ORIGINAL ARTICLE Annals of Nuclear Medicine Vol. 13, No. 6, 401-406, 1999 Reappraisal of Tc-99m DMSA scintigraphy for follow up in children with vesicoureteral reflux Eriko TSUKAMOTO,* Kazuo ITOH,*** Koichi MORITA,* Chietsugu KATOH,* Kunihiro NAKADA,* Katsuya NONOMURA,** Hidehiro KAKIZAKI,** Tomohiko KOYANAGI** and Nagara TAMAKI* *Department of Nuclear Medicine and **Department of Urology, Hokkaido University School of Medicine ***Department of Rediology, Sapporo JR General Hospital We reviewed Tc-99m DMSA scintigraphy in children with vesicoureteral reflux (VUR) in order to assess whether repeated Tc-99m DMSA scans are necessary for the follow up of these patients. Ninety-seven children who were followed up for more than one year ( 1-7.4 years, average 2.8 years) after the first DMSA scan were included in the study. Fifty-one patients had been diagnosed as primary VUR and 46 as secondary VUR. Age at the first examination ranged from O to 14 years (average 5.1 years). Planar images were taken 2 hours after injection. The % renal uptake per injected dose (%RU) was calculated from posterior images. Kidneys in 11 patients ( 11.3%) changed morphologically during the follow up. Of these, new photon deficient areas (PD) were detected in only 4 patients (4.1%). All of these 4 patients had neurogenic bladder and were managed with selfcatheterization. Of the remaining 7 patients, cortical thinning progressed in 5 patients (5.2%) and PDS resolved in 3 patients (3.1 %). In one of these 7 patients, PD resolved in one kidney and cortical thinning progressed in the contralateral kidney. Of 97 patients reviewed, % RU decreased more than 20% during the follow up in 6 patients (6.2%). All were diagnosed as secondary VUR due to neurogenic bladder. % RU decreased only in the contracted kidneys at the initial scan. Two of them underwent renal transplantation because of severe renal failure. In conclusion, new PD rarely developed and % RU decreased in only a few patients during the follow up of children with VUR. Repeated Tc-99m DMSA scintigraphy therefore seems to have little benefit in the follow up of children with VUR. It should be performed in selected patients with high risk of urinary tract infection or renal failure. Key words: Tc-99m DMSA, vesicoureteral reflux, urinary tract infection INTRODUCTION Tc-99m DMSA scintigraphy is now recognized as a valid tool for detecting upper urinary tract infections (UTD and renal scars.1-9 Reflux pyelonephritis is a major cause of reflux nephropathy and it will possibly lead children with vesicoureteral reflux (VUR) to renal failure. Repeated UTI and increased renal scars are high risk factors for reflux nephropathy. Long term follow up of the patients is therefore necessary to assess whether the children may Received July 7, 1999, revision accepted September 1 , 1999. For reprint contact: Eriko Tsukamoto, M.D., Department of Nuclear Medicine, Hokkaido University School of Medicine, Kita-15 Nishi-7, Kita-ku, Sapporo 060-8638, JAPAN. develop new renal scars or their kidneys remain stable.10,11 For monitoring renal morphology and function in children with VUR. Tc-99m DMSA scintigraphy is often repeated. On the other hand, it is known that repeated urinary tract infection or new renal scar formation does not frequently occur in children with VUR under proper medical care such as antibiotic prophylaxis.12-14 Moreover, the radiation dose to the kidneys from a DMSA scan is even slightly higher than an intravenous urogram.15,16 In view of this, we need to know if repeated DMSA scans are really necessary for the follow up of children with VUR. In this study, we reviewed the scintigrams of children with VUR at follow up and investigated how often we could find a morphological change in the kidneys during follow up in order to discuss the necessity of repeated DMSA scans. MATERIALS AND METHODS Patients Ninety-seven children (57 boys and 40 girls) who were followed for more than one year after the first scan in our hospital entered the study. Age ranged from O to 14 years (average 5.1+-3.6 years) at the first examination. They repeated the examinations from 2 to 7 times (average 3.1+-1.1times) during a period of 1-7.4 years (average 2.8+-1.6 years). Voiding cystourethrography (VCUG) was performed to detect VUR. Fifty-one had been diagnosed as primary VUR and 46 as secondary VUR (Table 1). Four patients had single kidneys. Reflux of the 169 renal units was graded from 1 to 5 according to the International Reflux Study Classification.17 Numbers of the units of Grades 1 to 5 were 16, 37, 31, 55 and 30, respectively. Patients were treated with antibiotics for the UTI and maintained on long-term low dose prophylaxis. Anticholinergic agents were given to the primary VUR patients with unstable bladder. Besides instructions for regular frequent voiding, patients with neurogenic bladder were placed on clean intermittent catheterization (CIC) whereas urethral obstruction was managed with transurethral incision. Anticholinergics were also given when they had detrusor hyperreflexia. They were followed up until the disappearance of VUR was confirmed with 3 successive VCUGs. During follow up, 27 patients had at least 1 recurrent urinary tract infection and 7 had on episode of fever of unknown origin. Before the first examination or during follow up, 38 patients underwent anti-reflux surgery for breakthrough UTI. Scintigraphy In all but a few patients with a febrile UTI episode, DMSA scan was performed at least 6 months after the eradication of UTI. All the patients or their parents gave informed consent to the DMSA examination. Patients who were unable to remain stationary during the Tc-99m DMSA study were sedated prior to the study. Tc-99m DMSA was prepared by adding freshly eluted Tc-99m to a commercially available freeze-dried kit (Daiichi Radioisotope Lab. Co., Tokyo). A single rotating gamma camera (Toshiba GCA-602A) equipped with a low energy high-resolution parallel-hole collimator was positioned posteriorly to the patient who was in the supine position. Posterior planar images were taken precisely 2 hours after injection with an age-adjusted dose (26-95 MBq) of Tc-99m DMSA for a preset time of 5 minutes on a 512 x 512 matrix. Supplemental posterior oblique images were also obtained in every case. On completion of the planar study, SPECT images were obtained but not used in this study because there was no information in addition to the planar images. % RU of Tc-99m DMSA was calculated from the planar posterior image data by using the equations previously described.2 Evaluation of scintigrams Two experienced nuclear physicians (K.I. and E.T.) reviewed and determined with consensus whether there were any changes in the morphology of the kidneys on serial DMSA scans. A photon deficient area (PD) with cortical loss was regarded as an infectious focus or a renal scar. RESULTS PDS suggestive of infectious foci or renal scars were found in 62 patients (63.9%) on the first examination. Kidneys in 11 (11.3%) of 97 patients changed morphologically during the follow up period. Of these 11 patients, new PDs were detected in 4 patients (4.1 %) (Table 2, Fig. 1 ). All of 4 patients with a new PD had been diagnosed as neurogenic bladder and managed with CIC. Fever due to UTI was evident in 2 patients before the repeated DMSA scan which demonstrated new PDs. A reflux grade greater than grade 3 was found in 3 renal units in 2 patients. Progression of cortical thinning was shown in 5 patients (5.2%) (Table 3. Fig. 2). The lesions resolved in the remaining 2 of the 11 patients (2.1 %) and in the kidney of one patient with progression of cortical thinning in the contralateral kidney (Table 4, Fig. 3). All of these 3 patients were under 1 year old at the first examination and had the episode of UTI within 6 months before the examination. % RU decreased more than 20% during the follow up in 6 patients (6.2%). New PDS were detected in 2 of them. All 6 patients had been diagnosed as having neurogenic bladder. Kidneys in which % RU decreased were all contracted at the first examination. Two of them subsequently underwent renal transplantation preceded by augmentation cystoplasty18 because of end-stage renal failure . DISCUSSION This study revealed that new renal scar formation was rarely developed in patients with VUR under proper medical care and treatment. % RU decreased in a few patients. All the patients with new lesions or decreased % RU had neurogenic bladder which may increase the chance of urinary tract infections and high intravesical pressure. Follow up results for children with VUR have been discussed in many articles. New scar development was reported to be 3-30%12,19-22 in children with primary VUR and up to 86%21,22 in children with secondary VUR. Compared to these previous data, our results showed quite a low rate of new scar development. No new scar formation was seen in the children with primary VUR and the rate was very low, even in the children with secondary VUR. Although the population of the patients and methods of evaluation of the renal scars are different, they do not explain this strikingly low rate of new scar development. Different treatment procedures at the centers in the previous articles may partly explain such a difference. Our urologists' principle of maintaining a low pressure urinary system, regular frequent voiding with or without anticholinergics in primary VUR, CIC in neurogenic bladder, and eradication of urethral obstruction with transurethral incision, in the management of VUR is believed to be instrumental in obtaining such a low rate of new scar formation. The fact that they adopted prompt antireflux surgery for breakthrough infection (38 out of 97 patients) whenever those conservative regimens failed must have also played a role. Another possible explanation is the different rate of recurrent urinary tract infection in different countries or in different races, which influences the rate of new scar development. According to the report from the European portion of the international reflux study in children 23 the incidence of urinary tract infection per patient per month at different centers revealed unexpected differences. It was the lowest in the Finnish (0.005) and the highest in German/Belgian (0.020) centers. There are few reports from Asian centers and our data are limited. We need to accumulate more data from different centers in Asia. The main purposes of follow up of the children with VUR are preserving their renal function and preventing sequelae of reflux nephropathy such as hypertension. We did not survey for hypertension but found that % RU indicating functioning renal mass decreased in only a few patients during the follow up. The kidneys with decreased % RU were all smaller than the contralateral kidney and associated with neurogenic bladder. We have previously reported that renal scars rarely reduced the functioning renal mass unless they had become relatively small.24 Others25,26 also reported that relative kidney size was closely related to renal function in children with VUR. The present data showed that relatively small kidneys have the potential to progress the renal dysfunction. Neurogenic bladder appeared to be a risk factor for both new PD formation and decreasing functioning renal mass. Renal damage in children with neurogenic bladder is related to either high intravesical pressure or the association of VUR.27 Moreover, high intravesical pressure often causes VUR. CIC is the recommended treatment for these children.28,29 Generally the outcome of CIC in the management of neurogenic bladder has been satisfactory both in the resolution and improvement of VUR and UTI.30 When this is not the case, either the lack of patient adherence to CIC or poorly compliant bladder to the extent of irreversibility must be considered. The former condition can be corrected by reeducation, whereas the latter may require augmentative cystoplasty with or without antireflux surgery before severe reflux nephropathy occurs.18 For these reasons, we need a close follow up of the children with neurogenic bladder, and scintigraphic evaluation with Tc-99m DMSA is an effective tool for their management. The problem in repeating Tc-99m DMSA scan is the high radiation dose to the kidneys. The radiation dose to the kidneys from Tc-99m DMSA is known to be higher than that from intravenous contrast urography. We should consider this disadvantage and therefore select high risk patients for repeated DMSA scintigraphy. CONCLUSION Our results indicated that renal morphology rarely changed and functional renal mass rarely decreased in children with VUR under proper urological care during follow up. Therefore, we should select the high risk subgroup of children with VUR for repeat Tc-99m DMSA renal scintigraphy to prevent unnecessary exposure to radiation. ACKNOWLEDGMENT We thank Mr. Fredrick Miller of Nikko Memorial Hospital, for assisting in preparing the manuscript. This work was partly presented at the 44th Annual Meeting of the Society of Nuclear Medicine, San Antonio, Texas, June 1-5, 1997. REFERENCES 1 . Rushton HG, Majd M. Dimercaptosuccinic acid renal scintigraphy for the evaluation of pyelonephritis and scarring: A review of experimental and clinical studies. J Urol 148: 1726-1732, 1992. 2. Itoh K, Asano Y, Tsukamoto E, Katoh C, Nakada K, Nagao K, et al. Single photon emission computed tomography with Tc-99m-dimercaptosuccinic acid in patients with upper urinary tract infection and/or vesicoureteral reflux. Ann Nucl Med 5: 29-34, 1991. 3. Joseph DB, Young DW, Jordon SP. Renal cortical scintigraphy and single photon emission computerized tomography (SPECT) in the assessment of renal defects in children. J Urol 144: 595-597, 1990. 4. Wallin L, Bajc M. The significance of vesicoureteric reflux on kidney development assessed by dimercaptosuccinate renal scintigraphy. J Urol 73 : 607-611, 1994. 5. Gordon AM, Aliabadi H, Churchill BM, Ash JM, Gilday DL. 99mTechnetium-dimercapto-succinic acid renal scanning and excretory in diagnosis of renal scars. J Urol 142: 790-792, 1989. 6. Massoud M, Rushton HG. Renal Cortical Scintigraphy in the diagnosis of acute pyelonephritis. Semin Nucl Med 22: 98-111 , 1992. 7. Arnold AJ, Brownless SM, Carty HM, Rickwood AMK. Detection of renal scarring by DMSA scanning--an experimental study. J Pediatr Surg 25: 319-393, 1991. 8. Rushton HG, Maiad M, Chandra R, Yim D. Evaluation of 99mTC-DMSA renal scans in experimental acute pyelonephritis in piglets. J Urol 140: 1169-1174, 1988. 9. Aprile C, Saponaro R, Di Maio D, et al. Cortical kidney scan evaluation in the follow up of children with vesico-ureteric reflux. J Nucl Biol Med 38: 89-95, 1994. 10. Bailey RR, Lynn KL, Smith AH. Long-term follow up of infants with gross vesicoureteral reflux. J Urol 148: 1709-171l, 1992. 11 . Arant BS Jr. Vesicoureteric reflux and renal injury. Am J Kidney Dis 17: 491-511, 1991. 12. Goldraich NP, Goldraich HG. Follow up of conservatively treated children with high and low grade vesicoureteral reflux: A prospective study. J Urol 148: 1688-1692, 1992. 13. Smellie J, Edwards D, Hunter N, Normand ICS, Prescod N. Vesico-ureteric and renal scarring. Kidney Int 8: S65-S72, 1975. 14. Bellinger MF. The management of vesicoureteric reflux. Clin N Amer 12: 23-29, 1985. 15. Smith T, Evans K, Lythgoe MF, Anderson PJ, Gordon I. Radiation dosimetry of technetium-99m-DMSA in children. J Nucl Med 37: 1336-1342, 1996. 16. Mackenzie JR. A review of renal scarring in children. Nucl Med Commun 17: 176-190, 1996. 17. Lebowitz RL, Olbing H, Parkkulainen KV. International system of radiographic grading of vesicoureteral reflux. Ped Rad 15: 105-l09, 1985. 18. Kobayashi S, Koyanagi T, Amoda K, Kakizaki H, Matsuura S, et al. Augmentation cystoplasty in children. Akt Urol 27: 35-37, 1996. 19. Hjalmas K, Lohr G, Tamminen-Mobius T, Seppanen J, Olbing H, Wikstrom S on behalf of the international reflux study in children. Surgical results in the intemational reflux study in children (Europe). J Urol 148: 1657-1661 , 1992. 20. Weiss R, Duckett J, Spier A on behalf of the intemational reflux study in children. Results of a randomized clinical trial of medical versus surgical management of infants and children with grades III and IV primary vesicoureteral reflux (United States). J Urol 148: 1667-1673, 1992. 21. Shimada K, Matsui T, Ogino T, Arima M, Mori Y, Ikoma F. Renal growth and progression of reflux nephropathy in children with vesicoureteral reflux. J Urol 140: 1097-1100, 1988. 22. Rushton HG, Majd M, Jantausch B, Wiedermann BL, Belman AB. Renal scarring following reflux and nonreflux pyelonephritis in children: Evaluation with 99m-technetium-dimercaptosuccinic acid scintigraphy. J Urol 147: 1327-1332, 1992. 23. Jodal U, Koskimies O, Hanson E, Lohr G. Olbing H, Smellie J, et al. Infection pattern in children with vesicoureteral reflux randomly allocated to operation or long-term antibacterial prophylaxis. J Urol 148: 1650-1652, 1992. 24. Tsukamoto E, Itoh K, Kanegae K, Mochizuki T, Shiga T, Katoh C, et al. Does renal scarring reduce functional renal mass? J Nucl Med 37: 290P, 1996. (abstract) 25. El-Khatib MT, Becker GJ, Kincaid-Smith PS. Morphometric aspects of reflux nephropathy. Kid Int 32: 261-266, 1987 26. Berg UB . Long-term follow up of renal morphology and function in children with recurrent pyelonephritis. J Urol 148: 1715-1720, 1992. 27. Fernandes ET, Reinberg Y, Vernier R. Gonzalez R. Neurogenic bladder dysfunction in children: Review of pathophysiology and current management. J Pediatr 124: 1-7. 1994. 28. Schlager TA, Dilks S. Trudell J, Whittam TS. Hendley O. Bacteriuria in children with neurogenic bladder treated with intermittent catheterization: Natural history. J Pediatr 126: 490-496, 1995. 29. Ottolini MC, Shaer CM, Rushton HG, Majd M. Gonsales EC. Patel KM. Relationship of asymptomatic bacteriuria and renal scarring in children with neuropathic bladders who are practicing clean intermittent catheterization. J Pediatr 127: 368-372, 1995. 30. Tanaka H, Ameda K. Shibata T. Kakizaki H, Kobayashi S, Koyanagi T. The outcome of the management based on urethral resistance in myelodysplastic children. Program and abstracts. International Symposium on spina bifida, school-age-adolescence, part II of III: 70, 1997.