UROL_V3_No2_001_Editorial.qxd Miscellaneous Ethylenedicysteine Versus Diethylenetriamine Pentaacetic Acid as the Carrier of Technetium Tc 99m in Diuretic Renography for Patients with Upper Urinary Tract Obstruction Hossein Shahrokh, Mansour Movahhed, Mohammad Ali Zargar Shoshtari, Amir Mohammad Orafa,* Sepideh Hekmat Department of Urology, Hasheminejad Hospital, Iran University of Medical Sciences, Tehran, Iran ABSTRACT Introduction: L,L-ethylenedicysteine (EC) is a new carrier of technetium Tc 99m (99mTc) with a lower affinity to plasma albumin in comparison with diethylenetriamine pentaacetic acid (DTPA). We compared 99mTc-EC scan with 99mTc-DTPA scan in diuretic renography for patients with obstructive uropathy. Materials and Methods: Thirty-three patients with upper urinary tract obstruction were randomly selected and underwent diuretic renographies by 99mTc-EC and 99mTc- DTPA. The counts of radioisotope per pixel in the target (the kidney) and background tissues as well as the clearance half-life of these two radiopharmaceuticals were measured and compared. Results: Mean counts of radioisotope per pixel in the target tissue was not different between 99mTc-EC and 99mTc-DTPA scans, but in the background tissue, it was less for 99mTc-EC (P = .003). Target-background ratio was higher for 99mTc-EC scan (3.80 ± 2.11 versus 2.48 ± 1.39; P < .001). Renal clearance half-life of radioisotope was shorter for 99mTc-EC scan than 99mTc-DTPA scan (58.15 ± 15.17 minutes versus 78.65 ± 19.99 minutes; P = .033). The results were similar for uremic patients (with a serum creatinine level > 2mg/dL). Conclusion: Target-background ratio of radiopharmaceutical uptake rates in diuretic renography was a good indicator of the higher resolution of 99mTc-EC than 99mTc-DTPA scan. We also demonstrated the faster clearance of 99mTc-EC than 99mTc-DTPA. This results in less radiation that is especially useful in children. To our opinion, 99mTc-EC can better depict the kidneys in comparison with 99mTc-DTPA. KEY WORDS: radioisotope renography, kidney function, diethylenetriamine pentaacetic acid, L,L-ethylenedicysteine, radiopharmaceutical, ureteral obstruction 97 Urology Journal UNRC/IUA Vol. 3, No. 2, 97-103 Spring 2006 Printed in IRAN Introduction Today, the advanced urology is based on disease knowledge, the most cost-effective diagnostic methods, the simplest treatment modality with minimal tissue injury, and finally, the most efficient and economical methods for follow-up. In other words, the use of invasive and expensive methods is not popular anymore. Diuretic renography plays a special role in the measurement of the kidney function and the location of obstruction in the upper urinary tract system. In Iran and many other countries, the Received July 2005 Accepted September 2005 *Corresponding author: Imam Sadegh Hospital, Meybod, Yazd, Iran Tel: +98 913 153 0820 E-mail: aorafa2001@yahoo.co.uk Technetium Tc 99m Ethylenedicysteine in Renography standard radiopharmaceutical for diuretic renography is technetium Tc 99m diethylene- triamine pentaacetic acid (99mTc-DTPA). But, notwithstanding its easy application and widespread clinical use, the background of images (especially in uremic patients and severely hydronephrotic kidneys) is obscured due to high uptake of radioactive substance by the liver and the spleen. Consequently, it cannot provide sufficient anatomic resolution for clinical judgment and decision-making in some cases of upper urinary tract obstruction. For this reason, it is inevitable for physicians to use invasive methods, although they usually impose high expenses to patients by accepting the risk of anesthesia and iatrogenic damage to the urinary tract. The most important cause of obscured images on 99mTc-DTPA scans is a tight protein binding of 99mTc-DTPA to plasma albumin and its tendency to be absorbed in the gastrointestinal tract.(1) Thus, it is reasonable to use radiopharmaceuticals with weaker protein binding and lower visceral uptake. One of these pharmaceuticals, which has recently been considered, is technetium Tc 99m L,L- ethylenedicysteine (99mTc-EC)(1); however, sufficient clinical evidence of its efficacy is lacking.(1) In this study, we compared the results of diuretic renography using 99mTc-EC and 99mTc- DTPA in a group of patients with upper urinary tract obstruction. Materials and Methods From April 2004 to March 2005, a total of 135 consecutive patients with upper urinary tract obstruction who had referred to Hasheminajad Hospital were initially evaluated by ultrasonography, intravenous urography, and, where required, retrograde and/or antegrade pyelography. Serum creatinine level was measured and urinalysis and urine culture were done. After documentation of obstruction with radiologic findings, 33 patients who had no indications for urgent interventions (eg, acute pyelonephritis, high fever, and sepsis) were randomly selected. All of the patients gave written informed consent. This study was approved by the ethics committee of Iran University of Medical Sciences. Diuretic renography was performed by either 99mTc-EC or 99mTc-DTPA while a Foley catheter was fixed and furosemide (in patients with normal serum creatinine levels, 20 mg; in those with impaired kidney function, 40 mg) was given 20 minutes after radiopharmaceutical injection (F+20 protocol). After a 2- or 3-day interval, the other radiopharmaceutical was used in a second diuretic renography with the same method. Bolus injections of 220 MBq to 300 MBq of 99mTc-EC and 450 MBq to 550 MBq of 99mTc-DTPA were administered. Both radioisotopes were made by the Iranian Atomic Energy Organization. Labeling was performed at the nuclear medicine department of the hospital in room temperature (Hot Lab). The kits were prepared rapidly and all at a same duration. Kidney imaging was performed using a single gamma camera in supine position with the nearest possible distance from the body surface. After assuring that the patient is hydrated, dynamic imaging was performed in vascular and excretory phases (within 20 minutes after the radiopharmaceutical injection) and after diuretic administration (at 10, 15, and 20 minutes after the injection). Delayed images were obtained up to 4 hours after the procedure, if necessary (in case of radiotracer in the pyelocaliceal system). A serum creatinine level higher than 2 mg/dL was considered as uremic. The examined parameters in this study were as follow: uptake rate of the radiopharmaceutical in the target tissue (kidney) and the background tissue (using count per pixel unit), target-background ratio of uptake, and clearance half-life of radio- pharmaceutical from the kidneys. The collected data were analyzed using SPSS software (Statistical Package for the Social Sciences, version 11.5, SPSS Inc, Chicago, Ill, USA). Paired t test was used to compare the uptake parameters of each scan. Continuous variables were demonstrated as means ± standard deviations and a P value less than .05 was considered significant. Results Thirty-three patients were enrolled in this study and 43 obstructive urinary tract units were evaluated. Twenty of the patients were men and 13 were women. Mean age of the patients was 54 ± 8 years. Mean serum level of creatinine was 4.2 ± 1.2 mg/dL. The serum level of creatinine was 2 mg/dL or less in 12 patients (nonuremic) and greater than 2 mg/dL in 21 (uremic). Mean counts of radioisotope per pixel in the target tissue was 85.91 ± 50.87 and 87.50 ± 55.27 in 99mTc-EC and 99mTc-DTPA scans (P = .802), and 98 Shahrokh et al in the background tissue, it was 25.76 ± 11.12 and 41.64 ± 23.52, respectively (P = .003). Mean counts of radioisotope per pixel in the target tissue were not significantly different between 99mTc-EC and 99mTc-DTPA scans neither in uremic nor in nonuremic patients. But, this rate in the background tissue was significantly lower for 99mTc-EC scan than 99mTc-DTPA scan in both groups of patients (Table 1). Target-background ratio was higher in 99mTc-EC scan (3.80 ± 2.11 versus 2.48 ± 1.39; P < .001). In both nonuremic and uremic patients, this ratio was significantly higher for 99mTc-EC scan (Table 1, Figure 1). Renal clearance half-life of the radioisotope was shorter for 99mTc-EC scan than 99mTc-DTPA scan (58.15 ± 15.17 minutes versus 78.65 ± 19.99 minutes; P = .033). In nonuremic patients, renal clearance half-life of the radioisotope substance was shorter for 99mTc-EC scan (23 ± 7.17 minutes versus 26.80 ± 9.5 minutes; P = .087), and it was 72.83 ± 28.35 minutes versus 100.25 ± 38.68 minutes in uremic patients (P = .043) (Figure 2). Discussion Technetium Tc 99m DTPA is an appropriate radiopharmaceutical for the evaluation of the kidney and glomerular filtration by diuretic renography. Of other characteristics of this radiopharmaceutical are low-dose radiation exposure to patient, reasonable cost, and availability. However, it is not suitable for the assessment of the renal cortex. Technetium Tc 99m EC is a tubular radiopharmaceutical with a N2S2 ligand. It is virtually a diacid derivative of a radiopharmaceutical used in brain scans called 99mTc-L,L-ethylenedicysteine diethylester. L,L- ethylenedicysteine easily binds to 99mTc in laboratory conditions and room temperature.(2) In this study, we showed that there is no significant difference between the uptake rate of the radioactive substance in the kidney tissue for 99mTc-EC and 99mTc-DTPA scans. In contrast, the mean rate of radioactive substance uptake in the background tissue was considerably less in 99mTc- EC scan; this could be due to the less protein binding and the weak binding of EC to red blood cells which eventually lead to a faster excretion of the radiopharmaceutical from the kidney (Figure 3).(3) Mean target-background uptake ratio of radioactive substance was greater for 99mTc-EC scan. This difference causes a higher resolution 99 TABLE 1. Counts of radioisotope per pixel in target (the kidney) and background tissues and target- background ratio for 99mTc-EC than 99mTc-DTPA scans *counts per pixel 99mTc-EC: technetium Tc 99m L,L-ethylenedicysteine, 99mTc-DTPA: technetium Tc 99m diethylenetriamine pentaacetic acid 99m Tc-EC 99m Tc-DTPA P value All patients Target tissue * 85.91 ± 50.87 87.50 ± 55.27 .80 Background tissue * 25.76 ± 11.12 41.64 ± 23.52 .003 Target-background 3.80 ± 2.11 2.48 ± 1.39 < .001 Patients with serum creatinine of 2 mg/dL or less Target tissue 97.87 ± 53.21 118.19 ± 49.76 .11 Background tissue 17.62 ± 10.97 32.62 ± 25.25 .086 Target-background 5.97 ± 1.69 4.01 ± 1.68 .019 Patients with serum creatinine greater than 2 mg/dL Target tissue 81.08 ± 48.06 84.67 ± 58.42 .68 Background tissue 29.15 ± 9.67 45.40 ± 22.82 .020 Target-background 2.89 ± 1.55 1.85 ± 0.54 .007 Technetium Tc 99m Ethylenedicysteine in Renography100 FIG. 1. Comparison of target-background ratio of 99mTc-EC and 99mTc-DTPA uptakes according to the serum creatinine level 0 1 2 3 4 5 6 7 8 <=1.5 1.6 to 2.5 3.6 to 4.5 4.6 to 5.5 > 5.5 Serum creatinine (mg/dL) T a rg e t- b a c k g ro u n d r a ti o o f ra d io is o to p e u p ta k e DTPA EC FIG. 2. Comparison of 99mTc-EC and 99mTc-DTPA renal clearance half-life according to the serum levels of creatinine 0 20 40 60 80 100 120 140 160 <=1.5 1.6 to 2.5 3.6 to 4.5 4.6 to 5.5 > 5.5 Serum creatinine (mg/dL) R e n a l C le a ra n c e h a lf -l if e DTPA EC Shahrokh et al for imaging with 99mTc-EC compared to 99mTc-DTPA regardless of the serum levels of creatinine. Das and colleagues compared 99mTc-EC scan and 99mTc-DTPA scan in a prospective study. In patients with a normal renal function, the results of these two scans were not significantly different, but 99mTc-EC scan had a higher imaging resolution and a faster clearance. In another group of patients who had an increased serum level of creatinine to a maximum of 3 mg/dL, reduction in glomerular filtration had confounded the background of the images and lack of sufficient resolution in images were significant in 99mTc-DTPA scan, whereas in 99mTc-EC scan, the images had a higher resolution, radioactive concentration in background tissue was less, and retention and concentration time of radioactive substance in the kidneys were shorter. They also studied a third group of patients who had a pathologic finding in the kidneys but were not uremic; there were no significant differences between the results of the two scans except for a higher resolution and a faster clearance of 99mTc-EC. Their study demonstrated the superiority of imaging with 99mTc-EC pharmaceutical in uremic patients, but it lacked a quantitative measurement of the parameters.(4) In a study by Eftekhari and colleagues,(5) 23 patients underwent diuretic renography with 99mTc-EC and 99mTc-DTPA. The mean serum creatinine level of the patients was 4.5 ± 4.11 mg/dL. In their study, mean target-background ratio of radioisotope uptake was greater for 99mTc-EC compared to 99mTc-DTPA. The mean counts of radioisotope per pixel in the background tissue was 3.31 ± 1.7 and 9.78 ± 2.76, respectively. Furthermore, renal clearance half- life of the radioactive substance after diuretic administration was shorter for 99mTc-EC. This means that 99mTc-EC is excreted more rapidly compared to 99mTc-DTPA; consequently, the exposure of patients to 99mTc-EC scan is shorter. They also reported that measurements of uptake rate in the upper and lower backgrounds of the kidney are not significantly different, especially for 99mTc-EC scan. When we evaluated the variables categorized according to the serum levels of creatinine, the results were considerable; in both uremic and nonuremic patients, there was no remarkable difference between 99mTc-EC and 99mTc-DTPA in the mean uptake rate in the target tissue (the kidney). This finding shows that patient's creatinine level has similar effects on the absorption of these two radiopharmaceuticals, and what may actually cause a high resolution on imaging in 99mTc-EC scans, especially in uremic patients, is the lower hepatobilliary excretion of this radiopharmaceutical. In 1998, Zakko and coworkers performed a study on 2213 people to evaluate the hepatobilliary excretion rate of 99mTc-EC. They reported that only 9 cases of gallbladder visualizations and/or biliary excretion were identified. In no case did biliary excretion affect the interpretation of the renal study. They concluded that hepatic uptake of this pharmaceutical is little; however, their measurement method was not quantitative.(6) Although the background uptake rate of 99mTc-EC in both uremic and nonuremic patients was less, this difference was statistically significant only in uremic patients. In other words, the background on 99mTc-DTPA scan can make the image more unclear if the patient's creatinine level is greater than 2 mg/dL. In our patients, renal clearance half-life of 99mTc-EC was significantly shorter after diuretic 101 FIG. 3. Comparison of 99mTc-EC and 99mTc-DTPA scans in a 67-year-old patient with prostate cancer, 20 minutes after radiopharmaceutical injection (A) and 20 minutes after furosemide injection. The 99mTc-EC scan could rule out ureterovesical junction obstruction 20 minutes after diuretic injection, because more than 50% of the radiopharmaceutical was excreted, but 99mTc-DTPA scan findings showed equivocal obstruction and more invasive methods such as nephrostography was needed to rule out obstruction. Technetium Tc 99m Ethylenedicysteine in Renography administration. However, this difference between 99mTc-EC and 99mTc-DTPA was significant in uremic patients but not in nonuremic ones. Renal clearance half-life as well as target-background ratio shows that in uremic patients, 99mTc-EC can be excreted from the kidneys more easily, hence creating a better anatomic visualization of the kidney. Meanwhile, in uremic patients, the shorter clearance of 99mTc-EC in comparison with 99mTc-DTPA reduces radiation exposure. Nowadays, 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) and iodine I 125 orthoiodo- hippurate (125I-OIH) are known as favorable radiopharmaceuticals for assessing the obstructive systems, which were not available for us. Stoffel and colleagues evaluated the safety and pharmacokinetics of iodine I 125 orthoiodohippurate (125I-OIH), 99mTc-MAG3, and 99mTc-EC. In their study, the clearance of 99mTc-EC and 99mTc-MAG3 averaged 71% and 52% of that of 125I-OIH, respectively. Volumes of distribution of 125I-OIH and 99mTc-EC were almost equal (%20 of body weight). The reasons were lower plasma protein binding (31% versus 50% to 70%), lower erythrocyte binding (%2 versus %5), and lower extrarenal clearance of 99mTc-EC which reduces its volume of distribution. These three factors result in equal volume of distribution for the two radiopharmaceuticals in uremic patients. Clearance of 99mTc-EC was 10 mL/min to 15 mL/min, while it was 30 mL/min for 125I-OIH. Their study also showed that hepatobiliary clearance of 99mTc-EC was a bit less than 125I- OIH.(2) Renal clearance of 99mTc-EC is fast.(1,7) Verbruggen and colleagues performed a study on mice, and compared 4 carriers of radioactive substances: OIH, DTPA, MAG3, and EC. They found that EC has a faster renal clearance and less retention in the kidneys, liver, intestines, and blood than did 99mTc-MAG3. They showed that renal excretion of EC is moderately more than MAG3, while hepatobiliary absorption of EC is considerably lower. This can explain a more similarity between EC and OIH.(1) Another study has revealed that lack of maturity in renal glomerular tissue of children usually results in better images by radiopharmaceuticals with tubular excretion (eg, 99mTc-MAG3 and 99mTc-EC) comparing with those with glomerular excretion (eg, 99mTc-DTPA).(8) It has been demonstrated that the resolution of 99mTc-EC scan is higher than 99mTc-MAG3 scan because of its higher extraction fraction (70% versus 50%). This finding is mainly due to less background and hepatic absorption of 99mTc-EC.(8) Taylor and coworkers published an article in 2004 in which they showed that the pharmacokinetic properties of 99mTc-MAG3 is far different from 125I-OIH and cannot be a substitute for it. Thus, they introduced a combination of EC and MAG3 named mercaptoacetamide-ethylene-cysteine (MAEC) for assessment of obstruction in the urinary tract. They showed that 99mTc-MAEC has a higher renal clearance compared to 99mTc- MAG3, providing a better image; however, 125I- OIH was still superior regarding clearance.(9) Conclusion Our study showed that target-background ratio of radiopharmaceutical uptake rates in diuretic renography can support the higher resolution of 99mTc-EC than 99mTc-DTPA scan. Hence, renography with 99mTc-EC can be more contributory in surgeon's decision-making. We also revealed the faster clearance of 99mTc-EC than 99mTc-DTPA. This can help us reduce radiation, especially in children. Comparing with the findings of previous studies on 99mTc-MAG3 as the current standard radiopharmaceutical in diuretic renography, 99mTc-EC has a higher laboratory stability, significantly lower hepatobiliary absorption, and shorter renal clearance time. In addition, it is produced more easily. We believe that 99mTc-EC can better depict the kidney in comparison with 99mTc-DTPA and can be an alternative to 125I-OIH. References 1. 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Biliary excretion of Tc-99m EC in renal studies. Clin Nucl Med. 1998;23:417-9. 7. Kabasakal L, Halac M, Yapar AF, et al. Prospective validation of single plasma sample 99mTc- ethylenedicysteine clearance in adults. J Nucl Med. 1999;40:429-31. 8. Tripathi M, Chandrashekar N, Phom H, et al. Evaluation of dilated upper renal tracts by technetium-99m ethylenedicysteine F+0 diuresis renography in infants and children. Ann Nucl Med. 2004;18:681-7. 9. Taylor AT, Lipowska M, Hansen L, Malveaux E, Marzilli LG. 99mTc-MAEC complexes: new renal radiopharmaceuticals combining characteristics of (99m)Tc-MAG3 and (99m)Tc-EC. J Nucl Med. 2004;45:885-91. 103