Keywords
contrast agents - bladder - ureter - ultrasound
Introduction
Vesicoureteral reflux (VUR) is the non-physiological backward flow of urine from the
bladder into the ureters due to an absence of preventive mechanisms [1]. This lack of preventive mechanisms can be either congenital (primary) or acquired
(secondary) [2].
With an incidence of 0.4–1.8 %, a primary genesis of vesicoureteral reflux is most
common. Incomplete closure of the vesicoureteral junction with a shortened intravesical
portion of the ureter occurs during embryogenesis [3].
The diagnosis of vesicoureteral reflux is typically made as part of expanded diagnostic
testing in the case of prenatal suspicion or recurrent febrile urinary tract infections
and more rarely in the case of voiding dysfunction or known hereditary predisposition
[4]. The probability of vesicoureteral reflux after a urinary tract infection is age-dependent
[4]. Further risk factors for vesicoureteral reflux include ethnicity, gender, and a
genetic/hereditary predisposition [5].
Secondary causes can be normal anatomical variants (subvesical obstruction), functional
disorders (bladder-bowel dysfunction), or a neurogenic voiding dysfunction [6].
Symptoms and initial diagnostic steps
Symptoms and initial diagnostic steps
Since patients with vesicoureteral reflux at a very young age often have recurrent
urinary tract infections, the first diagnostic measure is typically ultrasound of
the kidneys and the urinary tract. According to the S2K guidelines of the German Society
for Pediatric Nephrology, an ultrasound examination should be performed within 24
hours after the onset of a febrile urinary tract infection for orientation purposes
[4]. Scarring, inflammation, and urinary tract dilation can be diagnosed here.
Indirect signs of vesicoureteral reflux on B-mode ultrasound include parenchymal defects
(as part of reflux nephropathy), usually seen as wedge-shaped defects with retraction
of the renal parenchyma and enlarged renal calyces, a pronounced volume difference
of the kidneys, nephromegaly as part of a urinary tract infection, previscal dilation
of the ureter, dilation of the renal pelvis with varying widths depending on the bladder
filling, as well as a positive urothelial sign [4]. A comparison of the two kidneys is helpful here. However, the sensitivity and specificity
of B-mode ultrasound for diagnosing vesicoureteral reflux is not particularly high
so that a normal ultrasound examination does not rule out vesicoureteral reflux and
a positive urothelial sign is not necessarily indicative of vesicoureteral reflux
[7].
Indication for reflux testing
Indication for reflux testing
The indications for reflux testing varied between the American and European pediatric
and urological societies, but these have been adapted somewhat in recent years.
The current recommendation of the various professional societies is to perform reflux
testing in children under the age of two years in the case of two occurrences of pyelonephritis
and normal B-mode ultrasound examinations in order to avoid excessive diagnostic measures
after a single occurrence of pyelonephritis. Further indications are an abnormal B-mode
ultrasound examination with indirect signs of vesicoureteral reflux (B-mode ultrasound
should be performed after the first febrile urinary tract infection as mentioned above)
and an abnormal microbiological finding of non-E. coli infections [4]
[8]
[9]. A further indication is the diagnosis of vesicoureteral reflux in first degree
relatives.
Possibilities for reflux testing
Possibilities for reflux testing
Diagnostic possibilities for direct detection of vesicoureteral reflux include voiding
cystourethrography (VCUG), contrast-enhanced voiding urosonography (ceVUS), and radionuclide
cystography (RNC) [10]. There are also additional nuclear medicine methods that can diagnose the complications
of vesicoureteral reflux, like [99Tc]DMSA-scintigraphy of the kidneys to evaluate
possible parenchymal damage [11].
Classification of vesicoureteral reflux
Classification of vesicoureteral reflux
There are five grades of vesicoureteral reflux. This classification was published
in 1985 by Lebowitz et al. and is recognized by various guidelines [12]. The classification system is described in [Table 1]. Higher-grade vesicoureteral reflux is associated with intrarenal reflux (IRR),
which causes a pathological backward flow of urine into the renal parenchyma.
Table 1
Classification of vesicoureteral reflux according to Lebowitz.
|
Grade 1: Reflux only into the non-dilated ureter.
Grade 2: Reflux into the ureter and the renal pelvis without dilatation.
Grade 3: Reflux into the ureter (with or without kinking) and renal pelvis with mild to moderate
dilation. Normal or slightly deformed renal calyces.
Grade 4: Reflux into moderately dilated ureter (with or without kinking) and (slightly) dilated
renal calyces. The papillary impression is preserved.
Grade 5: Reflux with tortuous and significantly dilated ureter, dilation of the renal pelvis
and calyces with impressions with a loss of the renal papillae.
|
Vesicoureteral reflux is difficult to evaluate in the case of an additional obstruction
in the region of the urinary tract. Tortuous ureters can also occur in the case of
an obstruction and suggest higher grade vesicoureteral reflux [13]. It is not always easy to differentiate between the different grades of vesicoureteral
reflux since the transitions between the grades are fluid. [Fig. 1] shows a contrast-enhanced image of grade II vesicoureteral reflux in the proximal
ureter and renal pelvis with no dilation of the renal pelvis and with minor dilation
of the proximal ureter. Dilation of the renal pelvis must be present for the reflux
to be classified as grade III. The classification in [Fig. 2] as vesicoureteral reflux grade II is clearer but with a bifid ureter in duplex kidney.
[Fig. 3] also shows grade II vesicoureteral reflux but in this case with a mixed mode image
with overlay of the contrast-enhanced image and the B-mode image.
Fig. 1 Grade II VUR of the right kidney on comparison mode B-mode image (right) and contrast-enhanced
image (left). Imaging > 2 minutes after intravesical administration of contrast agent.
Fig. 2 A Contrast-enhanced ultrasound with grade II VUR of the right kidney. Imaging > 2 minutes
after intravesical administration of the contrast agent. White arrows: Image of the
contrast agent in the renal calyces. Red arrow: Contrast-enhanced image of the ureter
in bifid ureter. B B-mode examination of the right kidney. Urinary retention or dilation of the ureter
cannot be delimited. A parenchymal bridge (red arrow) can be detected as a secondary
finding.
Fig. 3 Mixed mode image with overlay of contrast-enhanced image and B-mode image of grade
II VUR of the right kidney.
[Fig. 4] shows a seven-year-old female patient with suspicion of vesicoureteral reflux after
recurrent pyelonephritis. The transition between the different grades is also fluid
here. Based on the indication of dilation of a renal calyx but the lack of pronounced
dilation of the renal pelvis and the ureter, grade III classification was assigned.
Fig. 4 After administration of contrast agent, mild to moderate dilation of the ureter and
renal pelvis and mild enlargement of the renal calyces can be detected. The finding
is consistent with grade III reflux.
The higher the grade of disease, the clearer the diagnosis. [Fig. 5] shows vesicoureteral reflux grade IV in a 6-year-old female patient with recurrent
pyelonephritis with mild impression but preserved papillary form and significantly
enlarged renal calyces. [Fig. 6] shows marked impressions with a loss of the papillae, which is consistent with grade
V vesicoureteral reflux. The origin of the proximal ureter must be additionally documented
when deciding to surgically treat higher grade vesicoureteral reflux.
Fig. 5 6-year old female patient with recurrent pyelonephritis. After contrast administration,
moderate dilation of the renal pelvis and enlarged renal calyces can be detected.
The finding is consistent with grade IV reflux. Comparison mode with B-mode ultrasound
image on the right and contrast-enhanced image on the left.
Fig. 6 7-year old female patient with recurrent pyelonephritis. After contrast administration,
pronounced dilation of the renal pelvis and calyces can be detected. There are marked
impressions with a loss of the papillae. The finding is consistent with grade V reflux.
Voiding cystourethrography and radionuclide cystography
Voiding cystourethrography and radionuclide cystography
To date, vesicoureteral reflux has been primarily diagnosed via voiding cystourethrography
(VCUG). In this examination method, intravesical contrast administration and X-ray
fluoroscopy are used to diagnose vesicoureteral reflux [14]. This method has been used for over 60 years and is considered the gold standard
[15]. The disadvantage of the examination is the use of radiation in the primarily young
patient population. In Germany, there are age- and weight-dependent diagnostic reference
values. These range from a dose area product of 5 [cGy∙cm2 = µGy∙m2] for newborns
(3 to < 5 kilograms or under 3 months of age) up to 30 [cGy∙cm2 = µGy∙m2] in children
between 5 and 10 years of age or between 19 and 32 kilograms [16]. In spite of the fact that this examination method has been in use for a long time
and numerous publications are available, a study by Schneider et al. was able to show
that both documentation and the examination procedure are not standardized in Europe
and the result of the examination, like in ceVUS, is highly dependent on the experience
of the examiner [17].
There are also nuclear medicine methods for diagnosing vesicoureteral reflux. Radionuclide
cystourethrography is performed as a direct method analogous to VCUG. This method
has a similar sensitivity to VCUG with slightly lower radiation exposure [18]. 99Tc-MAG3 renal scintigraphy can be used as an indirect method for detecting vesicoureteral
reflux. The advantage of this method is that the radiotracer is applied intravenously
so that the bladder does not need to be catheterized for the examination. However,
the sensitivity and specificity are significantly lower than that of VCUG and RNC.
Moreover, since urinary continence is necessary for examination planning and the patient
population is typically young, this method is not generally used for primary diagnosis
in the case of suspicion of vesicoureteral reflux [18].
Alternative method: ceVUS
Alternative method: ceVUS
Contrast-enhanced ultrasound examination (ceVUS) can be used as an alternative method
to reduce radiation exposure. Studies on the successful use of ultrasound to diagnose
vesicoureteral reflux have been available for years. In 1984, Schneider et al. described
the good sensitivity and specificity of B-mode ultrasound for higher grade vesicoureteral
reflux [19]. The currently available ceVUS examination method can be considered a further development
of the method described by Alzen et al. in 1994 in which vesicoureteral reflux was
diagnosed based on intravesically administered air bubbles. Using this method, higher
grade vesicoureteral reflux (starting at grade III) could be detected with a sensitivity
of 100 % and a specificity of 95.6 % [20]. Various studies by Darge played a major role in the further development of ceVUS
and the approval of the first-generation ultrasound contrast agent Levovist and were
able to show at least comparable diagnostic accuracy to that of VCUG [21]
[22]
[23]
[24]
[25]
[26]. This was then able to be confirmed in the following years in a number of studies
[27]
[28]
[29]
[30]. A meta-analysis by Darge from the year 2008 showed that more cases of vesicoureteral
reflux were detected with ceVUS than with VCUG and that the grade was higher in the
ceVUS examination than in VCUG in 19.6 % of the cases [22].
A meta-analysis from the year 2022 compared the sensitivity and specificity of ceVUS
examinations and calculated a sensitivity of 92 %, a specificity of 94 %, and an AUC
of 97 % on average for ultrasound contrast agents of the first generation. These values
were 93 %, 91 %, and 97 %, respectively, for ultrasound contrast agents of the second
generation [31]. The rate of false-negative ceVUS results was 3 % so that according to both the
study and the current S2k guidelines VCUG should be additionally performed in the
case of a negative ceVUS examination but persistent suspicion of vesicoureteral reflux
[4]. However, the clinical-therapeutic relevance of performing another invasive examination
should always be questioned here.
VCUG and ceVUS differ primarily with regard to the diagnosis of low-grade vesicoureteral
reflux since the distal ureters sometimes cannot be reliably evaluated on ceVUS due
to a lack of visibility of the distal ureters (e. g. in the case of intestinal gas
overlying the branches) or due to the high concentration of contrast medium in the
neighboring bladder [13]. In contrast, another study showed that 9 % more cases of vesicoureteral reflux
were able to be detected on ceVUS than VCUG [22]. An important reason why VCUG is preferred over ceVUS in many cases is the expertise
of the examiner. However, a single-center study showed a good learning curve for ceVUS
and that there is a lack of standardization in the examination procedure and documentation
for VCUG [17]
[31].
In addition to the advantage of reduced radiation exposure for the primarily young
patient population, legal guardians are more accepting of ceVUS than VCUG. In one
study, 92.9 % of surveyed parents preferred ceVUS over VCUG [32].
Which examination should be performed and when?
Which examination should be performed and when?
The pediatric and nephrology guidelines in Germany view the currently available diagnostic
methods as equivalent. The following recommendation is included in the S2k guidelines
on urinary tract infections in children from the year 2021: “If sufficient for the
particular diagnostic issue, sonographic reflux testing (ceVUS) should be given preference
over methods involving radiation provided that the examiner has the necessary experience”
[4]. This applies to an accordingly selected patient population.
If other diseases or anomalies of the urinary tract, e. g., a duplex kidney or ureterocele,
are suspected in addition to the suspicion of vesicoureteral reflux, VCUG should be
given preference over ceVUS [33]. In the case of suspected subvesical obstruction, both VCUG and ceVUS can provide
information about the cause [34]. On the other hand, ceVUS is particularly advantageous when intrarenal reflux (IRR)
is present in addition to vesicoureteral reflux [35]. Since IRR often occurs in addition to vesicoureteral reflux (averaged over all
VUR grades, IRR is seen in 3–10 % of cases), ceVUS should be used for the primary
diagnosis of vesicoureteral reflux provided that the corresponding requirements are
met by the hospital and examiner [36].
However, the selection of the examination method depends on the availability of resources
on-site, the specific clinical question, and the goal of ensuring the lowest possible
radiation exposure while obtaining maximum information.
The examination can first be performed after successful treatment of the urinary tract
infection/pyelonephritis. It must be taken into consideration that the examination
should not be performed too soon after an infection in order to avoid any false-negative
findings resulting from temporary infection-related swelling [37]. To ensure this and to avoid the transfer of bacteria from the bladder to the renal
pelvis as a result of the examination, the urine must be examined prior to ceVUS. The
examination should not be performed if intravesical bacteria is detected. A sterile
procedure is also important for bladder catheter placement and intravesical injection
of the contrast medium. There is currently only insufficient literature regarding
the periprocedural application of an antibiotic for ceVUS. Some individual studies
were performed without the administration of antibiotics [38] or with a single administration on the day of the examination [39]. In comparison, administration of an antibiotic the day before, the day of, and
the day after VCUG is recommended [40]. Since both examination procedures have the same risk factors for the development
of a urinary tract infection, we recommend using the same procedure for ceVUS.
Continuous antibiotic prophylaxis is recommended by current guidelines in the case
of diagnosed vesicoureteral reflux. However, this is being reexamined in new studies
from the year 2023 [4]
[41]. In the case of additional obstructive diseases of the urinary tract, antibiotic
prophylaxis should be implemented [38].
Types of contrast agent for diagnosing vesicoureteral reflux
Types of contrast agent for diagnosing vesicoureteral reflux
The ultrasound contrast agents typically used for diagnosing vesicoureteral reflux
are second-generation SonoVue (primarily in Europe) and Optison (primarily in the
US). First-generation Levovist was also used in initial studies [42]. The use of Levovist and SonoVue for detecting vesicoureteral reflux is included
in the product information. However, the production of Levovist has been discontinued.
General approval for use of Optison in minors is described [43]. Multiple studies on the safety of the intravesical administration of ultrasound
contrast agent have been conducted. No serious adverse events were reported. In one
study, the rate of non-serious adverse events was 0.31 %, with most issues being associated
with the placement of the urinary catheter [32]
[44]
[45]
[46].
ceVUS examination procedure
ceVUS examination procedure
The ceVUS examination procedure has already been described many times. Refer to the
ESPR reviews and the review by Ntoulia et al. from the year 2021 [44]. There are various techniques for filling the bladder with contrast agent. The contrast
agent can either be administered extracorporeally in a 0.9 % saline solution and continuously
applied during the course of the examination or the contrast agent can be administered
directly into the bladder after prior partial filling of the bladder with 0.9 % saline
solution. The mechanical index for the examination depends on the ultrasound transducer
but should ideally be under 0.1. The product information for SonoVue recommends a
value of less than 0.4 [47].
The examination should be performed during filling and emptying of the bladder. If
it is not possible to evaluate both kidneys and both ureters during emptying of the
bladder, the bladder can be filled again. By filling the bladder several times, the
sensitivity of the examination could be further increased.
Low-grade, particularly grade I, vesicoureteral reflux can often be effectively detected
in the filling phase of the examination, while the full bladder and the voiding phase
are the most suitable times for evaluating the severity of vesicoureteral reflux.
If the bladder is to be filled again, the extracorporeal mixing of ultrasound agent
and carrier solution is the most suitable method for achieving uniform contrast enhancement
during the examination.
Continuous scanning of the bladder during filling is not recommended since this will
destroy the contrast bubbles. Therefore, pauses at regular intervals are recommended.
Daily practice/recommended actions
Daily practice/recommended actions
Contrast-enhanced ultrasound examination of the bladder and the urinary tract is becoming
increasingly important in the diagnosis of vesicoureteral reflux and should be used
as the primary diagnostic method if the corresponding resources are available in suitable
cases. Suspicion of either primary or secondary vesicoureteral reflux is considered
an indication for examination. Indications include congenital hydronephrosis, a first
degree relative with vesicoureteral reflux, a urinary tract infection with non-E.
coli bacteria, an abnormal B-mode ultrasound examination after a febrile urinary tract
infection, or at least two occurrences of pyelonephritis in children under the age
of two. ceVUS can be quickly learned, is equivalent to the gold standard examination
(VCUG) and should be used as the primary diagnostic method in the often very young
patient population due to the lack of radiation exposure. The examination should not
be performed during a urinary tract infection/pyelonephritis but rather in the inflammation-free
period after treatment. It is important to wait long enough after treatment of the
infection to avoid false-negative findings due to temporary swelling of the ostium
and the distal section of the ureter.
Given method-based weaknesses regarding the diagnosis of low-grade vesicoureteral
reflux (grade I), VCUG or RNC can be additionally performed depending on the clinical
relevance in the case of persistent suspicion and a normal ceVUS examination. To coordinate
all examinations and ensure prompt introduction of any necessary treatment, patients
should be connected to a pediatric urological, surgical, or nephrological center.
The question currently under discussion regarding continuous antibiotic prophylaxis
can thus be clarified here, ideally in an interdisciplinary board, particularly in
the case of a conservative approach.
