The new england journal of medicine original article The Prevention of Radiocontrast-Agent– Induced Nephropathy by Hemofiltration Giancarlo Marenzi, M.D., Ivana Marana, M.D., Gianfranco Lauri, M.D., Emilio Assanelli, M.D., Marco Grazi, M.D., Jeness Campodonico, M.D., Daniela Trabattoni, M.D., Franco Fabbiocchi, M.D., Piero Montorsi, M.D., and Antonio L. Bartorelli, M.D. abstract background Nephropathy induced by exposure to radiocontrast agents, a possible complication of From the Centro Cardiologico Monzino, percutaneous coronary interventions, is associated with significant in-hospital and long- Istituto di Ricovero e Cura a Carattere Sci- entifico, Institute of Cardiology, Universi- term morbidity and mortality. Patients with preexisting renal failure are at particularly ty of Milan, Milan, Italy. Address reprint high risk. We investigated the role of hemofiltration, as compared with isotonic-saline requests to Dr. Marenzi at Centro Cardio- hydration, in preventing contrast-agent–induced nephropathy in patients with renal logico Monzino, Via Parea 4, 20138 Milan, Italy, or at giancarlo.marenzi@ failure. cardiologicomonzino.it. methods N Engl J Med 2003;349:1333-40. We studied 114 consecutive patients with chronic renal failure (serum creatinine con- Copyright © 2003 Massachusetts Medical Society. centration, >2 mg per deciliter [176.8 µmol per liter]) who were undergoing coronary interventions. We randomly assigned them to either hemofiltration in an intensive care unit (ICU) (58 patients, with a mean [±SD] serum creatinine concentration of 3.0±1.0 mg per deciliter [265.2±88.4 µmol per liter]) or isotonic-saline hydration at a rate of 1 ml per kilogram of body weight per hour given in a step-down unit (56 patients, with a mean serum creatinine concentration of 3.1±1.0 mg per deciliter [274.0±88.4 µmol per liter]). Hemofiltration (fluid replacement rate, 1000 ml per hour without weight loss) and saline hydration were initiated 4 to 8 hours before the coronary intervention and were continued for 18 to 24 hours after the procedure was completed. results An increase in the serum creatinine concentration of more than 25 percent from the base- line value after the coronary intervention occurred less frequently among the patients in the hemofiltration group than among the control patients (5 percent vs. 50 percent, P<0.001). Temporary renal-replacement therapy (hemodialysis or hemofiltration) was required in 25 percent of the control patients and in 3 percent of the patients in the hemo- filtration group. The rate of in-hospital events was 9 percent in the hemofiltration group and 52 percent in the control group (P<0.001). In-hospital mortality was 2 percent in the hemofiltration group and 14 percent in the control group (P=0.02), and the cumulative one-year mortality was 10 percent and 30 percent, respectively (P=0.01). conclusions In patients with chronic renal failure who are undergoing percutaneous coronary inter- ventions, periprocedural hemofiltration given in an ICU setting appears to be effective in preventing the deterioration of renal function due to contrast-agent–induced nephrop- athy and is associated with improved in-hospital and long-term outcomes. n engl j med 349;14 www.nejm.org october 2, 2003 1333 Downloaded from www.nejm.org by GEOFFREY K. LIGHTHALL MD on October 06, 2003. Copyright © 2003 Massachusetts Medical Society. All rights reserved. The new england journal of medicine adiocontrast-agent–induced trast agents from the circulation.24 This mecha- nephropathy is a common cause of acute nism, along with the dilution of contrast agents r 1-3 renal failure, which can range from a through the infusion of replacement fluid, lowers transient elevation of the serum creatinine concen- the concentration of the contrast agent in the blood tration to permanent renal failure necessitating di- and may reduce the exposure of the kidneys to the alysis. When contrast-agent–induced nephropathy nephrotoxic effects of these agents. We performed a complicates percutaneous coronary interventions, prospective, randomized study comparing hemofil- it is associated with significant in-hospital and long- tration with saline hydration for the prevention of term morbidity and mortality, as well as with a pro- contrast-agent–induced nephropathy in patients longed hospital stay.1-8 In addition, the clinical out- with renal insufficiency who were to undergo elec- come of patients who require emergency dialysis tive percutaneous coronary interventions. after a percutaneous coronary intervention is very poor, with a reported in-hospital mortality rate as methods high as 62 percent.9,10 Most patients in whom contrast-agent–induced study population nephropathy develops have risk factors for it.1-3,11,12 We enrolled 114 consecutive patients with chronic It has been reported that 90 percent of such ne- renal failure who were scheduled for coronary angi- phropathy occurs in patients with preexisting renal ography or an elective percutaneous coronary in- failure.3,11 Nevertheless, an increasing number of tervention at our institution, Centro Cardiologico patients with chronic renal failure are being referred Monzino in Milan, Italy, between January 1, 2000, for percutaneous coronary interventions, owing to and October 31, 2001. Eligible patients were those the greater prevalence of cardiovascular disease with a serum creatinine concentration exceeding among patients with renal failure, combined with 2 mg per deciliter (176.8 µmol per liter) and a creat- the prolongation of their life span.13 inine clearance rate of less than 50 ml per minute. Contrast-agent–induced nephropathy is a po- Patients with an acute coronary syndrome, cardio- tentially preventable condition. However, currently genic shock, long-term peritoneal dialysis or hemo- available strategies, such as hydration and the use dialysis treatment, overt congestive heart failure, of acetylcysteine, mannitol, furosemide, calcium recent major bleeding, or contraindications to an- antagonists, dopamine, fenoldopam, or other reno- ticoagulant therapy were excluded. A nonionic, low- protective drugs, have been shown to have no ben- osmolality contrast agent (Iopentol, Nycomed Im- efit or to reduce the incidence of such nephropathy aging) was used in all patients. Renoprotective drugs only in patients with mild renal impairment and ex- were not administered to any patient during the posure to a low volume of contrast agent.14-19 More- study. The ethics committee of our institution ap- over, prophylactic hemodialysis, started immediate- proved the protocol, and written informed consent ly after the administration of a contrast agent in was obtained from all patients. patients with reduced renal function, has demon- strated no net benefit.20 study protocol In contrast to hemodialysis, hemofiltration is a On the basis of computer-generated random num- continuous form of renal-replacement therapy that bers, patients were assigned to receive either hemo- constitutes an alternative strategy for the prevention filtration therapy in an intensive care unit (ICU) of contrast-agent–induced nephropathy in high-risk (hemofiltration group) or intravenous hydration patients.21,22 Hemofiltration is associated with he- with isotonic saline given in a step-down unit (con- modynamic stability21-23 and can exert a beneficial trol group). Patients randomly assigned to hemo- effect through other mechanisms as well. First, filtration were admitted to the ICU for the duration since periprocedural hydration has been proved to of treatment; those assigned to the control group be an efficacious and well-tolerated strategy, the were admitted to the contiguous step-down unit, potential benefit of hemofiltration can be markedly where they were followed by the medical and nurs- amplified by administering a volume of fluid per ing staff of the ICU, and were transferred to the ICU hour that is 10 to 15 times that delivered by stand- if there were major complications. The intensity of ard hydration, without an associated risk of fluid monitoring was lower in the step-down unit than in overload and lung congestion. Second, like glomer- the ICU: there was a ratio of patients to staff mem- ular filtration, hemofiltration is able to remove con- bers of approximately 2:1 in the ICU and 4:1 in the 1334 n engl j med 349;14 www.nejm.org october 2, 2003 Downloaded from www.nejm.org by GEOFFREY K. LIGHTHALL MD on October 06, 2003. Copyright © 2003 Massachusetts Medical Society. All rights reserved. prevention of radiocontrast-agent–induced nephropathy by hemofiltration step-down unit. For patients in the hemofiltration arinization was monitored by measurement of the group, a treatment session was started 4 to 6 hours activated partial-thromboplastin time. before the scheduled coronary procedure; treatment was resumed after the procedure was completed and statistical analysis continued for 18 to 24 hours. Hemofiltration treat- For the calculation of the sample size, we assumed ment was stopped during the coronary procedure, an incidence of contrast-agent–induced nephropa- and the hemofiltration circuit was temporarily filled thy of 40 percent in the control group and a 25 per- with a saline solution and was “short-circuited” to cent reduction with hemofiltration (an incidence of exclude the patient without interruption of the flow 30 percent); the inclusion of 50 patients in each through the circuit. Patients in the control group group allowed for 80 percent power with an alpha received a continuous intravenous infusion of iso- error of 0.05. All data are presented as means ±SD or tonic saline at a rate of 1 ml per kilogram of body as percentages. Comparisons of base-line variables weight per hour (0.5 ml per kilogram per hour if between the two treatment groups were performed the ejection fraction was less than 40 percent) for with Fisher’s exact test for categorical variables and 6 to 8 hours before and 24 hours after the coronary with Student’s unpaired t-test for continuous varia- procedure. bles. Changes during hemofiltration and hydration Blood urea nitrogen and serum creatinine were treatment were assessed with the use of repeated- measured at base line, immediately before angiog- measures analysis of covariance.