Pediatric Vesicoureteral Reflux Workup

Diagnosis of urinary tract infection (UTI) depends on obtaining accurate urine culture findings.

• The criterion standard for obtaining urine specimens remains the suprapubic aspiration. Any growth in such a sample should be considered significant. However, this procedure is rarely done in practice.
• Urethral catheterization provides substantially better specificity; more than 1000 colony-forming units (CFU)/mL is considered significant for these samples.
• In children who are toilet trained, culture of a clean-catch midstream specimen is an acceptable method. Growth of more than 100,000 CFU/mL is a significant finding on a midstream-voided specimen.
• The least reliable method (ie, bag collection) is the most common method of obtaining a urine specimen in babies. As many as 10% of specimens grow more than 50,000 CFU/mL with no correlation to actual presence of infection. A negative culture result is helpful because, although bag collection can produce false-positive results, false-negative results are very unlikely. A bag specimen with a positive result requires further investigation with ureteral catheterization. Bag collection should be strongly discouraged.

Although the WBC count, serum levels of C-reactive protein, and other blood tests are often used to assist with the diagnosis, no laboratory tests can reliably distinguish cystitis from pyelonephritis.

• Other laboratory testing should include serum chemistries to assess for baseline renal function.
• A CBC count can assist in tracking the response to treatment.
• Urinalysis also helps determine if proteinuria is present, which possibly indicates renal impairment.

Imaging is the basis of diagnosis and management of vesicoureteral reflux (VUR). The standard imaging tests include renal and bladder ultrasonography and voiding cystourethrography (VCUG), although numerous studies are available.

Imaging after the first UTI is indicated in all children younger than 5 years, children of any age with febrile UTI, and boys of any age with UTI. In addition, children with prenatally identified hydronephrosis should be evaluated postnatally. Ultrasonography performed during the first 3 days of life may have a high rate of false-negative results because of relative dehydration during the neonatal period.

Although the traditional approach in children with UTI has been evaluation for vesicoureteral reflux with VCUG or radionuclide cystography (RNC), some authorities are now advocating a "top-down" approach for children with UTI. In this algorithm, a child with a history of febrile UTI undergoes a dimercaptosuccinic acid (DMSA) renal scan to assess for evidence of kidney involvement, kidney scarring, or both. Negative DMSA scan findings suggest that clinically significant vesicoureteral reflux is unlikely, obviating the need for VCUG. However, if DMSA scan findings are positive, VCUG is recommended. The merits of alternative approaches to children with UTI are still discussed.

Using dimercapto-succinic acid scintigraphy, the data from one study found that the only independent risk factor for renal scar formation after acute pyelonephritis was the presence of vesicoureteral reflux. Reflux grade was significantly associated with the prevalence of renal scarring. VCUG is recommended after the first acute episode of infection is confirmed using dimercapto-succinic acid scintigraphy.^[5]

The criterion standard in diagnosis of vesicoureteral reflux is VCUG. This test provides precise anatomic detail and allows grading of the reflux.

• The International Classification System for vesicoureteral reflux combines features of systems previously used in Europe and in the United States.^[6]

  • Grade I - Reflux into nondilated ureter
  • Grade II - Reflux into renal pelvis and calyces without dilation
  • Grade III - Reflux with mild-to-moderate dilation and minimal blunting of fornices
  • Grade IV - Reflux with moderate ureteral tortuosity and dilation of pelvis and calyces
  • Grade V - Reflux with gross dilation of ureter, pelvis, and calyces, loss of papillary impressions, and ureteral tortuosity
• In general, VCUG should be performed after the child has fully recovered from the UTI.
• Performance of the study during an episode of acute cystitis can result in overestimation of the grade of reflux because of paralysis and laxity of the ureteral musculature by bacterial endotoxin. Conversely, some children demonstrate reflux only during an episode of cystitis.
• VCUG provides useful imaging of the urethra in males for evaluation of posterior urethral valves.
• VCUG provides information in both boys and girls about bladder capacity and emptying and may reveal signs of outlet obstruction, such as bladder trabeculae or diverticula.
• Standard VCUG is recommended as the initial study in boys.

RNC or nuclear cystography with instillation of technetium TC 99m pertechnetate into the bladder and observation with a gamma camera is a highly sensitive test for vesicoureteral reflux.

• Advantages include substantially lower radiation doses and the potential for increased sensitivity because of the ability to conduct prolonged periods of observation. Radiation exposure from RNC is about 10% of the exposure from VCUG with modern digital equipment and digital-spot film recording and is about 1% of the exposure from VCUG with conventional fluoroscopic equipment.
• Disadvantages primarily consist of the poor anatomic detail, especially of the male urethra. Grade I reflux is poorly detected by this study because the distal ureters are commonly obscured by the bladder. Grading by nuclear cystography is limited to mild, moderate, and severe grades.
• One approach is to perform RNC as the initial screening test in girls and then to perform standard VCUG when vesicoureteral reflux is observed. Other clinicians use VCUG for the initial diagnosis and use RNC for follow-up studies.

Advances in ultrasonography resolution and the incorporation of Doppler technology into ultrasonography units have made radiation-free screening with ultrasonic cystography an increasingly realistic possibility.

• These studies look for reversal of flow in the ureter during bladder filling. One recent series using injection of microbubbles as a contrast agent found a sensitivity of 92% and specificity of 93% compared to VCUG. However, this study has not received widespread acceptance.
• As with nuclear cystography, the primary disadvantage with this technology is the lack of precise anatomic detail, and, despite continuing research, sonographic cystography remains an experimental modality.

The primary purpose of the renal ultrasonography is to assess the kidneys for size, parenchymal thickness, and collecting system dilation.

• It has largely replaced intravenous urography as the screening test of choice for the upper urinary tract because of the absence of radiation, elimination of contrast reaction risk, and noninvasive technique.
• Despite these advantages, normal ultrasonography does not exclude vesicoureteral reflux. Only the VCUG or nuclear cystography can reliably exclude vesicoureteral reflux.

The primary radiopharmaceutical used with renal scintigraphy in the setting of pyelonephritis and vesicoureteral reflux is technetium TC 99m–labeled DMSA.

• This agent is rapidly taken up by proximal renal tubular cells and is an excellent indicator of functioning renal parenchyma. Areas of acute inflammation or scarring do not take up the radiopharmaceutical and are revealed as cold spots on imaging.
• DMSA scanning has 2 principle uses. First, DMSA is used to identify and monitor renal scarring. Patients who are medically treated and develop new or progressive scarring are often considered candidates for surgical correction of vesicoureteral reflux. For this reason, some clinicians obtain a baseline DMSA scan at the time of diagnosis; this can then be used for comparison with subsequent scans. DMSA can also be used as a diagnostic tool during suspected episodes of acute pyelonephritis. However, DMSA may not reveal abnormalities in every case of febrile UTI and its use in the acute setting is not well defined.
• Some authorities advocate the use of DMSA scans as a diagnostic tool during suspected episodes of acute pyelonephritis. However, the more common indication is to identify and monitor renal scarring. Patients who are medically treated who develop new or progressive scarring, even in the absence of clinical infection, may benefit from surgical intervention.
• Single-photon emission computed tomography (SPECT) is an evolution of this imaging technology that allows for higher resolution and more accuracy in detection of renal scarring.

Urodynamic studies reveal functional abnormalities of the lower urinary tract. Such testing is most important in patients in whom secondary reflux is suspected, such as patients with spina bifida or boys whose VCUG is suggestive of residual posterior urethral valves.

Because antireflux surgery is much less successful in patients with secondary reflux, identifying such patients before proceeding with operative intervention is critical.

The basic test is cystometrography (CMG), during which a catheter with an intrinsic or attached manometer is placed in the bladder and the bladder is filled slowly with fluid while its internal pressure is recorded. The CMG gives information about bladder capacity and leak point, pressures at various stages of filling, and the presence and frequency of uninhibited (involuntary) bladder contractions and compliance (ie, the ability of the bladder to accommodate increasing volume at constant pressure).

Detrusor instability is a common finding among children with reflux, and, in some cases, treatment with anticholinergic medication has resulted in resolution of the reflux.

The technical difficulty of performing urodynamic studies in small children, especially infants, is a significant obstacle.

Historically, cystoscopy was considered to be a basic element of evaluation for vesicoureteral reflux. The position and shape of the ureteral orifices were thought to correlate with the grade and prognosis. Subsequent data have demonstrated that cystoscopic observations do not significantly contribute to the radiographic findings. Cystoscopy is sometimes performed at the time of ureteral reimplant surgery to identify additional anatomic abnormalities, such as ureteral duplication and ureteral ectopia. However, cystoscopy is not needed in the evaluation of reflux.

Recently, some researchers have advocated a specialized test called positional instillation of contrast (PIC) cystography in children who have had clinical pyelonephritis but whose conventional VCUG or RNC findings do not reveal vesicoureteral reflux. In PIC cystography, a cystoscope is inserted into the bladder, and a jet of contrast is aimed from the beak of the cystoscope directly at the orifice of the ureter, where it enters the bladder. In some children, radiography reveals reflux of the contrast into the ureter in this situation. The significance of vesicoureteral reflux seen on PIC cystography is highly controversial. Advocates claim that the test can identify occult vesicoureteral reflux in children with recurrent infections of unknown origin. Skeptics note that the test is highly artificial, and that treating such "occult" reflux has not been shown to improve outcomes in children.

To the extent that the PIC cystography has any role, it is in the child with recurrent serious febrile urinary tract infections who has had a normal VCUG or RNC findings (preferrably both) who has been evaluated and treated for bladder and bowl dysfunction.

Pathologic evaluation does not play a significant role in the diagnosis of vesicoureteral reflux. However, differentiating between chronic pyelonephritis and renal damage from renal dysplasia, a congenital malformation of the renal parenchyma seen in association with vesicoureteral reflux, may explain the etiology of renal scarring in some children.