- Email: [email protected]
Contrast media nephropathy: Intravenous CT angiography versus intraarterial digital subtraction angiography in renal artery stenosis: A prospective randomized trial
ORIGINAL INVESTIGATIONS Pathogenesis and Treatment of Kidney Disease and Hypertension
Contrast Media Nephropathy: Intravenous CT Angiography Versus Intraarterial Digital Subtraction Angiography in Renal Artery Stenosis: A Prospective Randomized Trial Volkmar Lufft, MD, Linda Hoogestraat-Lufft, MD, Lu¨der M. Fels, PhD, Daniel Egbeyong-Baiyee, MD, Gu¨nter Tusch, PhD, Michael Galanski, MD, and Christoph J. Olbricht, MD ● Background: Spiral computed tomographic angiography (CTA) is a noninvasive method to diagnose renal artery stenosis (RAS). In digital subtraction angiography (DSA), contrast media (CM) is injected directly into the renal artery; in CTA, a greater amount of CM is injected intravenously, potentally leading to an increased incidence of CM nephropathy. Methods: We investigated 80 patients with suspected RAS randomized to either CTA or DSA prospectively. The following parameters were determined: serum creatinine level and single-shot inulin clearance for evaluation of renal function and urine ␣1-microglobulin and beta-N-acetyl-glucoseaminidase (beta-NAG) as markers for tubular toxicity. Data from 16 patients undergoing angioplasty in the same session were excluded. Results: In the CTA and DSA groups, 163 ⴞ 13 and 104 ⴞ 56 mL of CM (mean ⴞ SD; P < 0.0001) were administered, respectively. Mean serum creatinine levels increased from 1.78 ⴞ 1.61 to 1.92 ⴞ1 .73 mg/dL (157 ⴞ 142 to 170 ⴞ 153 mol/L; P ⴝ 0.00001) in the CTA group and from 1.52 ⴞ 1.23 to 1.60 ⴞ 1.28 mg/dL (134 ⴞ 109 to 141 ⴞ 113 mol/L; P ⴝ 0.01) in the DSA group. Mean inulin clearance decreased from 63 ⴞ 28 to 58 ⴞ 23 mL/min (P ⴝ 0.01) and 65 ⴞ 26 to 62 ⴞ 26 mL/min (P < 0.01), median beta-NAG levels increased from 4.6 to 6.0 U/g creatinine (P ⴝ not significant) and 2.5 to 8.0 U/g creatinine (P < 0.001), and median ␣1-microglobulin levels increased from 13 to 17 g/g creatinine (P < 0.025) and 11 to 21 g/g creatinine (P ⴝ not significant) in the CTA and DSA groups, respectively. CM nephropathy occurred in 3 of 33 patients in the CTA group and 2 of 31 patients in the DSA group. The increase in creatinine level was reversible in all patients within 7 days. Conclusion: On this study, CTA performed for the detection of RAS is not associated with an increased risk for CM nephropathy compared with intraarterial DSA despite a greater dose of CM. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: ␣1-Microglobulin; beta-N-acetyl-glucoseaminidase (beta-NAG); contrast media (CM) nephrotoxicity; computed tomographic angiography (CTA); digital subtraction angiography (DSA); inulin clearance.
C
OMPUTED tomographic angiography (CTA) has been shown to have accuracy for the diagnosis of renal artery stenosis (RAS) similar to that of digital subtraction angiography (DSA).1-6 It is minimally invasive and based on spiral computed tomography. From the Abteilung Nephrologie, Abteilung Diagnostische Radiologie, Klinik fu¨r Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover; Nephrologisches Zentrum am Krankenhaus Rendsburg; and the Klinik fu¨r Nieren- und Hochdruckkrankheiten, Katharinenhospital, Stuttgart, Germany. Received October 31, 2001; accepted in revised form March 29, 2002. Supported in part by Nycomed, Munich, Germany. Address reprint requests to Volkmar Lufft, MD, Nephrologisches Zentrum am Krankenhaus Rendsburg, Lilienstrasse 20-28, 24768 Rendsburg, Germany. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/4002-0003$35.00/0 doi:10.1053/ajkd.2002.34501 236
Nevertheless, arteriography remains the gold standard. However, this method is associated with patient discomfort and such risks as bleeding, arterial emboli, and development of an arteriovenous fistula and/or cholesterol emboli. Both methods render the patient susceptible to contrast media (CM) nephropathy. In arteriography, CM is injected into the aorta; a selective injection directly into the renal arteries follows if more detailed images of the renal arteries are required. In CTA, a greater amount of CM is administered through a peripheral vein. However, greater doses of CM increase the risk for CM nephrotoxicity.7 However, DSA carries the risk for renal function impairment by cholesterol emboli. Whether the different volume of CM and/or different mode of application result in a different nephrotoxicity is unknown. This is especially important because such factors associated with atherosclerotic RAS as diabetes mellitus or
American Journal of Kidney Diseases, Vol 40, No 2 (August), 2002: pp 236-242
CONTRAST MEDIA NEPHROPATHY
renal function impairment render patients susceptible to a greater risk for CM nephropathy.8-13 To determine the potential nephrotoxicity of CTA compared with DSA in patients with suspected RAS, we performed a controlled, prospective, randomized trial. SUBJECTS AND METHODS
Study Population Eighty consecutive patients with suspected RAS were prospectively enrolled. All patients had a history of hypertension, with diastolic blood pressure exceeding 95 mm Hg. Clinical criteria leading to the suspicion of RAS were malignant hypertension, hypertension with unexplained impairment of renal function, presence of flank bruits, hypertension accompanied by occlusive disease in the peripheral or coronary circulation, and sudden worsening of hypertension.14 Subjects were randomly assigned to undergo either CTA or DSA. Patients with renal grafts, a history of allergic reactions to CM, or severe heart failure were excluded. Data from patients who underwent angioplasty (AP) in the same session were not included.
DSA Arteriography was performed by digital subtraction technique using a transfemoral approach. Initially, abdominal screening flush aortography using a 5 F pigtail catheter in the Seldinger technique with approximately 30 mL of CM injected at 12 mL/s was performed. Afterward, a bilateral selective angiogram of each renal artery, with manual injection of CM, was performed using a preformed end-hole catheter. Images were obtained in the anteroposterior projection, either with electrocardiographic triggering or at a rate of 2 frames/s in patients with cardiac arrhythmia or a heart rate less than 60 beats/min. Additional projections to image the origin of the vessel without the overlying aorta were obtained when needed.
CTA CTA was performed using a Somatom Plus scanner (Siemens AG, Erlangen, Germany), described previously.2 In brief, after a localizer CT scan beginning at the 12th thoracic vertebra and including the kidneys below that level, 10 to 15 mL of CM was manually injected into an arm vein as a bolus. A short dynamic sequence of scans was obtained afterward at approximately the level of the renal arteries to estimate the transit time of CM from the site of injection to the renal arteries and determine the interval for maximum contrast. For the subsequent spiral CT scan starting at the level of the superior mesenteric artery, 150 mL of CM was administered at a flow rate of 4 mL/s using an automatic injector (CT injector; Ulrich, Ulm, Germany). For DSA and CTA, the same type of CM was used: iopentol (Imagopaque; Nycomed, Munich, Germany). It is a nonionic, low-osmolar (640 mOsm/kg H2O), monomeric agent and contains 300 mg iodine/mL.
237
Study Design and Parameters Tested The study was reviewed and approved by the Ethics Comittee of the Medical School Hannover, Germany. Patients were informed and gave written consent to participate in the study. All subjects were studied as in-patients in the Departments of Nephrology and Radiology of the Medical School Hannover. Antihypertensive drug therapy, including calcium channel blockers and diuretics, was not discontinued to keep blood pressure under control. Theophylline therapy was discontinued because it may mitigate CM nephrotoxicity.15 Data were analyzed retrospectively if patients were on acetylcysteine therapy because this recently was shown to blunt CM nephropathy.16 Patients were hydrated with 1 L of intravenous 0.45% saline starting 1 hour before the investigation. In addition, they were advised to drink 1.5 L/d of fluid. Fluid balance was monitored by recording intake and output and daily control of body weight. Serum creatinine was measured by using standard methods (modified Jaffe´ reaction) the day before and until 2 days after the investigation (blood samples obtained early in the morning). Inulin clearance was measured the day before and day after the investigation by means of the single-shot method. After an injection of 5 g of inulin over 4 minutes, plasma inulin was measured at 0, 5, 15, 30, 60, 90, 120, 160, 200, and 240 minutes by means of an enzymatic assay, described elsewhere.17 Plasma clearance was calculated by using a computerized aid with specific software (Inusoft, Inutest version 1.1; Laevosan Gesellschaft, Linz, Austria). CM nephrotoxicity was defined as an increase in serum creatinine level greater than 25% or 0.5 mg/dL (44 mol/L) compared with baseline values within 2 days after the investigation. Preexisting renal function impairment was defined as a serum creatinine level greater than 1.5 mg/dL (132 mol/L) or inulin clearance less than 75 mL/min. The day before and day after the investigation, urine was obtained early in the morning from a spot sample, and the following urinary enzyme levels were determined: ␣1microglobulin, by means of an indirect noncompetitive enzyme-linked immunosorbent assay (solid-phase technique; Elias-Medizintechnik, Freiburg, Germany), and betaN-acetyl-glucosaminidase (beta-NAG), by means of a colorimetric assay, described previously.18
Statistical Analysis Data are given as mean ⫾ SD or median with 5th and 95th percentiles, as indicated. Data were analyzed using Student’s t-test for paired or unpaired data, Wilcoxon’s test, or Fisher’s exact test, as appropriate. The study was planned in advance and performed as an equivalence trial with an interim analysis after 80 patients. Sample size was not calculated before the study. Statistical analysis was based on the use of (1 to 2␣) confidence intervals.19 Equivalence was inferred when the entire confidence interval was within equivalence margins. Changes in renal function caused by CTA or DSA were determined by the percentage of increase or decrease in serum creatinine level and inulin clearance. Equivalence margins were set at ⫾6.25% of mean changes in the total study population. For this test, statistical significance is considered P less than 0.05.
238
LUFFT ET AL
The influence of various factors on renal function impairment determined by serum creatinine level and inulin clearance was investigated by performing a multivariate analysis using the linear and logistic regression model with a backward selection procedure. The following factors were analyzed: radiological method (CTA or DSA), diabetes mellitus, calcium channel blockers, CM volume, percutanous AP, RAS, renal function (before CM application) determined by serum creatinine level and inulin clearance, age, weight, and sex. For this analysis, all patients investigated were included.
RESULTS
CTA and DSA were performed in 33 and 47 patients, respectively. Data from 16 patients who underwent AP in the same session were not included. Sixty-eight patients were randomized: 33 patients to the CTA group and 35 patients to the DSA group. RAS was diagnosed in 14 patients (42%) in the CTA group; 12 patients underwent AP 4 weeks later. In the DSA group, RAS was diagnosed in 10 patients (29%); 4 of those patients underwent AP in the same session, leaving 6 patients in the DSA group without AP. Single-shot inulin clearances were determined in 33 patients in the CTA group and 27 patients in the DSA group (without AP). Serum creatinine was measured in 32 and 29 patients, respectively. Clinical data characterizing both groups are listed in Table 1. There were no statistically significant differences with regard to sex; age; therapy with Table 1.
Clinical Data Characterizing the CTA and DSA Groups
No. of patients Sex (M/F) Age (y) Diabetes mellitus NSAID CCB Diuretics Renal insufficiency Serum creatinine Inulin clearance
CTA Group
DSA Group*
33 20/13 56 ⫾ 14 3 2 22 19
31 17/14 52 ⫾ 12 4 0 13 21
12 24
10 17
NOTE. Values expressed as number of patients or mean ⫾ SD. There were no statistically significant differences. Renal insufficiency indicates the number of patients with a serum creatinine level greater than 1.5 mg/dL (132 mol/L) or an inulin clearance less than 75 mL/min. Abbreviations: NSAID, non-steroidal anti-inflammatory drug; CCB, calcium channel blocker. *Data from patients who underwent AP in the same session are not included.
nonsteroidal anti-inflammatory drugs, calcium channel blockers, or diuretics; or number of patients with diabetes mellitus or preexisting renal function impairment determined by serum creatinine level and single-shot inulin clearance. None of the patients was on acetylcysteine therapy. There was a significant difference in amount of CM administered: 163 ⫾ 13 mL in the CTA group compared with 104 ⫾ 56 mL in the DSA group (P ⬍ 0.0001). There was no difference in incidence of CM nephrotoxicity: it occurred in three patients in the CTA group and two patients in the DSA group. In each group, one patient with CM nephrotoxicity had preexisting impairment of renal function or diabetes, respectively. In all patients, the increase in creatinine level was fully reversible within 7 days; hemodialysis was not required in any of those patients. Mean serum creatinine level increased and mean inulin clearance decreased in each group slightly, but significantly (serum creatinine: CTA group, 1.78 ⫾ 1.61 to 1.92 ⫾ 1.73 mg/dL [157 ⫾ 142 to 170 ⫾ 153 mol/L]; P ⫽ 0.0001; DSA group, 1.52 ⫾ 1.23 to 1.60 ⫾ 1.28 mg/dL [134 ⫾ 109 to 141 ⫾ 113 mol/L]; P ⫽ 0.01; inulin clearance: CTA group, 63 ⫾ 28 to 58 ⫾ 23 mL/min; P ⫽ 0.01; DSA group, 65 ⫾ 26 to 62 ⫾ 26 mL/min; P ⬍ 0.01). Individual values for inulin clearances are shown in Fig 1. Mean values for subgroups of patients with normal and impaired renal function (serum creatinine ⬍ or ⬎ 1.5 mg/dL [132 mol/L], inulin clearance ⬍ or ⬎ 75 mL/min) are listed in Table 2. Serum creatinine levels increased and inulin clearances decreased slightly in all subgroups. All differences reached statistical significance, apart from changes in serum creatinine levels in the DSA subgroup with impaired renal function. Mean increases in serum creatinine levels in the CTA and DSA groups were 0.14 ⫾ 0.23 and 0.08 ⫾ 0.16 mg/dL [12 ⫾ 20 and 7 ⫾ 14 mol/L], respectively. Mean decreases in inulin clearances in the CTA and DSA groups were 4.4 ⫾ 5.7 and 3.2 ⫾ 4.4 mL/min, respectively. These changes were not significantly different and proved to be equivalent: (1 to 2␣) confidence intervals of both serum creatinine level (⫺3.7% to ⫹5.8%) and inulin clearance (⫺3.7% to ⫹4.5%) were within margins of equivalence
CONTRAST MEDIA NEPHROPATHY
239
Fig 1. Inulin clearances before and after CM administration. Each line represents one patient who underwent either spiral CTA or DSA. Heavy grey lines represent mean values for all patients.
(⫾6.25%). Multivariate analysis showed that diabetes mellitus and preexisting renal function impairment were independent risk factors for CMinduced renal function impairment. All other parameters tested, including CTA and DSA, had no influence. Values for beta-NAG and ␣1-microglobulin are shown in Fig 2A and B, respectively. Values (median and 5th and 95th percentiles) were widely scattered and had a non-Gaussian distribution. Differences for baseline values of betaNAG and ␣1-microglobulin between both groups were not significant. Beta-NAG levels increased from 4.6 U/g creatinine (5th and 95th percenTable 2.
tiles, 0.2 and 16.4 U/g creatinine) to 6.0 U/g creatinine (5th and 95th percentiles, 0.2 and 15.0 U/g creatinine) and 2.5 U/g creatinine (5th and 95th percentiles, 0.1 and 13.5 U/g creatinine) to 8.0 U/g creatinine (5th and 95th percentiles, 0.1 and 33.5 U/g creatinine), and ␣1-microglobulin levels increased from 13 g/g creatinine (5th and 95th percentiles, 1 and 254 g/g creatinine) to 17 g/g creatinine (5th and 95th percentiles, 1 and 210 g/g creatinine) and 11 g/g creatinine (5th and 95th percentiles, 1 and 263g/g creatinine) to 21 g/g creatinine (5th and 95th percentiles, 11 and 356 g/g creatinine) in the CTA and DSA groups, respectively. Increases in beta-NAG lev-
Serum Creatinine Levels and Inulin Clearances of Patients With Normal and Impaired Renal Function CTA Before
Serum creatinine (mg/dL) Normal renal function 0.94 ⫾ 0.26 Renal insufficiency 3.19 ⫾ 1.91 Inulin clearance (mL/min) Normal renal function 102 ⫾ 18 Renal insufficiency 48 ⫾ 12
n ⫽ 20 n ⫽ 12 n⫽9 n ⫽ 24
DSA After
Before
1.02 ⫾ 0.33*
0.80 ⫾ 0.21
3.43 ⫾ 2.06†
2.85 ⫾ 1.27
91 ⫾ 13†
94 ⫾ 15
46 ⫾ 11†
49 ⫾ 13
After
n ⫽ 19 n ⫽ 10 n ⫽ 10 n ⫽ 17
0.87 ⫾ 0.21† 2.95 ⫾ 1.35‡ 89 ⫾ 16* 46 ⫾ 14†
NOTE. Values for serum creatinine and inulin clearances are shown as mean ⫾ SD. Serum creatinine level was determined in 32 and 29 patients of the CTA and DSA groups, respectively. Inulin clearance was determined in 33 and 27 patients of the CTA and DSA groups, respectively. Renal insufficiency was defined as serum creatinine level greater than 1.5 mg/dL (132 mol/L) or an inulin clearance less than 75 mL/min. *P ⬍ 0.01. †P ⬍ 0.05. ‡P ⫽ not significant.
240
LUFFT ET AL
tively. Differences were not statistically significant. DISCUSSION
Fig 2. Values (median, 5th and 95th percentile) for (A) beta-NAG and (B) ␣1-microglobulin before and after CM administration for spiral CTA or DSA.
els in the DSA group and ␣1-microglobulin levels in the CTA group reached statistical significance. Beta-NAG levels increased in the CTA group in patients on calcium channel blocker therapy from 4.0 U/g creatinine (5th and 95th percentiles, 0.2 and 14.0 U/g creatinine) to 5.8 U/g creatinine (5th and 95th percentiles, 0.4 and 15.1 U/g creatinine) compared with 4.8 U/g creatinine (5th and 95th percentiles, 0.3 and 16.2 U/g creatinine) and 6.6 U/g creatinine (5th and 95th percentiles, 0.5 and 16.4 U/g creatinine) in patients not on calcium channel blocker therapy. In the DSA group, beta-NAG levels increased from 2.3 U/g creatinine (5th and 95th percentiles, 0.1 and 11.8 U/g creatinine) to 7.2 U/g creatinine (5th and 95th percentiles, 0.1 and 20.1 U/g creatinine) compared with 2.7 U/g creatinine (5th and 95th percentiles, 0.3 and 13.5 U/g creatinine) to 8.4 U/g creatinine (5th and 95th percentiles, 0.5 and 33.5 U/g creatinine), respec-
Advantages of CTA compared with DSA for the diagnosis of RAS may be limited by a greater incidence of CM nephropathy caused by a greater amount of CM. Other methods, such as colorcoded duplex sonography and magnetic resonance angiography, are of similar diagnostic value. However, both methods are associated with specific drawbacks. Color-coded duplex sonography can be limited by high intraobserver variability and technical failure caused by obesity and bowel gas. Magnetic resonance angiography has limited visualization of intrarenal arteries and may not be as widely available as CTA.20 We therefore compared CTA and DSA in a randomized prospective fashion with regard to impairment of renal function. In addition to serum creatinine measurements, plasma clearances for inulin using the single-shot method were measured. This method has been shown to have a high correlation with renal clearance for inulin, the gold standard for determination of glomerular filtration rate.21 Both groups were similar with regard to clinical parameters relevant for CM nephropathy, such as preexisting renal function impairment, presence of diabetes mellitus, and use of calcium channel blockers and nonsteroidal anti-inflammatory drugs.8-13,22 Reduction in effective arterial volume is an additional risk factor.7 Thus, all patients were prehydrated. Furthermore, hydration status was thoroughly monitored to avoid changes in renal function caused by changes in fluid status. Studies of the incidence of CM nephrotoxicity have produced variable results because of differences in the definition of CM nephrotoxicity and/or patient comorbidity.23 On this study, CM nephrotoxicity, as well as preexisting impairment in renal function, was defined in accordance with generally accepted often-applied criteria.9,10,15,24-26 Mean renal function in both groups, determined by serum creatinine levels and inulin clearances, was similar, and renal impairment was common. Thus, the study population had increased susceptibility for CM nephropathy. Therefore, the combination of this high-risk population and precise method to deter-
CONTRAST MEDIA NEPHROPATHY
mine renal function resulted in a sensitive study design to detect even subtle CM-associated changes in renal function. In both groups, there was a small but significant increase in serum creatinine levels regarding the entire groups, as well as subgroups of patients with normal and impaired renal function, except for the DSA group with impaired renal function. In this subgroup, the increase in serum creatinine level did not reach statistical significance because of the small number of patients and high SD. Inulin clearances decreased in both groups and all subgroups significantly. Increases in serum creatinine levels and decreases in inulin clearances were not statistically different between groups. However, concluding clinical equivalence is not necessarily appropriate because the number of cases could be too small. Therefore, the study was performed as an equivalence trial. In this case, equivalence is proven by the prespecified statistical significance, which can only be established by using a sufficient number of patients. Percentages were used because the distribution of initial values was widely spread for both serum creatinine and inulin clearance. The primary objective, to show that CM nephropathy of CTA and DSA differ by a clinically unimportant amount, is shown by showing that the true difference in renal function impairment is likely to lie between a lower and upper equivalence margin of clinically acceptable differences. An interim analysis after 80 patients was planned in advance to determine whether previous assumptions concerning sample size and extent of renal function impairment, which were based on uncertain information, were still valid. It turned out that our assumptions were too cautious. Thus, in the interim analysis, we could already prove equivalence. Margins of equivalence in bioequivalence studies are usually set at 75% of the SD, including the entire study population. This would be ⫾7.1% for inulin clearance and ⫾8.2% for serum creatinine level. Margins of equivalence here were defined at even closer limits: ⫾6.25% for both parameters. This was based on the clinical definition of CM nephropathy: increase in serum creatinine level by 25% or more. Thus, only absolute changes in inulin clearance or serum creatinine level less than 6.25% were considered clinically
241
irrelevant, which is a range of 12.5%, or half the definition or only a quarter of the increase of 25%. Despite this tight definition of clinical relevance, equivalence of both methods was proven because confidence intervals for both parameters were within these limits. In addition, multivariate analysis confirmed this result: CTA and DSA had no influence on renal function impairment. However, diabetes mellitus and preexisting renal function impairment proved to be independent risk factors for CM nephropathy. This finding confirms current literature data8-13 and is further proof that results of our study are valid. Thus, a clinically relevant difference in renal function impairment after CM administration between the CTA and DSA groups (patients with normal or impaired renal function) could not be shown. CM nephrotoxicity is partially mediated by toxic tubular damage.7 Tubular toxicity of CM may occur without deterioration in glomerular filtration rate.27,28 Urinary tubular enzymes as markers of tubular damage thus may serve as additional more sensitive indicators of CM nephrotoxicity. Therefore, beta-NAG and ␣1-microglobulin excretion were measured. Increases in both parameters in the CTA and DSA groups indicates a similar tubular toxicity of both methods. A greater proportion of patients in the CTA group was on calcium channel blocker therapy, although this difference was not statistically different. These drugs may blunt beta-NAG excretion after CM administration.21 However, the increase in beta-NAG excretion in patients with and without calcium channel blocker therapy was not different in either group. Therefore, there is no evidence that calcium channel blockers have a different effect on beta-NAG excretion in both groups. This study could not show that the intravenous administration of a greater amount of CM in CTA for the detection of RAS is associated with a greater risk for renal function impairment or tubular toxicity compared with intraarterially administered CM in DSA, although very sensitive methods in a population with a high risk for CM nephropathy were applied. Thus, our results indicate that with regard to CM nephrotoxicity, CTA, being less invasive than DSA, can be performed safely for the diagnosis of RAS.
242
LUFFT ET AL
REFERENCES 1. Galanski M, Prokop M, Chavan A, Scha¨fer CM, Jandeleit K, Nischelski JE: Spiral CT angiography. Radiology 189:185-192, 1993 2. Olbricht CJ, Paul K, Prokop M, et al: Minimally invasive diagnosis of renal artery stenosis by spiral computed tomography angiography. Kidney Int 48:1332-1337, 1995 3. Elkohen M, Beregi JP, Deklunder G, Artaud D, Mounier-Vehier C, Carre AG: A prospective study of helical computed tomography angiography versus angiography for the detection of renal artery stenosis in hypertensive patients. J Hypertens 14:525-528, 1996 4. Kaatee R, Beek FJ, de Lange EE, et al: Renal artery stenosis: Detection and quantification with spiral CT angiography versus optimized digital subtraction angiography. Radiology 205:121-127, 1997 5. Beregi JP, Elkohen M, Deklunder G, Artaud D, Coullet JM, Wattinne L: Helical CT angiography compared with arteriography in the detection of renal artery stenosis. AJR Am J Roentgenol 167:495-501, 1996 6. Rubin GD, Dake MD, Napel S, et al: Spiral CT of renal artery stenosis: Comparison of three-dimensional rendering techniques. Radiology 190:181-190, 1994 7. Barrett BJ: Contrast nephrotoxicity. J Am Soc Nephrol 5:125-137, 1994 8. Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med 89:615-620, 1990 9. Parfrey PS, Griffiths SM, Barrett BJ, et al: Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency or both. N Engl J Med 320:143-149, 1989 10. Rudnick MR, Goldfarb S, Wexler L, et al for the Iohexol Cooperative Study: Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: A randomized trial. Kidney Int 47:254-261, 1995 11. Weisberg LS, Kurnik PB, Kurnik BRC: Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int 45:259-265, 1994 12. Lautin EM, Freeman NJ, Schoenfeld AH, et al: Radiocontrast associated renal dysfunction: A comparison of lowerosmolality and conventional high-osmolality contrast media. AJR Am J Roentgenol 157:59-65, 1991 13. Moore RD, Steinberg EP, Powe NR, et al: Nephrotoxicity of high-osmolality versus low-osmolality contrast media: Randomized clinical trial. Radiology 182:649-655, 1992 14. Working Group on Renovascular Hypertension: Detection, evaluation and treatment of renovascular hypertension. Arch Intern Med 147:820-829, 1987 15. Erley CE, Duda SH, Schlepckow S, et al: Adenosine
antagonist theophylline prevents the reduction of glomerular filtration rate after contrast media application. Kidney Int 45:1425-1430, 1994 16. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W: Prevention of radiographic-contrastagent-induced reductions in renal function by acetylcysteine. N Engl J Med 343:180-184, 2000 17. Kuehnle HF, van Dahl K, Schmidt FH: Fully enzymatic inulin determination in small volume samples without deproteinization. Nephron 62:104-107, 1992 18. Yuen CP, Kind PRN, Price RG, Prail PGF, Richardson AC: Colorimetric assay for N-acetyl-beta-D-glucosaminidase in pathological urine using the w-nitrostyryl substrate: The development of a kit of manual procedure with automated fluorometric method. Ann Clin Biochem 21:295-300, 1984 19. Westlake WJ: Statistical aspects of comparative bioavailability trials. Biometrics 35:273-280, 1979 20. Krumme B, Mann JFE: Atherosclerotic renal artery stenosis in 2001—Are we less confused than before? Nephrol Dial Transplant 16:2124-2127, 2001 21. Gretz N, Ecker-Tschirner KH, Ku¨hnle HF, et al: Practicability of the inulin plasma single-shot clearance, in Albertazzi A, Cappelli P, Del Rosso G, et al (eds): Contributions to Nephrology. Basel, Switzerland, Karger, 1990, pp 220-228 22. Neumayer HH, Junge W, Kufner A, Wenning A: Prevention of radiocontrast-media-induced nephrotoxicity by the calcium channel blocker: A prospective randomised clinical trial. Nephrol Dial Transplant 4:1030-1036, 1989 23. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. J Am Soc Nephrol 11:177-182, 2000 24. Solomon R, Werner C, Mann D, D’Elia J, Silva P: Effects of saline, mannitol and furosemide on acute decreases in renal function induced by radiocontrast agents. N Engl J Med 331:1416-1431, 1994 25. Schwab SJ, Hlatky MA, Pieper KS, et al: Contrast nephrotoxicity: A randomized controlled trial of a nonionic and an ionic radiographic contrast agent. N Engl J Med 320:149-153, 1989 26. Weisberg LS, Kurnik PB, Kurnik BRC: Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int 45:259-265, 1994 27. Jevnikar AM, Finnie KJC, Dennis B, Plummer DT, Avila A, Linton AL: Nephrotoxicity of high- and low osmolality contrast media. Nephron 48:300-305, 1988 28. Donadio C, Lucchesi A, Tramonti G, Calderazzi A, Gibilisco G, Paolicchi A: Glomerular and tubular effects of contrast media diatrizoate and iopromide. Ren Fail 18:657666, 1996
Contrast Media Nephropathy: Intravenous CT Angiography Versus Intraarterial Digital Subtraction Angiography in Renal Artery Stenosis: A Prospective Randomized Trial Volkmar Lufft, MD, Linda Hoogestraat-Lufft, MD, Lu¨der M. Fels, PhD, Daniel Egbeyong-Baiyee, MD, Gu¨nter Tusch, PhD, Michael Galanski, MD, and Christoph J. Olbricht, MD ● Background: Spiral computed tomographic angiography (CTA) is a noninvasive method to diagnose renal artery stenosis (RAS). In digital subtraction angiography (DSA), contrast media (CM) is injected directly into the renal artery; in CTA, a greater amount of CM is injected intravenously, potentally leading to an increased incidence of CM nephropathy. Methods: We investigated 80 patients with suspected RAS randomized to either CTA or DSA prospectively. The following parameters were determined: serum creatinine level and single-shot inulin clearance for evaluation of renal function and urine ␣1-microglobulin and beta-N-acetyl-glucoseaminidase (beta-NAG) as markers for tubular toxicity. Data from 16 patients undergoing angioplasty in the same session were excluded. Results: In the CTA and DSA groups, 163 ⴞ 13 and 104 ⴞ 56 mL of CM (mean ⴞ SD; P < 0.0001) were administered, respectively. Mean serum creatinine levels increased from 1.78 ⴞ 1.61 to 1.92 ⴞ1 .73 mg/dL (157 ⴞ 142 to 170 ⴞ 153 mol/L; P ⴝ 0.00001) in the CTA group and from 1.52 ⴞ 1.23 to 1.60 ⴞ 1.28 mg/dL (134 ⴞ 109 to 141 ⴞ 113 mol/L; P ⴝ 0.01) in the DSA group. Mean inulin clearance decreased from 63 ⴞ 28 to 58 ⴞ 23 mL/min (P ⴝ 0.01) and 65 ⴞ 26 to 62 ⴞ 26 mL/min (P < 0.01), median beta-NAG levels increased from 4.6 to 6.0 U/g creatinine (P ⴝ not significant) and 2.5 to 8.0 U/g creatinine (P < 0.001), and median ␣1-microglobulin levels increased from 13 to 17 g/g creatinine (P < 0.025) and 11 to 21 g/g creatinine (P ⴝ not significant) in the CTA and DSA groups, respectively. CM nephropathy occurred in 3 of 33 patients in the CTA group and 2 of 31 patients in the DSA group. The increase in creatinine level was reversible in all patients within 7 days. Conclusion: On this study, CTA performed for the detection of RAS is not associated with an increased risk for CM nephropathy compared with intraarterial DSA despite a greater dose of CM. © 2002 by the National Kidney Foundation, Inc. INDEX WORDS: ␣1-Microglobulin; beta-N-acetyl-glucoseaminidase (beta-NAG); contrast media (CM) nephrotoxicity; computed tomographic angiography (CTA); digital subtraction angiography (DSA); inulin clearance.
C
OMPUTED tomographic angiography (CTA) has been shown to have accuracy for the diagnosis of renal artery stenosis (RAS) similar to that of digital subtraction angiography (DSA).1-6 It is minimally invasive and based on spiral computed tomography. From the Abteilung Nephrologie, Abteilung Diagnostische Radiologie, Klinik fu¨r Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover; Nephrologisches Zentrum am Krankenhaus Rendsburg; and the Klinik fu¨r Nieren- und Hochdruckkrankheiten, Katharinenhospital, Stuttgart, Germany. Received October 31, 2001; accepted in revised form March 29, 2002. Supported in part by Nycomed, Munich, Germany. Address reprint requests to Volkmar Lufft, MD, Nephrologisches Zentrum am Krankenhaus Rendsburg, Lilienstrasse 20-28, 24768 Rendsburg, Germany. E-mail: [email protected] © 2002 by the National Kidney Foundation, Inc. 0272-6386/02/4002-0003$35.00/0 doi:10.1053/ajkd.2002.34501 236
Nevertheless, arteriography remains the gold standard. However, this method is associated with patient discomfort and such risks as bleeding, arterial emboli, and development of an arteriovenous fistula and/or cholesterol emboli. Both methods render the patient susceptible to contrast media (CM) nephropathy. In arteriography, CM is injected into the aorta; a selective injection directly into the renal arteries follows if more detailed images of the renal arteries are required. In CTA, a greater amount of CM is administered through a peripheral vein. However, greater doses of CM increase the risk for CM nephrotoxicity.7 However, DSA carries the risk for renal function impairment by cholesterol emboli. Whether the different volume of CM and/or different mode of application result in a different nephrotoxicity is unknown. This is especially important because such factors associated with atherosclerotic RAS as diabetes mellitus or
American Journal of Kidney Diseases, Vol 40, No 2 (August), 2002: pp 236-242
CONTRAST MEDIA NEPHROPATHY
renal function impairment render patients susceptible to a greater risk for CM nephropathy.8-13 To determine the potential nephrotoxicity of CTA compared with DSA in patients with suspected RAS, we performed a controlled, prospective, randomized trial. SUBJECTS AND METHODS
Study Population Eighty consecutive patients with suspected RAS were prospectively enrolled. All patients had a history of hypertension, with diastolic blood pressure exceeding 95 mm Hg. Clinical criteria leading to the suspicion of RAS were malignant hypertension, hypertension with unexplained impairment of renal function, presence of flank bruits, hypertension accompanied by occlusive disease in the peripheral or coronary circulation, and sudden worsening of hypertension.14 Subjects were randomly assigned to undergo either CTA or DSA. Patients with renal grafts, a history of allergic reactions to CM, or severe heart failure were excluded. Data from patients who underwent angioplasty (AP) in the same session were not included.
DSA Arteriography was performed by digital subtraction technique using a transfemoral approach. Initially, abdominal screening flush aortography using a 5 F pigtail catheter in the Seldinger technique with approximately 30 mL of CM injected at 12 mL/s was performed. Afterward, a bilateral selective angiogram of each renal artery, with manual injection of CM, was performed using a preformed end-hole catheter. Images were obtained in the anteroposterior projection, either with electrocardiographic triggering or at a rate of 2 frames/s in patients with cardiac arrhythmia or a heart rate less than 60 beats/min. Additional projections to image the origin of the vessel without the overlying aorta were obtained when needed.
CTA CTA was performed using a Somatom Plus scanner (Siemens AG, Erlangen, Germany), described previously.2 In brief, after a localizer CT scan beginning at the 12th thoracic vertebra and including the kidneys below that level, 10 to 15 mL of CM was manually injected into an arm vein as a bolus. A short dynamic sequence of scans was obtained afterward at approximately the level of the renal arteries to estimate the transit time of CM from the site of injection to the renal arteries and determine the interval for maximum contrast. For the subsequent spiral CT scan starting at the level of the superior mesenteric artery, 150 mL of CM was administered at a flow rate of 4 mL/s using an automatic injector (CT injector; Ulrich, Ulm, Germany). For DSA and CTA, the same type of CM was used: iopentol (Imagopaque; Nycomed, Munich, Germany). It is a nonionic, low-osmolar (640 mOsm/kg H2O), monomeric agent and contains 300 mg iodine/mL.
237
Study Design and Parameters Tested The study was reviewed and approved by the Ethics Comittee of the Medical School Hannover, Germany. Patients were informed and gave written consent to participate in the study. All subjects were studied as in-patients in the Departments of Nephrology and Radiology of the Medical School Hannover. Antihypertensive drug therapy, including calcium channel blockers and diuretics, was not discontinued to keep blood pressure under control. Theophylline therapy was discontinued because it may mitigate CM nephrotoxicity.15 Data were analyzed retrospectively if patients were on acetylcysteine therapy because this recently was shown to blunt CM nephropathy.16 Patients were hydrated with 1 L of intravenous 0.45% saline starting 1 hour before the investigation. In addition, they were advised to drink 1.5 L/d of fluid. Fluid balance was monitored by recording intake and output and daily control of body weight. Serum creatinine was measured by using standard methods (modified Jaffe´ reaction) the day before and until 2 days after the investigation (blood samples obtained early in the morning). Inulin clearance was measured the day before and day after the investigation by means of the single-shot method. After an injection of 5 g of inulin over 4 minutes, plasma inulin was measured at 0, 5, 15, 30, 60, 90, 120, 160, 200, and 240 minutes by means of an enzymatic assay, described elsewhere.17 Plasma clearance was calculated by using a computerized aid with specific software (Inusoft, Inutest version 1.1; Laevosan Gesellschaft, Linz, Austria). CM nephrotoxicity was defined as an increase in serum creatinine level greater than 25% or 0.5 mg/dL (44 mol/L) compared with baseline values within 2 days after the investigation. Preexisting renal function impairment was defined as a serum creatinine level greater than 1.5 mg/dL (132 mol/L) or inulin clearance less than 75 mL/min. The day before and day after the investigation, urine was obtained early in the morning from a spot sample, and the following urinary enzyme levels were determined: ␣1microglobulin, by means of an indirect noncompetitive enzyme-linked immunosorbent assay (solid-phase technique; Elias-Medizintechnik, Freiburg, Germany), and betaN-acetyl-glucosaminidase (beta-NAG), by means of a colorimetric assay, described previously.18
Statistical Analysis Data are given as mean ⫾ SD or median with 5th and 95th percentiles, as indicated. Data were analyzed using Student’s t-test for paired or unpaired data, Wilcoxon’s test, or Fisher’s exact test, as appropriate. The study was planned in advance and performed as an equivalence trial with an interim analysis after 80 patients. Sample size was not calculated before the study. Statistical analysis was based on the use of (1 to 2␣) confidence intervals.19 Equivalence was inferred when the entire confidence interval was within equivalence margins. Changes in renal function caused by CTA or DSA were determined by the percentage of increase or decrease in serum creatinine level and inulin clearance. Equivalence margins were set at ⫾6.25% of mean changes in the total study population. For this test, statistical significance is considered P less than 0.05.
238
LUFFT ET AL
The influence of various factors on renal function impairment determined by serum creatinine level and inulin clearance was investigated by performing a multivariate analysis using the linear and logistic regression model with a backward selection procedure. The following factors were analyzed: radiological method (CTA or DSA), diabetes mellitus, calcium channel blockers, CM volume, percutanous AP, RAS, renal function (before CM application) determined by serum creatinine level and inulin clearance, age, weight, and sex. For this analysis, all patients investigated were included.
RESULTS
CTA and DSA were performed in 33 and 47 patients, respectively. Data from 16 patients who underwent AP in the same session were not included. Sixty-eight patients were randomized: 33 patients to the CTA group and 35 patients to the DSA group. RAS was diagnosed in 14 patients (42%) in the CTA group; 12 patients underwent AP 4 weeks later. In the DSA group, RAS was diagnosed in 10 patients (29%); 4 of those patients underwent AP in the same session, leaving 6 patients in the DSA group without AP. Single-shot inulin clearances were determined in 33 patients in the CTA group and 27 patients in the DSA group (without AP). Serum creatinine was measured in 32 and 29 patients, respectively. Clinical data characterizing both groups are listed in Table 1. There were no statistically significant differences with regard to sex; age; therapy with Table 1.
Clinical Data Characterizing the CTA and DSA Groups
No. of patients Sex (M/F) Age (y) Diabetes mellitus NSAID CCB Diuretics Renal insufficiency Serum creatinine Inulin clearance
CTA Group
DSA Group*
33 20/13 56 ⫾ 14 3 2 22 19
31 17/14 52 ⫾ 12 4 0 13 21
12 24
10 17
NOTE. Values expressed as number of patients or mean ⫾ SD. There were no statistically significant differences. Renal insufficiency indicates the number of patients with a serum creatinine level greater than 1.5 mg/dL (132 mol/L) or an inulin clearance less than 75 mL/min. Abbreviations: NSAID, non-steroidal anti-inflammatory drug; CCB, calcium channel blocker. *Data from patients who underwent AP in the same session are not included.
nonsteroidal anti-inflammatory drugs, calcium channel blockers, or diuretics; or number of patients with diabetes mellitus or preexisting renal function impairment determined by serum creatinine level and single-shot inulin clearance. None of the patients was on acetylcysteine therapy. There was a significant difference in amount of CM administered: 163 ⫾ 13 mL in the CTA group compared with 104 ⫾ 56 mL in the DSA group (P ⬍ 0.0001). There was no difference in incidence of CM nephrotoxicity: it occurred in three patients in the CTA group and two patients in the DSA group. In each group, one patient with CM nephrotoxicity had preexisting impairment of renal function or diabetes, respectively. In all patients, the increase in creatinine level was fully reversible within 7 days; hemodialysis was not required in any of those patients. Mean serum creatinine level increased and mean inulin clearance decreased in each group slightly, but significantly (serum creatinine: CTA group, 1.78 ⫾ 1.61 to 1.92 ⫾ 1.73 mg/dL [157 ⫾ 142 to 170 ⫾ 153 mol/L]; P ⫽ 0.0001; DSA group, 1.52 ⫾ 1.23 to 1.60 ⫾ 1.28 mg/dL [134 ⫾ 109 to 141 ⫾ 113 mol/L]; P ⫽ 0.01; inulin clearance: CTA group, 63 ⫾ 28 to 58 ⫾ 23 mL/min; P ⫽ 0.01; DSA group, 65 ⫾ 26 to 62 ⫾ 26 mL/min; P ⬍ 0.01). Individual values for inulin clearances are shown in Fig 1. Mean values for subgroups of patients with normal and impaired renal function (serum creatinine ⬍ or ⬎ 1.5 mg/dL [132 mol/L], inulin clearance ⬍ or ⬎ 75 mL/min) are listed in Table 2. Serum creatinine levels increased and inulin clearances decreased slightly in all subgroups. All differences reached statistical significance, apart from changes in serum creatinine levels in the DSA subgroup with impaired renal function. Mean increases in serum creatinine levels in the CTA and DSA groups were 0.14 ⫾ 0.23 and 0.08 ⫾ 0.16 mg/dL [12 ⫾ 20 and 7 ⫾ 14 mol/L], respectively. Mean decreases in inulin clearances in the CTA and DSA groups were 4.4 ⫾ 5.7 and 3.2 ⫾ 4.4 mL/min, respectively. These changes were not significantly different and proved to be equivalent: (1 to 2␣) confidence intervals of both serum creatinine level (⫺3.7% to ⫹5.8%) and inulin clearance (⫺3.7% to ⫹4.5%) were within margins of equivalence
CONTRAST MEDIA NEPHROPATHY
239
Fig 1. Inulin clearances before and after CM administration. Each line represents one patient who underwent either spiral CTA or DSA. Heavy grey lines represent mean values for all patients.
(⫾6.25%). Multivariate analysis showed that diabetes mellitus and preexisting renal function impairment were independent risk factors for CMinduced renal function impairment. All other parameters tested, including CTA and DSA, had no influence. Values for beta-NAG and ␣1-microglobulin are shown in Fig 2A and B, respectively. Values (median and 5th and 95th percentiles) were widely scattered and had a non-Gaussian distribution. Differences for baseline values of betaNAG and ␣1-microglobulin between both groups were not significant. Beta-NAG levels increased from 4.6 U/g creatinine (5th and 95th percenTable 2.
tiles, 0.2 and 16.4 U/g creatinine) to 6.0 U/g creatinine (5th and 95th percentiles, 0.2 and 15.0 U/g creatinine) and 2.5 U/g creatinine (5th and 95th percentiles, 0.1 and 13.5 U/g creatinine) to 8.0 U/g creatinine (5th and 95th percentiles, 0.1 and 33.5 U/g creatinine), and ␣1-microglobulin levels increased from 13 g/g creatinine (5th and 95th percentiles, 1 and 254 g/g creatinine) to 17 g/g creatinine (5th and 95th percentiles, 1 and 210 g/g creatinine) and 11 g/g creatinine (5th and 95th percentiles, 1 and 263g/g creatinine) to 21 g/g creatinine (5th and 95th percentiles, 11 and 356 g/g creatinine) in the CTA and DSA groups, respectively. Increases in beta-NAG lev-
Serum Creatinine Levels and Inulin Clearances of Patients With Normal and Impaired Renal Function CTA Before
Serum creatinine (mg/dL) Normal renal function 0.94 ⫾ 0.26 Renal insufficiency 3.19 ⫾ 1.91 Inulin clearance (mL/min) Normal renal function 102 ⫾ 18 Renal insufficiency 48 ⫾ 12
n ⫽ 20 n ⫽ 12 n⫽9 n ⫽ 24
DSA After
Before
1.02 ⫾ 0.33*
0.80 ⫾ 0.21
3.43 ⫾ 2.06†
2.85 ⫾ 1.27
91 ⫾ 13†
94 ⫾ 15
46 ⫾ 11†
49 ⫾ 13
After
n ⫽ 19 n ⫽ 10 n ⫽ 10 n ⫽ 17
0.87 ⫾ 0.21† 2.95 ⫾ 1.35‡ 89 ⫾ 16* 46 ⫾ 14†
NOTE. Values for serum creatinine and inulin clearances are shown as mean ⫾ SD. Serum creatinine level was determined in 32 and 29 patients of the CTA and DSA groups, respectively. Inulin clearance was determined in 33 and 27 patients of the CTA and DSA groups, respectively. Renal insufficiency was defined as serum creatinine level greater than 1.5 mg/dL (132 mol/L) or an inulin clearance less than 75 mL/min. *P ⬍ 0.01. †P ⬍ 0.05. ‡P ⫽ not significant.
240
LUFFT ET AL
tively. Differences were not statistically significant. DISCUSSION
Fig 2. Values (median, 5th and 95th percentile) for (A) beta-NAG and (B) ␣1-microglobulin before and after CM administration for spiral CTA or DSA.
els in the DSA group and ␣1-microglobulin levels in the CTA group reached statistical significance. Beta-NAG levels increased in the CTA group in patients on calcium channel blocker therapy from 4.0 U/g creatinine (5th and 95th percentiles, 0.2 and 14.0 U/g creatinine) to 5.8 U/g creatinine (5th and 95th percentiles, 0.4 and 15.1 U/g creatinine) compared with 4.8 U/g creatinine (5th and 95th percentiles, 0.3 and 16.2 U/g creatinine) and 6.6 U/g creatinine (5th and 95th percentiles, 0.5 and 16.4 U/g creatinine) in patients not on calcium channel blocker therapy. In the DSA group, beta-NAG levels increased from 2.3 U/g creatinine (5th and 95th percentiles, 0.1 and 11.8 U/g creatinine) to 7.2 U/g creatinine (5th and 95th percentiles, 0.1 and 20.1 U/g creatinine) compared with 2.7 U/g creatinine (5th and 95th percentiles, 0.3 and 13.5 U/g creatinine) to 8.4 U/g creatinine (5th and 95th percentiles, 0.5 and 33.5 U/g creatinine), respec-
Advantages of CTA compared with DSA for the diagnosis of RAS may be limited by a greater incidence of CM nephropathy caused by a greater amount of CM. Other methods, such as colorcoded duplex sonography and magnetic resonance angiography, are of similar diagnostic value. However, both methods are associated with specific drawbacks. Color-coded duplex sonography can be limited by high intraobserver variability and technical failure caused by obesity and bowel gas. Magnetic resonance angiography has limited visualization of intrarenal arteries and may not be as widely available as CTA.20 We therefore compared CTA and DSA in a randomized prospective fashion with regard to impairment of renal function. In addition to serum creatinine measurements, plasma clearances for inulin using the single-shot method were measured. This method has been shown to have a high correlation with renal clearance for inulin, the gold standard for determination of glomerular filtration rate.21 Both groups were similar with regard to clinical parameters relevant for CM nephropathy, such as preexisting renal function impairment, presence of diabetes mellitus, and use of calcium channel blockers and nonsteroidal anti-inflammatory drugs.8-13,22 Reduction in effective arterial volume is an additional risk factor.7 Thus, all patients were prehydrated. Furthermore, hydration status was thoroughly monitored to avoid changes in renal function caused by changes in fluid status. Studies of the incidence of CM nephrotoxicity have produced variable results because of differences in the definition of CM nephrotoxicity and/or patient comorbidity.23 On this study, CM nephrotoxicity, as well as preexisting impairment in renal function, was defined in accordance with generally accepted often-applied criteria.9,10,15,24-26 Mean renal function in both groups, determined by serum creatinine levels and inulin clearances, was similar, and renal impairment was common. Thus, the study population had increased susceptibility for CM nephropathy. Therefore, the combination of this high-risk population and precise method to deter-
CONTRAST MEDIA NEPHROPATHY
mine renal function resulted in a sensitive study design to detect even subtle CM-associated changes in renal function. In both groups, there was a small but significant increase in serum creatinine levels regarding the entire groups, as well as subgroups of patients with normal and impaired renal function, except for the DSA group with impaired renal function. In this subgroup, the increase in serum creatinine level did not reach statistical significance because of the small number of patients and high SD. Inulin clearances decreased in both groups and all subgroups significantly. Increases in serum creatinine levels and decreases in inulin clearances were not statistically different between groups. However, concluding clinical equivalence is not necessarily appropriate because the number of cases could be too small. Therefore, the study was performed as an equivalence trial. In this case, equivalence is proven by the prespecified statistical significance, which can only be established by using a sufficient number of patients. Percentages were used because the distribution of initial values was widely spread for both serum creatinine and inulin clearance. The primary objective, to show that CM nephropathy of CTA and DSA differ by a clinically unimportant amount, is shown by showing that the true difference in renal function impairment is likely to lie between a lower and upper equivalence margin of clinically acceptable differences. An interim analysis after 80 patients was planned in advance to determine whether previous assumptions concerning sample size and extent of renal function impairment, which were based on uncertain information, were still valid. It turned out that our assumptions were too cautious. Thus, in the interim analysis, we could already prove equivalence. Margins of equivalence in bioequivalence studies are usually set at 75% of the SD, including the entire study population. This would be ⫾7.1% for inulin clearance and ⫾8.2% for serum creatinine level. Margins of equivalence here were defined at even closer limits: ⫾6.25% for both parameters. This was based on the clinical definition of CM nephropathy: increase in serum creatinine level by 25% or more. Thus, only absolute changes in inulin clearance or serum creatinine level less than 6.25% were considered clinically
241
irrelevant, which is a range of 12.5%, or half the definition or only a quarter of the increase of 25%. Despite this tight definition of clinical relevance, equivalence of both methods was proven because confidence intervals for both parameters were within these limits. In addition, multivariate analysis confirmed this result: CTA and DSA had no influence on renal function impairment. However, diabetes mellitus and preexisting renal function impairment proved to be independent risk factors for CM nephropathy. This finding confirms current literature data8-13 and is further proof that results of our study are valid. Thus, a clinically relevant difference in renal function impairment after CM administration between the CTA and DSA groups (patients with normal or impaired renal function) could not be shown. CM nephrotoxicity is partially mediated by toxic tubular damage.7 Tubular toxicity of CM may occur without deterioration in glomerular filtration rate.27,28 Urinary tubular enzymes as markers of tubular damage thus may serve as additional more sensitive indicators of CM nephrotoxicity. Therefore, beta-NAG and ␣1-microglobulin excretion were measured. Increases in both parameters in the CTA and DSA groups indicates a similar tubular toxicity of both methods. A greater proportion of patients in the CTA group was on calcium channel blocker therapy, although this difference was not statistically different. These drugs may blunt beta-NAG excretion after CM administration.21 However, the increase in beta-NAG excretion in patients with and without calcium channel blocker therapy was not different in either group. Therefore, there is no evidence that calcium channel blockers have a different effect on beta-NAG excretion in both groups. This study could not show that the intravenous administration of a greater amount of CM in CTA for the detection of RAS is associated with a greater risk for renal function impairment or tubular toxicity compared with intraarterially administered CM in DSA, although very sensitive methods in a population with a high risk for CM nephropathy were applied. Thus, our results indicate that with regard to CM nephrotoxicity, CTA, being less invasive than DSA, can be performed safely for the diagnosis of RAS.
242
LUFFT ET AL
REFERENCES 1. Galanski M, Prokop M, Chavan A, Scha¨fer CM, Jandeleit K, Nischelski JE: Spiral CT angiography. Radiology 189:185-192, 1993 2. Olbricht CJ, Paul K, Prokop M, et al: Minimally invasive diagnosis of renal artery stenosis by spiral computed tomography angiography. Kidney Int 48:1332-1337, 1995 3. Elkohen M, Beregi JP, Deklunder G, Artaud D, Mounier-Vehier C, Carre AG: A prospective study of helical computed tomography angiography versus angiography for the detection of renal artery stenosis in hypertensive patients. J Hypertens 14:525-528, 1996 4. Kaatee R, Beek FJ, de Lange EE, et al: Renal artery stenosis: Detection and quantification with spiral CT angiography versus optimized digital subtraction angiography. Radiology 205:121-127, 1997 5. Beregi JP, Elkohen M, Deklunder G, Artaud D, Coullet JM, Wattinne L: Helical CT angiography compared with arteriography in the detection of renal artery stenosis. AJR Am J Roentgenol 167:495-501, 1996 6. Rubin GD, Dake MD, Napel S, et al: Spiral CT of renal artery stenosis: Comparison of three-dimensional rendering techniques. Radiology 190:181-190, 1994 7. Barrett BJ: Contrast nephrotoxicity. J Am Soc Nephrol 5:125-137, 1994 8. Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med 89:615-620, 1990 9. Parfrey PS, Griffiths SM, Barrett BJ, et al: Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency or both. N Engl J Med 320:143-149, 1989 10. Rudnick MR, Goldfarb S, Wexler L, et al for the Iohexol Cooperative Study: Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: A randomized trial. Kidney Int 47:254-261, 1995 11. Weisberg LS, Kurnik PB, Kurnik BRC: Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int 45:259-265, 1994 12. Lautin EM, Freeman NJ, Schoenfeld AH, et al: Radiocontrast associated renal dysfunction: A comparison of lowerosmolality and conventional high-osmolality contrast media. AJR Am J Roentgenol 157:59-65, 1991 13. Moore RD, Steinberg EP, Powe NR, et al: Nephrotoxicity of high-osmolality versus low-osmolality contrast media: Randomized clinical trial. Radiology 182:649-655, 1992 14. Working Group on Renovascular Hypertension: Detection, evaluation and treatment of renovascular hypertension. Arch Intern Med 147:820-829, 1987 15. Erley CE, Duda SH, Schlepckow S, et al: Adenosine
antagonist theophylline prevents the reduction of glomerular filtration rate after contrast media application. Kidney Int 45:1425-1430, 1994 16. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W: Prevention of radiographic-contrastagent-induced reductions in renal function by acetylcysteine. N Engl J Med 343:180-184, 2000 17. Kuehnle HF, van Dahl K, Schmidt FH: Fully enzymatic inulin determination in small volume samples without deproteinization. Nephron 62:104-107, 1992 18. Yuen CP, Kind PRN, Price RG, Prail PGF, Richardson AC: Colorimetric assay for N-acetyl-beta-D-glucosaminidase in pathological urine using the w-nitrostyryl substrate: The development of a kit of manual procedure with automated fluorometric method. Ann Clin Biochem 21:295-300, 1984 19. Westlake WJ: Statistical aspects of comparative bioavailability trials. Biometrics 35:273-280, 1979 20. Krumme B, Mann JFE: Atherosclerotic renal artery stenosis in 2001—Are we less confused than before? Nephrol Dial Transplant 16:2124-2127, 2001 21. Gretz N, Ecker-Tschirner KH, Ku¨hnle HF, et al: Practicability of the inulin plasma single-shot clearance, in Albertazzi A, Cappelli P, Del Rosso G, et al (eds): Contributions to Nephrology. Basel, Switzerland, Karger, 1990, pp 220-228 22. Neumayer HH, Junge W, Kufner A, Wenning A: Prevention of radiocontrast-media-induced nephrotoxicity by the calcium channel blocker: A prospective randomised clinical trial. Nephrol Dial Transplant 4:1030-1036, 1989 23. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. J Am Soc Nephrol 11:177-182, 2000 24. Solomon R, Werner C, Mann D, D’Elia J, Silva P: Effects of saline, mannitol and furosemide on acute decreases in renal function induced by radiocontrast agents. N Engl J Med 331:1416-1431, 1994 25. Schwab SJ, Hlatky MA, Pieper KS, et al: Contrast nephrotoxicity: A randomized controlled trial of a nonionic and an ionic radiographic contrast agent. N Engl J Med 320:149-153, 1989 26. Weisberg LS, Kurnik PB, Kurnik BRC: Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int 45:259-265, 1994 27. Jevnikar AM, Finnie KJC, Dennis B, Plummer DT, Avila A, Linton AL: Nephrotoxicity of high- and low osmolality contrast media. Nephron 48:300-305, 1988 28. Donadio C, Lucchesi A, Tramonti G, Calderazzi A, Gibilisco G, Paolicchi A: Glomerular and tubular effects of contrast media diatrizoate and iopromide. Ren Fail 18:657666, 1996