directed catheters, forced hydration with marked elevations of urine output to reduce the transit time of iodinated contrast in the renal tubules, systemic cooling, and novel, hopefully less toxic forms of radio-opaque contrast agents. If cardiovascular procedures could be performed with no risk of AKI, it is expected that major adverse cardiac and medical complications could be appreciably reduced. This is exactly the hypothesis that is encouraged in future, large-scale outcome trials of contrast-induced AKI prevention. In conclusion, the REMEDIAL study reminds us that the results of small, unblinded clinical trials of popular treatment strategies may reflect random error and are not sufficient to change clinical practice. Instead, we should cultivate an expectation for multicenter, large-scale randomized trials of preventive strategies. Future, nontoxic imaging agents are needed to manage the ever-increasing numbers of vulnerable patients undergoing contrast procedures. Support: None. Financial Disclosure: None. In ReplyAmerican Journal of Kidney DiseasesVol. 51Issue 6PreviewThe Consensus Statement 6 (and now an American College of Cardiology/American Heart Association Class IA indication for the use of iodixanol) is based on the meta-analysis of 2,727 patients in head-to-head randomized trials demonstrating 62% and 80% relative risk reductions in all and those with diabetic chronic kidney disease, respectively (P < 0.001; P = 0.003).1,2 Full-Text PDF Multimodality Prevention of Contrast-Induced Acute Kidney InjuryAmerican Journal of Kidney DiseasesVol. 51Issue 6PreviewWe read with interest Dr McCullough's editorial on the REMEDIAL (Renal Insufficiency Following Contrast Media Administration Trial) study.1-2 We would like to make some comments. Full-Text PDF