Background Radiographic contrast agents can cause a reductionin renal function that may be due to reactive oxygen species.Whether the reduction can be prevented by the administrationof antioxidants is unknown.
Methods We prospectively studied 83 patients with chronic renalinsufficiency (mean [±SD] serum creatinine concentration,2.4±1.3 mg per deciliter [216± 116 µmolper liter]) who were undergoing computed tomography with iopromide,a nonionic, low-osmolality contrast agent. Patients were randomlyassigned either to receive the antioxidant acetylcysteine (600mg orally twice daily) and 0.45 percent saline intravenously,before and after administration of the contrast agent, or toreceive placebo and saline.
Results Ten of the 83 patients (12 percent) had an increaseof at least 0.5 mg per deciliter (44 µmol per liter) inthe serum creatinine concentration 48 hours after administrationof the contrast agent: 1 of the 41 patients in the acetylcysteinegroup (2 percent) and 9 of the 42 patients in the control group(21 percent; P=0.01; relative risk, 0.1; 95 percent confidenceinterval, 0.02 to 0.9). In the acetylcysteine group, the meanserum creatinine concentration decreased significantly (P<0.001),from 2.5±1.3 to 2.1±1.3 mg per deciliter (220±118to 186±112 µmol per liter) 48 hours after the administrationof the contrast medium, whereas in the control group, the meanserum creatinine concentration increased nonsignificantly (P=0.18),from 2.4±1.3 to 2.6±1.5 mg per deciliter (212±114to 226± 133 µmol per liter) (P<0.001 for thecomparison between groups).
Conclusions Prophylactic oral administration of the antioxidantacetylcysteine, along with hydration, prevents the reductionin renal function induced by iopromide, a nonionic, low-osmolalitycontrast agent, in patients with chronic renal insufficiency.
Administration of radiographic contrast agents often resultsin an acute reduction in renal function.1,2,3,4,5 The reductioncan cause substantial morbidity and mortality during hospitalizationand can lead to chronic end-stage renal disease.1,5 Importantrisk factors for contrast-agent–induced reductions inrenal function are preexisting renal dysfunction, particularlythat caused by diabetic nephropathy; reduced effective arterialvolume; concomitant administration of drugs that interfere withthe regulation of renal perfusion, such as angiotensin-converting–enzymeinhibitors; and a higher volume of contrast agent administered.1,2,6
In patients with chronic renal insufficiency, hydration hasbeen reported to ameliorate contrast-agent–induced reductionsin renal function, but the administration of drugs such as calciumantagonists, theophylline, dopamine, and atrial natriureticpeptide does not prevent the reduction.5,6,7,8,9,10,11,12 Contrastagents reduce renal function by altering renal hemodynamicsand by exerting direct toxic effects on tubular epithelial cells.There is accumulating evidence that reactive oxygen specieshave a role in the renal damage caused by contrast agents.13,14,15In rats, contrast agents increased lipid peroxidation,16 andsuperoxide dismutase, a scavenger of reactive oxygen species,preserved renal function.14
On the assumption that reactive oxygen species might be involvedin the pathogenesis of acute contrast-agent–induced reductionsin renal function, we studied the effects of the prophylacticoral administration of the antioxidant acetylcysteine in a prospective,placebo-controlled, randomized trial involving patients withchronic renal insufficiency who were at high risk for contrast-agent–inducedrenal damage.
Methods
Patients
We prospectively studied 83 patients with a serum creatinineconcentration above 1.2 mg per deciliter (106 µmol perliter) or creatinine clearance of less than 50 ml per minute(0.8 ml per second). Creatinine clearance was estimated on thebasis of the serum creatinine concentration, weight, age, andsex.17 Only patients known to have a history of chronic renalfailure and with stable serum creatinine concentrations wereincluded. Repeated measurements during the week before the administrationof the contrast agent revealed only minor changes in serum creatinineconcentrations (mean [±SD] variation, 0.1±0.3mg per deciliter [9±26 µmol per liter]; P=0.12).No patient with acute renal failure was included. The causeof renal insufficiency was diabetic nephropathy in 27 patients,nephrosclerosis in 20 patients, glomerulonephritis in 12 patients,tubulointerstitial nephritis in 4 patients, and unknown in 20patients. All the patients underwent elective computed tomography(CT) with a nonionic low-osmolality radiographic contrast agent.The indications for CT were determined by each patient's physician.Most patients underwent CT for the evaluation of an abdominalor thoracic illness.
The study protocol was approved by the local ethics committee,and all patients gave written informed consent.
Study Protocol
The patients were randomly assigned to receive either the antioxidantacetylcysteine and intravenous saline before and after administrationof the contrast agent (acetylcysteine group) or placebo andsaline (control group). Acetylcysteine was given orally at adose of 600 mg twice daily, on the day before and on the dayof administration of the contrast agent, for a total of twodays. Saline (0.45 percent) was given intravenously at a rateof 1 ml per kilogram of body weight per hour for 12 hours beforeand 12 hours after administration of the contrast agent. Allpatients were encouraged to drink if they were thirsty. Thedose of nonionic, low-osmolality contrast agent (iopromide;Ultravist-300, Schering, Berlin, Germany) was 75 ml for allpatients. The infusion contained 0.623 g of iopromide per milliliter,and the iodine content was 300 mg per milliliter. None of thepatients received theophylline, dopamine, mannitol, or furosemideduring the study. Serum creatinine and urea nitrogen were measuredrepeatedly during the week before administration of the contrastagent, as noted above, and immediately before, 48 hours after,and 6 days after administration of the contrast agent. An acutecontrast-agent–induced reduction in renal function wasdefined as an increase in the serum creatinine concentrationof at least 0.5 mg per deciliter (44 µmol per liter) 48hours after administration of the contrast agent.
Acetylcysteine (final concentration, 2.5 mmol per liter) wasadded in vitro to serum samples from the patients, and serumcreatinine was measured. In the presence of acetylcysteine,the mean serum creatinine concentration was 100±1 percentof the serum creatinine concentration in the absence of acetylcysteine.
Statistical Analysis
The final analysis was conducted on an intention-to-treat basis.Categorical variables (e.g., the incidence of acute contrast-agent–inducedreductions in renal function) were analyzed by Fisher's exacttest. Differences between the groups in serum creatinine concentrationswere analyzed by the nonparametric Wilcoxon–Mann–Whitneytest. A multiple logistic-regression analysis was used to examinethe effect of acetylcysteine, with adjustment for base-lineblood pressure. The logistic-regression analysis was performedwith the acute contrast-agent–induced reduction in renalfunction as the dependent variable. Analyses were performedwith GraphPad Prism software (version 3.0, GraphPad Software,San Diego, Calif.), or SPSS software (release 8.0.0, SPSS, Chicago).All statistical tests were two-sided.
Results
The clinical and biochemical characteristics of the patientsare shown in Table 1. The mean weights of the patients weresimilar at the start of the study (control group, 76±13kg; acetylcysteine group, 77±12 kg) and at the end (controlgroup, 77±13 kg; acetylcysteine group, 78±12 kg),suggesting a similar fluid balance.
Table 1. Clinical and Biochemical Characteristics of the Study Patients.
The mean serum creatinine concentration for all patients was2.4±1.3 mg per deciliter (216±116 µmol perliter). In the control group, the mean serum creatinine concentrationincreased from 2.4±1.3 to 2.6± 1.5 mg per deciliter(212±114 to 226±133 µmol per liter) 48 hoursafter administration of the contrast agent (P=0.18) (Figure 1).In the acetylcysteine group, the mean serum creatinine concentrationdecreased from 2.5±1.3 to 2.1±1.3 mg per deciliter(220±118 to 186±112 µmol per liter) 48 hoursafter administration of the contrast agent (P<0.001). Theabsolute change in serum creatinine concentration was significantlygreater in the control group than in the acetylcysteine group(P<0.001) (Table 2).
Figure 1. Serum Creatinine Concentrations before and 48 Hours after the Administration of Contrast Agent to Patients with Chronic Renal Insufficiency.
Mean (±SD) concentrations for the acetylcysteine group (41 patients) and for the control group (42 patients) are indicated by squares and vertical lines. To convert values for serum creatinine to micromoles per liter, multiply by 88.4.
Table 2. Base-Line Serum Creatinine Concentrations, Absolute Changes in Serum Creatinine Concentrations after Administration of the Contrast Agent, and Incidence of Acute Reductions in Renal Function in the Acetylcysteine and Control Groups.
In the control group, the mean serum urea nitrogen concentrationwas 44±26 mg per deciliter (15±9 mmol per liter)before and 47±29 mg per deciliter (17±10 mmolper liter) 48 hours after administration of the contrast agent(P=0.38). In the acetylcysteine group, the mean serum urea nitrogenconcentration significantly decreased from 51±28 mg perdeciliter (18±10 mmol per liter) before to 44±29mg per deciliter (16±10 mmol per liter) 48 hours afteradministration of the contrast agent (P<0.001).
An acute contrast-agent–induced reduction in renal functionwas defined as an increase in the serum creatinine concentrationof at least 0.5 mg per deciliter (44 µmol per liter) 48hours after administration of the contrast agent. Such an increaseoccurred in 10 of the 83 patients (12 percent): 1 of the 41patients in the acetylcysteine group (2 percent) and 9 of the42 patients in the control group (21 percent; P=0.01; relativerisk, 0.1; 95 percent confidence interval, 0.02 to 0.9). Base-linesystolic and diastolic blood pressure did not influence thefindings. Five of the 10 patients with an acute contrast-agent–inducedreduction in renal function had diabetes mellitus.
In the acetylcysteine group, 13 patients (32 percent) had base-lineserum creatinine concentrations above 2.5 mg per deciliter (221µmol per liter), as did 12 patients (29 percent) in thecontrol group. Among these patients with elevated base-linecreatinine concentrations, none of the 13 patients in the acetylcysteinegroup and 5 of the 12 patients in the control group (42 percent)had an acute contrast-agent–induced reduction in renalfunction (P=0.02).
Among the patients with an acute contrast-agent–inducedreduction in renal function, the mean serum creatinine concentrationwas still elevated on day 6 after the administration of thecontrast agent (by 0.5±0.6 mg per deciliter [43±50µmol per liter] over base line). None of the patientsrequired dialysis. Three of the 41 patients in the acetylcysteinegroup (7 percent) and 5 of the 42 patients in the control group(12 percent) reported temporary gastrointestinal discomfortduring the study; 4 patients in the acetylcysteine group (10percent) and 3 patients in the control group (7 percent) reporteddizziness. There were no other adverse effects.
Discussion
The important finding of this study is that prophylactic oraladministration of the antioxidant acetylcysteine reduced theincidence of acute contrast-agent–induced reductions inrenal function. In addition, the absolute change in the serumcreatinine concentration after administration of the contrastagent was less in the acetylcysteine group than in the controlgroup. The results were similar in the subgroup of patientswith initial serum creatinine concentrations above 2.5 mg perdeciliter. To exclude the possibility that the effects of acetylcysteinewere due only to a direct effect on the tubular secretion ofcreatinine, with renal function left unaffected, we also measuredserum urea nitrogen. The changes in serum urea nitrogen concentrationswere similar to those in serum creatinine concentrations, suggestingthat changes in glomerular filtration may underlie the observedchanges in serum creatinine concentrations.
The incidence of acute contrast-agent–induced reductionsin renal function varies from 0 to 90 percent, depending onthe presence of risk factors, including chronic renal insufficiency,diabetes mellitus, and a higher volume of contrast agent administered.1,2,3,4,5,6,7,8The incidence of acute contrast-agent–induced reductionsin renal function among patients with diabetes has been reportedto be 9 to 40 percent in patients with mild-to-moderate chronicrenal insufficiency and 50 to 90 percent in patients with severechronic renal insufficiency.1,2 The present study included diabeticas well as nondiabetic patients with chronic renal insufficiency,since diabetic patients are thought to be at high risk for contrast-agent–inducedreductions in renal function.
As recommended in earlier studies, we defined an acute contrast-agent–inducedreduction in renal function as an increase in the serum creatinineconcentration of at least 0.5 mg per deciliter 48 hours afteradministration of the contrast agent.1,2,3,4,5,6,7,8 Such anincrease may be important, because it can increase the durationof hospitalization.5 To avoid any bias due to the use of differenttypes of contrast agent or the administration of different volumes,75 ml of the same nonionic, low-osmolality contrast agent wasgiven to all the patients. The use of such agents is associatedwith a lower incidence of acute reductions in renal functionthan the use of ionic, high-osmolality agents.6,18 Earlier studiessupport the use of hydration in patients with chronic renalinsufficiency to prevent acute contrast-agent–inducedreductions in renal function.4,5,6,7,8
How can the beneficial effect of acetylcysteine be explained?Contrast-agent–induced reductions in renal function aredue to alterations in renal hemodynamics and direct toxic effectson tubular epithelial cells. The toxic renal damage may contributeto the formation of reactive oxygen species or to reduced antioxidantactivity.13,14,15 Recent studies suggest that acetylcysteinehas vasodilatory properties.19,20 In animals, acetylcysteinecan ameliorate ischemic renal failure,21,22 and it has beenreported to block the expression of vascular-cell adhesion molecule1 and the activation of nuclear factor-B in glomerular mesangialcells.23 Early administration of acetylcysteine prevents a reductionin renal function in patients with acetaminophen poisoning whohave liver failure.24,25 A recent nonrandomized study suggestedthat acetylcysteine may improve renal function in patients withthe hepatorenal syndrome.26 Therefore, it may be capable ofpreventing a contrast-agent–induced reduction in renalfunction both by improving renal hemodynamics and by preventingdirect oxidative tissue damage.
In conclusion, prophylactic oral administration of the antioxidantacetylcysteine at a dose of 600 mg twice daily on the day beforeand on the day of administration of the contrast agent, togetherwith hydration with saline, is an effective means of preventingrenal damage induced by a nonionic, low-osmolality contrastagent in patients with chronic renal insufficiency.
Source Information
From the Medizinische Klinik I (M.T., M.G., W.Z.) and the Radiologische Klinik (C.S., U.L., D.L.), Universitätsklinik Marienhospital, Ruhr-Universität Bochum, Herne, Germany.
Address reprint requests to Dr. Tepel at the Medizinische Klinik I, Universitätsklinik Marienhospital, Ruhr-Universität Bochum, Hölkeskampring 40, D-44625 Herne, Germany, or at martin.tepel{at}ruhr-uni-bochum.de.
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B in glomerular mesangial cells.23 Early administration of acetylcysteine prevents a reduction in renal function in patients with acetaminophen poisoning who have liver failure.24,25 A recent nonrandomized study suggested that acetylcysteine may improve renal function in patients with the hepatorenal syndrome.26 Therefore, it may be capable of preventing a contrast-agent–induced reduction in renal function both by improving renal hemodynamics and by preventing direct oxidative tissue damage. 
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