Background. The aim of the study was to evaluate a new diagnostic procedure, ultrasound contrast‐enhanced voiding cystography (USVC), for vesicoureteral reflux (VUR) in renal transplant recipients and to compare it with radionuclide voiding cystography (RVC).
Methods. Twenty‐three renal transplant recipients with recurrent urinary tract infection were investigated simultaneously by RVC and USVC. After catheterization, the empty bladder was filled with normal saline (mean 250±30 ml) and 30–45 mBq of 99mTc‐labelled colloid. At the end of filling the bladder, 19.5 ml of galactose‐based, microbubble‐containing echo‐enhancing agent, at a concentration of 200 mg/ml, was instilled. During the filling and voiding phases the movement of the radiotracer was recorded by a gamma camera and the presence of microbubbles in the urinary tract by ultrasound. RVC was used to detecte and grade the degree of VUR.
Results. Nuclear studies identified VUR in 16 (69.6%) of 23 recipients with recurrent urinary tract infection: VUR grade I in three (13%) recipients, grade II in eight (34.8%) and grade III in five (21.7%) using a simplified grading system. USVC with contrast‐enhancement detected VUR in 14 (60.9%) recipients. Overall sensitivity and specificity of contrast‐enhanced USVC was 75 and 71%, respectively. Statistical analysis showed that the accuracy of this procedure increased with higher grades of VUR and its sensitivity reached 100% for detection of VUR grade III.
Conclusion. In our preliminary study, contrast‐enhanced USVC has proved to be an effective examination, with the same accuracy rate as RVC in detecting grade III VUR episodes with low diagnostic accuracy for low reflux grades.
Urinary tract infections remain a serious problem in renal transplant recipients . In individuals with compromised defense mechanisms, recurrent urinary tract infection may occur in the form of life‐threatening pyelonephritis and sepsis . Vesicoureteral reflux (VUR) is one of the risk factors for urinary tract infection. Most experience with the diagnosis and treatment of VUR has been gained in children. It is well known that urinary tract infections are related to VUR and reflux nephropathy . Yet, the significance of VUR for future renal damage in the absence of urinary tract infection has been questioned [3,4], and some authors maintain that VUR has no detrimental effects on the transplanted kidney unless associated with urinary tract infection . Some investigators evaluate patients by voiding cystography as early as 5 days after transplantation, and others several weeks after the procedure . Since the incidence of VUR in renal recipients tends to increase with time [1,13], follow‐up of patients with VUR using voiding cystourethrography (VCUG) or radionuclide voiding cystographies (RVC) is mandatory. Ultrasound voiding cystography (USVC) with contrast enhancement has proved to be an effective examination for identifying VUR in children with urinary tract infection [6–9]. RVC has some advantages over VCUG with respect to accuracy and less radiation exposure, so it appears to be a good standard in detecting VUR in transplanted recipients . This study was undertaken to ascertain the effectiveness of contrast‐enhanced USVC in comparison with RVC for detecting VUR in adult renal transplant recipients.
Subjects and methods
Twenty‐three renal transplant recipients (two men and 21 women), aged 23–60 years (mean±SD 39±15.6 years), with a graft functioning from 10 months to 10 years (mean 5±1.3 years). Recipients having one or more episode of urinary tract infection in the last year were included in the study. The majority of them were women. Basic diagnosis of renal failure was: undefined nephropathy in three cases, analgetic nephropathy in two, diabetic nephropathy in four, focal glomerulosclerosis in three, Iga glomerulonephritis in one, polycystic kidney disease in four, chronic atrophic pyelonephritis in two and reflux nephropathy (prior transplantation endoscopic, surgical correction or nephroureterectomy was undertaken) in four. In all recipients, the ureteral implantation was made according to extravesical surgical technique. By previous ultrasound evaluation, no dilatation of the urinary tract was found with allografts.To ascertain the diagnostic efficacy of contrast‐enhanced USVC with respect to RVC, both procedures were carried out simultaneously. The procedure was performed after a dose of cefuroxime had been administered intravenously to each subject as a prophylaxis 1 h prior to testing.
Radionuclide voiding cystography
A catheter was inserted into the bladder and urine was allowed to drain. The bladder was then filled with 30–45 mBq of 99mTc‐labelled colloid diluted in 200–320 ml of normal saline (mean 250±30 ml) maintaned at body temperature. The patient was kept in supine position throughout the study. The distribution of radiotracer was continuously recorded by the gamma camera (Siemens Basicam, IL, USA) throughout the filling and voiding phases at a rate of one image every 5 s. A detector equipped with an all‐purpose collimator was positioned under the examination table. At the end of filling of the bladder with saline and radiotracer, an echo‐enhancing agent was administred intravesically through the same catheter. At completion a clamp was put on the catheter for some minutes before voiding. The results of RVC were evaluated by two independent observers who were blinded to the results of USVC. Due to poor resolution of radionuclide images, a simplified grading system of VUR, as proposed by Fettich et al. , was used:
0: no VUR;
VUR grade I: radiotracer detected only in the ureter;
VUR grade II: radiotracer reached the ureter and renal pelvis, without renal pelvis dilatation;
VUR grade III: radiotracer reached the ureter and renal pelvis with renal pelvis dilatation.
Ultrasound voiding cystography
Sonography was performed using a real‐time scanner Acuson 128/10 (Acuson Corporation, Mountain View, CA, USA) with a convex 3.5 mHz transducer. Four grams of microbubble‐containing echo‐enhancing agent (LevovistR, Schering AG, Germany) was administered intravesically. The volume of the instilled contrast‐enhanced suspension was 19.5 ml at a concentration of ∼200 mg/ml. The proportion of contrast medium was 10–15% of the total fluid volume instilled into the bladder. Before the RVC procedure started, ultrasound image of graft collecting system, ureter and bladder was obtained through the ventral approach. While the echo‐enhanced contrast was administered and awaiting micturiction, the renal graft and ureter were scanned again. Scanning continued until the spontaneous voiding completed. VUR was identified when moving microbubbles in the ureter and/or renal graft collecting system was documented by ultrasound. VUR grading was the same as that used for RVC. The investigator performing USVC and grading was blinded to the results of RVC.
Statistical analysis was done using Medcalc for sensitivity and specificity assessment. The Mann–Whitney test was used to test the relationship between USVC and the mean degree of VUR established by RVC. The Pearson χ2 test was used for the correlation between VUR grade, determined by RVC and positive USVC.
The study was approved by the Medical Ethics Committee at the Ministry of Health, Republic of Slovenia, and written informed consent was obtained from all participants.
In a group of 23 renal transplant recipients with urinary tract infection, VUR was evaluated by echo‐enhanced USVC and RVC, and the two methods were compared for their diagnostic efficacy. RVC identified VUR in 16 (69.6%) of 23 patients: grade I reflux in three (13%), grade II in eight (34.8%) and grade III in five (21.7%), while echo‐enhanced USVC detected VUR in 14 (60.9%) of 23 patients, in 12 with RVC positive results and two with RVC‐negative results. Table 1 indicates the sensitivity and specificity of contrast‐enhanced urosonography relative to the degree of reflux episodes ascertained by RVC (Table 1).
Simultaneous evaluation of VUR by RVC and contrast‐enhanced USVC enabled us to compare the diagnostic accuracy of both examinations. Table 2 shows positive and negative results obtained by contrast‐enhanced USVC and the mean grade of VUR determined by RVC. Higher or lower mean rank value of RVC implies lower or higher mean VUR grade at negative or positive USVC (Table 2). The mean grade of VUR determined by RVC in VUR‐positive echo‐enhanced USVC was statistically more significant (P<0.05 by the Mann–Whitney test) than in the VUR‐negative one.
The higher the grade of reflux diagnosed by RVC, the greater was the rate of positive sonographic results (P<0.05 by the Pearson χ2 test). This linear correlation is statistically significant (P=0.017). The higher the established degree of VUR, the more reliable the results provided by the ultrasound examination using echo‐enhancing contrast (Figures 1 and 2). No adverse events due to intravesical aplication of ultrasound contrast and radionuclide, either simultaneously, during or after the examination, were observed.
|RVC VUR grade||USVC|
|RVC VUR grade||USVC|
|mean VUR grade±SD||mean rank of VUR grade|
|mean VUR grade±SD||mean rank of VUR grade|
|RVC grade of VUR||Total n||Positive USVC n (%)|
|RVC grade of VUR||Total n||Positive USVC n (%)|
The causes of VUR occurring after renal transplantation still remain to be clarified. Some authors blame the technique of anastomosing the ureter to the bladder mucosa [12–14], while others believe that VUR is due to rejection after renal transplantation [1,15]. A higher incidence of VUR has been reported with recurrent rejection episodes . The impact of VUR on the function of renal transplant has not yet been determined. Some studies have provided evidence that in the first 5 years post‐transplantation, VUR does not affect survival and function of the graft , but 9 years after transplantation, life span of the graft was found to be shorter in patients with VUR episodes compared with those with no VUR . It is thought that reflux produces no renal damage unless associated with urinary tract infections . Radiological studies and, less frequently, radionuclide examinations reported in the literature have confirmed VUR in 1–65% of renal transplant recipients . Reports in the literature indicate that VUR is not routinely evaluated in all recipients but in the case of recurrent urinary tract infections or graft pyelonephritis [13,14]. Yet some authors prefer VUR evaluation 4–5 months or 1 year after transplantation [5,13]. It has been reported that the incidence and severity of VUR episodes tend to increase in the long term . In our subjects, examination to detect VUR is undertaken only in cases of recurrent urinary tract infection.
In all our recipients who received a renal cadaveric transplant, extravesical ureterovesical anastomosis during transplantation procedure was performed. Graft ureter was anastomosed to the native bladder mucosa, creating an antireflux submucosal tunnel by using bladder muscle according to the Lich technique . Stents (JJ stents) were used in all recipients. Methods for detecting VUR in renal transplant recipients with urinary tract infections should be easy to perform and with none or minimal radiation exposure. RVC was selected as a reference method to evaluate USVC as it is more sensitive for detection of VUR than standard contrast X‐ray cystography and involves the use of less radiation. Its high sensitivity as compared with X‐ray technique is due to the fact that it allows continuous monitoring of reflux from the beginning of filling of the bladder until after voiding is completed. By choosing RVC we were able to carry out both RVC and USVC investigations simultaneously rather than consecutively. The same event was evaluated concomitantly by two different modalities. Due to the well known variability of VUR we believe that this approach enhanced the value of our results. RVC identified VUR in nearly 70% of cases, while echo‐enhanced USVC identified VUR in 61% of recipients with recurrent urinary tract infection in this group. For ultrasound examination the movement of air microbubble‐containing echo‐enhancer in the urinary bladder, ureter and renal collecting system is recorded throughout the examination. In a grafted ureter there can be some difficulty in clearly identifying and documenting the microbubbles, resulting in some misinterpretation of low‐grade VUR in USVC. Also, the ureter is sometimes concealed by unusual structures such as lymphocoele or haematoma. All of these events may explain the low sensitivity of USVC in low‐grade VUR (grades I–II). The visibility of the microbubbles in the ureter might be improved using more than the 200 mg/ml concentration of the ultrasound contrast agent. It is also possible that two cases of false‐positive results were in fact true‐positive (i.e. false‐negative by RVC evaluation) since RVC may not detect low‐grade VUR in the proximity of the bladder due to scattered radiation from high radioactivity in the bladder. Nevertheless, our results showed with statistical significance that the higher the grade of reflux, the greater the rate of positve USVC results. In VUR, grade III echo‐enhanced USVC has proved to be as effective as RVC. We suggest that the difficulties with identification of low‐grade VUR do not diminish the clinical value of the USVC imaging method as a screening method for the detection of grade III reflux in recipients with recurrent urinary tract infections. According to our experience, the procedure requires the considerable expertise of the examining physician and its sensitivity and accuracy increases with the experience gained by the examiner.
USVC using echo‐enhancing agent instilled in the bladder could be a reliable method to document VUR of high grade in renal transplant recipients with recurrent urinary tract infection. An important advantage of echo‐enhanced USVC is that it can be performed easily on an outpatient basis during routine ultrasound examination, serving as a method of outpatient selection for further radionuclide or radiological investigation.
Correspondence and offprint requests to: Andrej Kmetec, MD, Department for Urology, University Medical Centre, Zalos˘ka 7, 1000 Ljubljana, Slovenia.
This study was supported by a grant (L3–1369–0312/99) from the Ministry of Science and Techology of the Republic of Slovenia.