OVERVIEW: What every practitioner needs to know

Vesicoureteral reflux (VUR ) is the retrograde flow of urine from the bladder into the ureters and kidneys. It is the most common urologic pathology in children, occurring in about 1% of newborns and 30%-40% of young patients with a UTI. In neonates with prenatal hydronephrosis, the prevalence of VUR is as high as 15%.

Primary reflux is VUR in an otherwise normally functioning lower urinary tract, whereas secondary reflux is VUR that is associated with or caused by an obstructed or poorly functioning lower urinary tract which causes abnormally high bladder pressures, or a fixed abnormality of the ureterovesical junction.

Although VUR in and of itself is associated with little morbidity, the concern is the risk of retrograde ascent of bacteria from the bladder to the upper urinary tract which can lead to pyelonephritis and subsequent renal scarring.

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Are you sure your patient has VUR? What are the typical findings for this disease?

Currently, the diagnosis of VUR is made by a contrast fluoroscopic voiding cystourethrography (VCUG) or nuclear cystography (RNC). A contrast VCUG is recommended as the initial study for the assessment of VUR as it allows for the identification of bladder and bladder outlet pathology, which may affect the resolution of VUR, as well as for the grading of VUR. Subsequent follow-up studies can be VCUGs or RNCs, depending on the physician and institution preference.

A VCUG or RNC is typically obtained 12-18 months after the initial diagnosis. The decision of VCUG or RNC depends on the institution’s ability to perform RNCs and/or low radiation exposure VCUGs. The RNC is accurate in determining whether or not vesicoureteral reflux is present, but does not allow for accurate grading of vesicoureteral reflux.

What are the typical findings/symptoms for this disease?

There are 3 settings in which VUR is typically identified.

One is during the evaluation of an infant with a history of prenatal hydronephrosis. Male infants with high grade VUR are often identified as having hydronephrosis on prenatal ultrasound. These infants are asymptomatic.

Second, a child may present with a history of a urinary tract infection, often a febrile urinary tract infection. Older children may complain of lower urinary tract symptoms, new onset of urinary incontinence, nausea, abdominal/flank discomfort, or hematuria. Infants may present with irritability, fussiness, poor oral intake, foul smelling urine in the diaper, or a fever.

Lastly, VUR may be identified as part of a sibling or offspring screening work-up for VUR.

What other disease/condition shares some of these symptoms?

Other urologic conditions associated with a risk of developing a urinary tract infection include: ureteropelvic junction obstruction, UTI, posterior urethral valves, dysfunctional voiding, megaureter (refluxing, nonrefluxing, nonrefluxing obstructive, and refluxing obstructive), ureterocele, and ectopic ureter.

Prenatal hydronephrosis may be the result of a ureteropelvic junction obstruction, nonobstructive hydronephrosis, bladder outlet obstruction, ectopic ureter, ureterocele, and megaureter.

What cause primary reflux to develop?

Embryologically, the ureteric bud induces differentiation of the nephrogenic blastema into the metanephros or the final stage of renal development. There is a strong genetic predisposition for primary VUR, although specific modes of inheritance are unknown. Siblings of children with VUR have a 25-33% risk of also having VUR, whereas children of parents with reflux have as high as 66% incidence.

Primary reflux is a congenital anomaly of the ureterovesical junction, wherein a deficiency of the longitudinal muscle of the intravesical ureter results in an inadequate valvular mechanism. Competence of the ureterovesical junction is most dependent on the length of the submucosal ureter relative to its diameter, with normal children without reflux having approximately a 5:1 ratio of tunnel length to ureteral diameter.

What causes secondary reflux to develop?

Secondary reflux is caused by bladder outlet obstruction (i.e. posterior urethral valves, anterior urethral valves), neuropathic bladder dysfunction, detrusor sphincter dyssynergia (neuropathic or that related to dysfunctional voiding) and the elevated bladder pressures that occur with it. In addition, a fixed abnormality of the ureterovesical junction, such as bladder diverticulum, may cause reflux. There is a strong association between bladder pressures greater than 40 cm H20 and the presence of reflux in children with neuropathic bladders.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

VUR is often identified in children who present with a history of urinary tract infections. Thus, children presenting with lower urinary tract symptoms (i.e. frequency, urgency, dysuria, suprapubic pain, new onset incontinence) should have a urinalysis obtained. If the urinalysis demonstrates pyuria, then a urine culture should be obtained.

Infants and small children may present with fever or malaise, and a urinalysis (and if warranted urine culture) should be obtained. In a toilet-trained child, a midstream voided specimen is adequate. In infants and non-toilet trained children, catheterization is the preferred method since collection of urine by means of adhesive bags carries a high risk of contamination.

In those children with a febrile urinary tract infection, a CBC may be helpful to follow the progress of treatment. Additionally, young infants require a blood culture since bacteremia is a frequency consequence of an inflamed kidney.

Would imaging studies be helpful? If so, which ones?

VUR is typically diagnosed by either fluoroscopic voiding cystourethrography (VCUG) or nuclear cystography (RNC). VCUG provides more anatomical details than RNC and thus is often performed as the initial procedure. Subsequent studies may be VCUGs or RNCs, depending on physician and institution preference.

Ultrasonography is used to evaluate the upper urinary tract in children with suspected or proven VUR. The ultrasound provides an assessment of the overall renal size, parenchymal thickness and echogenicity, and the presence of scars, hydronephrosis, or other renal and ureteral anomalies. In addition, bladder wall thickness and postvoid residual (in toilet-trained children) may be assessed.

In those children in who renal scarring is suspected and those with high grade VUR, a DMSA (dimercaptosuccinic acid scintigraphy) renal scan may identify renal scarring and/or dysplasia. A DMSA renal scan is the best study to detect pyelonephritis.

The presence of a sacrum full of stool behind the bladder should not be ignored as it can contribute to UTIs.

Currently it is recommended that any child under 5 with a UTI, a child presenting with a febrile UTI ,or a boy of any age with a UTI merits imaging, including an US and VCUG.

How is VUR graded?

VCUG allows for the initial grading of VUR, which has prognostic significance in terms of the likelihood of resolution of VUR. The grading is as follows:

Grade I – Reflux into nondilated ureter

Grade II – Reflux into ureter, renal pelvis and calyces without dilation

Grade III – Reflux with mild to moderate dilation and minimal blunting of calyces

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.

Confirming the diagnosis

The traditional approach to the evaluation for underlying VUR is that a renal ultrasound and VCUG be obtained for any child under 5 with a UTI, a child presenting with a febrile UTI ,or a boy of any age with a UTI. A VCUG is also recommended in a child with prenatally identified hydronephrosis that is confirmed postnatally. A VCUG is also recommended as a baseline study in an infant with a multicystic dysplastic kidney, given the significant risk of contralateral VUR.

More recently, a “top down approach” has been advocated as a method of identifying those children who warrant further evaluation for VUR. This approach involves performing a DMSA scan first to assess for pyelonephritis/renal scarring and if present, then performing a VCUG. Proponents of this approach argue that DMSA scan identifies those children at risk for renal scarring (the children who truly warrant further evaluation and treatment) and thus significantly reduces the number of unnecessary VCUGs that are obtained. However, it is not always practical to obtain a DMSA scan during an acute episode of suspected pyelonephritis.

If you are able to confirm that the patient has VUR, what treatment should be initiated?

The management of children with VUR continues to evolve. For the majority of children, prophylactic antibiotics and periodic radiologic evaluation is warranted, given the success rates for spontaneous resolution, as well as the low morbidity associated with prophylactic antibiotics. The resolution rates for VUR range from 56-80% for grade 2%-30% for grade 4.

In select cases, surgical intervention may be warranted. The typical indications for surgical intervention include: breakthrough urinary tract infections despite prophylactic antibiotics, noncompliance with medical management, severe grades of VUR (grades 4 and 5), especially with renal scarring and/or dysplasia, failure of renal growth, new scars, or deterioration of renal function on serial ultrasounds or DMSA renal scans, persistent VUR, and reflux associated with congenital anomalies at the ureterovesical junction (i.e., bladder diverticula).

Some propose that antibiotic prophylaxis may be stopped in older children (>5-7 years) with low grade VUR and non-documented renal scarring.

The most commonly used antibiotics include: amoxicillin in the newborn period until approximately 8 weeks of age, at which time the child can be switched to trimethoprim-sulfamethoxazole (TMP-sulfa). An alternative to TMP-sulfa is nitrofurantoin. In those children with resistant organisms, alternatives include cephalexin. The typical dose administered is 1/3 to 1/2 of the treatment dose once a day.

Surgical treatment consists of open surgical treatment (either by an extravesical or intravesical approach) and a minimally invasive approach, cystoscopy and endoscopic injection of dextranomer/hyaluronic acid. In some institutions, laparoscopic/robotic ureteral reimplantation is also an option.

Open surgical intervention is associated with the highest success rate (98-100%) but also the greatest morbidity (transient frequency, urgency, dysuria and hematuria). Endoscopic injection therapy is performed as an outpatient procedure with minimal if any discomfort, but is associated with success rates up to 80%, varying with the grade of VUR.

What are the adverse effects associated with each treatment option?

Medical management side effects can occur with any of the antibiotics chosen, and periodic surveillance (such as a CBC in those patients treated with TMP-sulfa) may be indicated. There is also the morbidity associated with VCUG, with some parents requesting sedated studies to minimize the trauma associated with the study. The development of resistant organisms is also a risk.

Dextranomer/hyaluronic acid: Minimally adverse effects are associated with endoscopic injetion of dextranomer/hyaluronic acid. The risk of obstruction is minimal. There is a risk of recurrent VUR after successful injection ranges from 4 to 10%. New onset of contralateral VUR occurs in up to 12.5% of children undergoing a unilateral procedure.

Surgery: Short-term complications with intravesical approaches to ureteral reimplantation include dysuria, frequency, urgency, and hematuria, which typically resolve by one week post-operation. Long-term complications, which are infrequent, consist of ureteral obstruction and persistent VUR. With the extravesical approach, the risk of postoperative lower urinary tract symptoms is much lower. With the extravesical approach, the risk of postoperative lower urinary tract symptoms is much lower. The long-term risks are the same as for the intravesical approach. New onset of contralateral VUR occurs in up to 20% of children undergoing treatment for unilateral VUR.

What are the possible outcomes of VUR?

VUR may spontaneously resolve over time. The likelihood of resolution varies with the age of presentation and the grade of VUR. The higher the grade and the older the age at presentation, the lower the likelihood of resolution. Underlying bladder and voiding dysfunction may adversely affect the likelihood of resolution.

How do these pathogens/genes/exposures cause the disease?

Reflux of urine leads to chronic stasis which leads to bacterial growth and proliferation and thus a UTI. Common pathogens are E.coli, Klebsiella, Proteus and Enterococci.

Other clinical manifestations that might help with diagnosis and management

Neonates can present with jaundice, vomiting, and irritability along with fever and failure to thrive. Infants can present with poor feeding, vomiting, irritability along with fever, strong smelling urine, and abdominal pain. Preschoolers can present with vomiting and enuresis along with the aforementioned urinary symptoms.

What complications might you expect from the disease or treatment of the disease?

Complications of untreated VUR can be pyelonephritis, which leads to scarring, which can lead to hypertension and, less commonly, renal insufficiency.

Are additional laboratory studies available; even some that are not widely available?

Currently, there are no other laboratory studies available. A variety of laboratory tests have been used to try to localize infections to the kidneys, including beta2-macroglobulin, lactate dehydrogenase, and antibody-coated bacteria, but the results have been equivocal.

Several markers of pyelonephritis or scarring including antibodies to Tamm-Horsfall protein, N-acetyl-D-glucosaminidase (NAG), serum intracellular adhesion molecule (ICAM-1) and epidermal growth factor, but their role in clinical practice has not been identified.

How can VUR be prevented?

Primary VUR is congenital and cannot be prevented. The complications of VUR can be prevented by treatment such as prophylactic antibodies, but primary VUR itself cannot be prevented. Secondary VUR can be prevented by behavioral techniques such as proper voiding technique.

In children with neuropathic bladders and detrusor sphincter dyssynergia, the use of anticholinergic therapy and clean intermittent catheterization (or bladder augmentation in refractory patients) has been helpful in reducing intravesicular pressure and improving/resolving secondary VUR.

Regular voiding and bowel habits may also help decrease the risk of developing a urinary tract infection and should be promoted in children with VUR. Furthermore, dysfunctional voiding has been demonstrated to adversely affect VUR resolution.

There is up to a 30% risk of VUR in siblings of a child with VUR; thus, parents should be counseled regarding the pros and cons of sibling screening.

What is the evidence?

Large randomized controlled trials are lacking that objectively compare each treatment side to side. Just recently, however, the Swedish Reflux Study, a prospective, multicenter RCT, studied the management of grade III – IV reflux, and compared antibiotic prophylaxis and dextranomer/hyaluronic acid to surveillance with antibiotics. Results have shown that dextranomer/hyaluronic acid was superior among the three groups for treating reflux and that antibiotic prophylaxis and dextranomer/hyaluronic acid were superior compared to surveillance only, especially in females.

Brandström, P, Esbjörner, E, Herthelius, M. “The Swedish reflux trial in children: I. Study design and study population characteristics”. J Urol. vol. 184. 2010. pp. 274-9.

Holmdahl, G, Brandström, P, Läckgren, G. “The Swedish reflux trial in children: II. Vesicoureteral reflux outcome”. J Urol. vol. 184. 2010. pp. 280-5.

Brandström, P, Esbjörner, R, Herthelius, M. “The Swedish reflux trial in children. III. Urinary tract infection pattern”. J Urol. vol. 184. 2010. pp. 286-91.

Brandström, P, Nevéus, T, Sixt, R. “The Swedish reflux trial in children: IV. Renal Damage”. J Urol. vol. 184. 2010. pp. 292-7.

Weiss, R, Duckett, J, Spitzer, A. “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). The International Reflux Study In Children”. J Urol. vol. 148. 1992. pp. 1667-73.

“Management and screening of primary vesicoureteral reflux in children: AUA Guideline (2010)”.

Ongoing controversies regarding etiology, diagnosis, treatment

The management of VUR continues to evolve. More recently, the focus is on identifying those children who are at greatest risk for renal scarring, thus avoiding the morbidity of VCUGs in the remainder of children. Similarly, the role of stopping medical therapy and observing older children with persistent low grade VUR in the absence of scarring has also been proposed. The RIVUR study as noted above hopes to address some of these controversies.