Vesicoureteral Reflux Imaging
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Vesicoureteral reflux (VUR) is the abnormal flow of urine from the bladder into the upper urinary tract and the most common urologic disease in childhood. Its presence is pathologic, and it represents the most significant risk factor for childhood renal scarring and its sequelae. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]
For many years, the emphasis on the investigation of the child with UTI has centered on diagnosis of VUR. More recently, some authors have suggested that the focus should be whether the child has renal scarring or is at risk for renal scarring. The natural tendency for VUR to resolve spontaneously during childhood warrants initial medical management of most patients with low-grade reflux.
The majority of cases (90%) in children represent a primary congenital failure of the natural passive 1-way mechanism of the ureterovesical junction (UVJ) to maintain unidirectional urine flow. A minority of VUR cases (10%) occur secondary to abnormalities of the ureteral insertion in association with renal transplantation, ureterocele, ureteral duplication anomalies, obstruction of the bladder outlet (posterior urethral valves in boys), dysfunctional voiding, or constipation.
See the images of vesicoureteral reflux below.
Leonardo da Vinci was the first to describe and depict the UVJ. VUR was demonstrated experimentally in 1883, and the initial observation of VUR in humans was recorded in 1893. Reflux occurs naturally in some other species, including dogs, cats, and rabbits.
The average patient age at diagnosis is 2-3 years. With the advent of prenatal sonographic screening, the evaluation for hydronephrosis and possible contribution of vesicoureteral reflux (VUR) is being performed in the neonatal and infant period. Most cases of VUR resolve by about age 8 years, depending on the grade.
There is a documented association of VUR with congenital upper urinary tract abnormalities such as renal agenesis, multicystic dysplastic kidney, and obstruction of the ureteropelvic junction (UPJ).
Voiding cystourethrography (VCUG) is the screening urologic imaging study of choice. American urologists, pediatricians, and radiologists recommend this study to detect vesicoureteral reflux (VUR), ureterocele, posterior urethral valves in boys, or bladder wall thickening. [11, 12, 13] Up to 50% of children with proven urinary tract infection (UTI) undergoing VCUG have some degree of reflux. Sonography of the kidneys should be performed in conjunction with VCUG to document the size of the kidneys and to look for obstruction, hydronephrosis, or other congenital malformations. [7, 14, 15, 16] When VUR is found to distend the upper tract, postvoiding decompression at the upper tracts should be observed.
Reflux is generally intermittent and may escape detection on VCUG. This difficulty may be compounded by the desire to limit the child’s exposure to ionizing radiation as much as possible. The influence of body position on the occurrence and detection of reflux has not been well studied in children. Incomplete bladder filling decreases the sensitivity of the study.
The results of sonographic evaluation for hydronephrosis or pelvicaliceal dilatation may vary greatly between the second and third trimesters. Abnormalities may not be detectable until the third trimester, later than the common second trimester screening examination.
In the prenatal period, VUR is detected more frequently in boys than in girls, with a male-to-female of 5:1. Low-grade reflux is often associated with other prenatal urologic abnormalities. Mild pelviectasis is seen in 0.5-1% of all pregnancies. The widespread use of prenatal sonography has produced a marked increase in the early detection of urinary tract pathology in infants. The most common conditions identified are hydronephrosis and hydroureteronephrosis. Hydronephrosis is most often transient, but primary VUR is found in 10-40% of prenatally detected cases of hydronephrosis.
With the advent of prenatal sonographic screening, the evaluation for hydronephrosis, and subsequently VUR, is being performed in the neonatal period. The neonate with sonographic signs of renal pathology and possible reflux should be given prophylactic antibiotics and undergo VCUG. The risk of renal scarring from neonatal and infant reflux of infected urine is too great to ignore. [17, 18, 19]
According to Fefferman et al, fluoroscopically captured images are adequate in documenting the absence of vesicoureteral reflux (VUR) on VCUG examinations, making radiographic spot images unnecessary and thereby reducing patient exposure to radiation. The diagnostic accuracy of the fluoroscopically captured spot (FCS) images regarding binary characterization of reflux as negative or positive was 97.2%; the sensitivity of the FCS images was 92.6%; and the specificity of the FCS images was 98.6%. [1]
Menezes and Puri, in a study of 251 siblings of 215 index patients with grade III to V VUR, noted that the familial nature of VUR is well recognized but that the screening of siblings for VUR remains controversial. In their study, the authors found that the incidence of sibling VUR is maximal in patients younger than 3 years and that reflux in these patients is usually high grade and associated with a higher incidence of renal scarring. The authors recommended that screening be performed on all siblings who are younger than 3 years of index patients with grades III to V VUR. [3]
Radiologic evidence of renal scarring is present in 30-60% of children with VUR, and VUR is present in almost all children (97%) with severe renal scarring. However, most kidneys (60%) with acute cortical defects do not demonstrate reflux, which highlights that ascending urinary tract infection (UTI) is quite common despite the absence of demonstrated VUR.
The kidney is most susceptible to scarring from intrarenal reflux in the first year of life and probably at the time of first upper tract infection. [5] Renal scars less frequently develop after age 5 years. New renal scars develop almost exclusively in the presence of UTI and intrarenal reflux, but the presence of intrarenal reflux alone does not equate with renal scarring. Infected urine is believed to cause an exudative reaction that leads to fibrosis and scarring of papillae. Intrarenal reflux is a phenomenon that is likely underreported due to its fleeting nature and occurrence at peak reflux.
The diagnosis of vesicoureteral reflux (VUR) is accurately established with fluoroscopic voiding cystourethrography (VCUG). This study permits assessment for the presence and extent of reflux, and it clearly delineates the bladder outline, bladder neck, and ureteral and urethral anatomy. Fluoroscopic VCUG also gives an accurate estimation of bladder capacity.
The retention of contrast material within the upper tracts after voiding without decompression suggests UPJ or ureterovesical junction (UVJ) obstruction. VUR may occur with bladder filling, during voiding, or both. Cyclical VCUG, repeated bladder filling and fluoroscopic examination, which is primarily performed in patients younger than 1 year, depicts reflux an additional 10% of the time.
In children older than 3-4 years who have signs only of lower UTI, VCUG is not recommended if renal sonograms are normal. Whether VCUG is done while the initial UTI is being treated or several weeks afterward is not important, so long as the child is responding appropriately to treatment and has normal bladder function. VCUG may be performed as soon as the urine is sterile and bladder irritability has disappeared.
VUR is graded according to the International Reflux Classification outlined by the International Reflux Study Group in 1985. [20, 21] This classification scheme is widely accepted and shown below:
Grade I – Reflux into the ureter only (see the image below)
Grade II – Reflux into the collecting system, without dilatation (see the images below)
Grade III – Reflux into the collecting system with mild dilatation, slight ureteral tortuosity, and no or slight blunting of the fornices (see the images below)
Grade IV – Moderate dilatation and/or tortuosity of the ureter and moderate dilatation of the renal pelvis and calyces, with complete obliteration of the sharp angle of the fornices but maintenance of the papillary impressions in the majority of calyces (see the image below).
Grade V – Gross dilatation and tortuosity of the ureter, with gross dilatation of the renal pelvis and calyces and nonmaintained papillary impressions (see the images below).
Intrarenal reflux appears as contrast medium extending from the calyces into the polar renal collecting tubules in the form of striations. This can be identified most often in neonates and infants with moderate or severe reflux (5-15%). The presence of intrarenal reflux does not change the grade or treatment of VUR.
Nuclear imaging and sonography have replaced excretory urography (EU) as the preferred radiologic examination of the upper urinary tract. EU can demonstrate renal scarring but is less sensitive than DMSA or GH scintigraphy. The use of EU is exceptional and indicated only in those cases presenting with confusing collecting system anatomy or where demonstration of the calyces is important.
On excretory urograms, the scars of reflux nephropathy are typically detected about 2 years after infection. When uncomplicated, they have characteristic imaging features that include a deformed (clubbed) calyx and thinning of the overlying renal parenchyma, often with a notch in the surface of the kidney immediately opposite the affected calyx. Ureteral dilatation suggesting VUR may also be seen.
Although CT can provide excellent anatomic and functional information in children with reflux nephropathy, it does not currently have a primary role in the usual diagnostic algorithm or follow-up of such children. Still, hydronephrosis and ureteral dilatation are easily seen in patients with vesicoureteral reflux (VUR) who happen to undergo CT examination (see the images below).
At times in severe pyelonephritis, CT with intravenous contrast enhancement may be helpful in assessing for intrarenal suppuration and extrarenal extension of infection.
The widespread use of prenatal sonography has produced a marked increase in the early detection of urinary-tract pathology in infants. The most common conditions identified are hydronephrosis and hydroureteronephrosis. Hydronephrosis is most often transient, but primary VUR is found in 10-40% of prenatally detected cases of hydronephrosis. [14, 22, 19]
Ultrasonography is best used in conjunction with screening VCUG to assess for renal size; upper tract abnormalities, such as hydronephrosis and ureteral dilatation; obvious scarring; ureteral ectopia or bladder abnormalities, such as ureterocele; and bladder wall thickening. See the images below.
Prenatally detected primary vesicoureteral reflux (VUR) is found in males (male-to-female ratio, 5:1) most of whom have bilateral high-grade reflux. [8] Low-grade reflux is often associated with other prenatal urologic abnormalities. Mild pelviectasis is seen in 0.5-1% of all pregnancies. The significance of mild pelvic and/or pelvicaliceal dilatation as a marker of VUR is poorly validated but dilatation beyond 15 mm has proven significant and should prompt a thorough search for other urologic abnormalities.
The neonate with sonographic signs of renal pathology and possible reflux should be given prophylactic antibiotics and examined with voiding cystourethrography (VCUG). The risk of renal scarring from neonatal and infant pyelonephritis is too great to ignore.
Generally speaking, ultrasonography is an unreliable modality for the detection of VUR. It cannot be used as the sole means to exclude clinically significant VUR, even when the results are normal. Nevertheless, clues to the presence of VUR can be inferred from certain sonographic findings, namely complete duplication, peristaltic ureteral dilatation and calyceal dilatation. Sonographic measurement of kidney size is an important aspect of the screening examination. An abnormally small kidney in the child suggests parenchymal thinning, even in the absence of visible scar.
Obtaining reproducible sonograms is highly operator dependent. Full assessment of the bladder and urethra can sometimes be difficult. Smaller scars are less well visualized with sonography than with technetium-99m dimercaptosuccinic acid (DMSA) or glucoheptonate (GH) cortical scanning.
Sonography has been proposed for follow up of patients with reflux or for detecting reflux in siblings. New techniques involve instilling carbonated solutions or sonicated albumin into the bladder. Presently, the false-negative rate associated with this procedure is high, and it is not recommended as a routine test for VUR.
Approximately 74% of kidneys with reflux at VCUG were normal on sonograms obtained on the same day, and approximately 25% of the refluxing kidneys that are missed have reflux of grade III or worse.
The results of sonographic evaluation for hydronephrosis or pelvicaliceal dilatation may vary greatly between the second and third trimesters. Abnormalities may not be detectable until the third trimester, later than the common second trimester screening examination.
Direct radionuclide cystography with a99m Tc-labeled agent (sulfur colloid, diethylenetriamine penta-acetate [DTPA], or pertechnetate) is a well-accepted alternative to fluoroscopic VCUG for screening asymptomatic siblings or offspring, for follow-up examination of children with vesicoureteral reflux (VUR), for postoperative evaluation after ureteral reimplantation, and for excluding VUR when it is not seriously considered (especially in girls).
Direct radionuclide cystography is more sensitive than VCUG. It can depict as little as 1 mL of refluxed urine. Grade I reflux affects the ureter only, grade II reflux involves the kidney with no pelvic dilatation, and grade III reflux is reflux with pelvic dilatation. Renal cortical scintigraphy demonstrates twice as many scars as sonography and 4 times as many scars as EU.
The advantages of this study include continuous monitoring and imaging, high sensitivity, and a decreased radiation dose for a voiding imaging study. The dose to the pelvic organs was significantly lower when the study was popularized in the screen film cassette spot film era of former fluoroscopic equipment. With modern digital fluoroscopy units that reduce dose by pulsed fluoroscopy or other dose reduction strategy combined with video frame grabbing spot images, the dose reduction advantage of the isotope cystogram is only marginal.
Patients with VUR are typically followed up with serial radionuclide cystography every 12-24 months (see the image below). The International Classification of Reflux is not commonly applied to radionuclide studies, but the amount of activity that appears in the upper urinary tracts can be quantified into 1 of 3 levels of severity and used as a basis of comparison in serial follow-up examinations.
The indirect radionuclide cystogram (no catheterization) using99m Tc mercaptoacetyltriglycine (MAG3) can be performed in the toilet-trained child, but its specificity is decreased. It is not recommended as a routine screening procedure for evaluating VUR.
The most accurate evaluation of renal scarring and renal function is performed with intravenously injected99m Tc DMSA or GH. DMSA (see the image below) accumulates in the distal tubular cells and provides excellent visualization of the renal cortex, correlating with histopathologic findings in 95% of experimental animals.
Single photon emission computed tomography (SPECT) is superior to planar imaging techniques, especially in children younger than 3 years. Renal scars detected with DMSA scintigraphy appear as focal or generalized areas of diminished radioisotope uptake associated with loss or contraction of functioning renal cortex. This may appear as thinning or flattening of the cortex in some kidneys, while in others renal scars appear as classic discrete wedge-shaped parenchymal defects.
About 63-75% of patients with acute inflammatory changes on the initial DMSA renal scans do not have VUR, and reflux is present in only 25-50% of kidneys that develop new renal scarring. Although not a prerequisite for acquired renal scarring, VUR is still a risk factor that cannot be discounted and should be evaluated.
If a DMSA or GH study is being performed to detect reflux nephropathy with scar formation, it should be undertaken at least 6 months after a documented UTI because an upper-tract infection causes an abnormal appearance on DMSA or GH scans. Abnormalities resulting from infection are transient, whereas scars result in a permanent abnormality.
In the setting of acute infection, granulocyte aggregation, complement activation, and compression of the renal microcirculation from interstitial edema cause ischemia. Overall, the effect is of reduced regional blood flow and radiotracer uptake. Although this may be a transient phenomenon, it cannot be distinguished from scarring in the acute setting.
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Veronica Rooks, MD Military Chief of Pediatric Radiology, Pediatric Radiologist, Tripler Army Medical Center; Assistant Professor of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences
Veronica Rooks, MD is a member of the following medical societies: American College of Radiology, American Roentgen Ray Society, Radiological Society of North America, Society for Pediatric Radiology, Association of Program Directors in Radiology
Disclosure: Nothing to disclose.
Bernard D Coombs, MB, ChB, PhD Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand
Disclosure: Nothing to disclose.
Eugene C Lin, MD Attending Radiologist, Teaching Coordinator for Cardiac Imaging, Radiology Residency Program, Virginia Mason Medical Center; Clinical Assistant Professor of Radiology, University of Washington School of Medicine
Eugene C Lin, MD is a member of the following medical societies: American College of Nuclear Medicine, American College of Radiology, Radiological Society of North America, Society of Nuclear Medicine and Molecular Imaging
Disclosure: Nothing to disclose.
Henrique M Lederman, MD, PhD Professor of Radiology and Pediatric Radiology, Chief, Division of Diagnostic Imaging in Pediatrics, Federal University of Sao Paulo, Brazil
Henrique M Lederman, MD, PhD is a member of the following medical societies: Society for Pediatric Radiology
Disclosure: Nothing to disclose.
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Kevin F McCarthy, MD,to the development and writing of this article.
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