AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Vesicoureteral reflux (VUR), or the retrograde flow of urine from the bladder into the ureter, is an anatomic and functional disorder with potentially serious consequences. Primary reflux is vesicoureteral reflux in an otherwise normally functioning lower urinary tract, whereas secondary reflux is vesicoureteral reflux that is associated with or caused by an obstructed or poorly functioning lower urinary tract, such as that observed with posterior urethral valves or a neurogenic bladder. In both conditions, the ureterovesical junction (UVJ) fails to function as a one-way valve, giving lower urinary tract bacteria access to the normally sterile upper tracts. Although vesicoureteral reflux has been recognized as an anatomic phenomenon for centuries, not until relatively recently were the substantial morbidity and mortality associated with the condition recognized.

Early studies demonstrated a correlation between reflux and chronic pyelonephritis in paraplegic individuals and a correlation among urinary tract infection (UTI), reflux, and chronic pyelonephritis in children, which suggested that prevention of vesicoureteral reflux may result in reduced prevalence of renal complications. The subsequent developments in the medical and surgical management of vesicoureteral reflux formed the basis of the evolving field of pediatric urology.

The objectives in the current treatment of vesicoureteral reflux are twofold. The first goal is the prevention of episodes of acute pyelonephritis with its associated morbidity and mortality. The second goal is to prevent the scarring of the kidney associated with vesicoureteral reflux (reflux nephropathy), which increases the risk of hypertension and renal failure in children and adults with vesicoureteral reflux. Controversy persists over the optimal management of vesicoureteral reflux, specifically with respect to the timing, technique, and benefits of surgical correction.

Pathophysiology

After entering the bladder through the muscular hiatus of the detrusor muscle, the normal distal ureter passes through a submucosal tunnel before opening into the bladder lumen via the ureteral orifice. If the length of the submucosal tunnel or its muscular backing is inadequate, the valve mechanism is incompetent, resulting in reflux. Careful anatomic measurements suggest that the ratio of tunnel length to ureteral diameter must be at least 5:1 to prevent reflux. This fundamental observation is the basis for almost all surgical procedures to correct the disorder.

Beyond the fetal stage, anatomic reflux alone rarely produces renal damage. Experiments in pigs have demonstrated renal scarring in sterile refluxing systems; although the kidneys may display scarring, dysplasia, or both in some patients with prenatally identified and presumably sterile reflux, the overwhelming majority of data implicate ascending infection and pyelonephritis as the essential causes of reflux nephropathy. Large studies have repeatedly demonstrated a close correlation between the frequency of UTI and severity of reflux nephropathy in patients with vesicoureteral reflux.^{1, 2, 3}

Scarring may result from a single episode of pyelonephritis, especially in very young patients. Ransley and Risdon named this occurrence the "big bang" effect.⁴ Most scarring tends to occur at the renal poles, where the anatomy of the renal papillae permits backflow of urine into the collecting ducts. This phenomenon is referred to as intrarenal reflux and gives pathogenic bacteria access to the renal tubules. The subsequent cascade of inflammation, with release of superoxide and other mediators, results in local tissue ischemia and fibrosis. Over time, when enough renal parenchyma is affected, hypertension, renal insufficiency, and renal failure can result. The reason kidneys of children are so susceptible to damage is unclear; this may be due to reduced levels of renal superoxide dismutase in children.

Frequency

United States

Overall prevalence of vesicoureteral reflux is unknown because many children are asymptomatic and the invasive testing required for diagnosis is performed only when clinically indicated. Several older reports of imaging studies performed on healthy children prior to oversight by institutional review boards demonstrated rates of 1-2%, but most of these studies were small and failed to clearly characterize their subject populations. The evidence is clear that the prevalence of vesicoureteral reflux is higher among children with UTIs (15-70%, depending on age). Among infants prenatally identified with hydronephrosis on ultrasonography, approximately one third were postnatally found to have vesicoureteral reflux.

The incidence of reflux clearly is influenced by genetic factors, although specific modes of inheritance have yet to be identified. Siblings of children with vesicoureteral reflux have a 25-33% risk of also having vesicoureteral reflux, whereas offspring of parents with reflux have a 66% incidence (higher in female offspring than male offspring). Even when asymptomatic, these siblings and offspring can have high-grade reflux and often have renal scarring at evaluation.

Screening of asymptomatic siblings and offspring continues to be an area of controversy. Advocates point out that early identification of children with reflux may prevent episodes of UTI and renal scarring, but other authorities feel that screening asymptomatic individuals is likely to result in significant overtreatment of clinically insignificant vesicoureteral reflux, with associated morbidity. As a middle ground, some pediatric urologists screen newborn siblings of children with vesicoureteral reflux but not their older, asymptomatic siblings.

International

Many large studies have been performed in Europe, where prevalence is estimated to be similar to that in the United States. Disease frequency in other parts of the world is not well described but has been shown to be lower in people of West African descent.

Mortality/Morbidity

With modern antibiotics and supportive care, mortality from acute pyelonephritis in children with vesicoureteral reflux is very rare. However, morbidity associated with vesicoureteral reflux is substantial, both from acute infection and from the sequelae of reflux nephropathy.

• Changes in renal function: Decreases in urine-concentrating ability (proportional to the degree of reflux) and in glomerular filtration rate (proportional to the degree of renal scarring) have been measured in children with vesicoureteral reflux.
• Decreased renal and somatic growth: Although renal growth assessment in children is difficult because of imaging variability, several studies have documented smaller kidneys in children with reflux and recurrent infections. Surgery may improve growth rates, but small, scarred kidneys are unlikely to grow. Although early studies suggested that somatic growth is negatively affected in children with reflux, more recent data have shown that carefully monitored, properly treated children with vesicoureteral reflux have growth rates within normal ranges. In contrast, children with significant renal insufficiency or end-stage renal disease clearly have decreased growth rates.
• Hypertension and renal failure
• • Reflux nephropathy may be the most common cause of childhood hypertension. Presence of hypertension correlates well with the degree of renal scarring, especially when scarring is bilateral. The mechanism is thought to be elevated renin levels produced by damaged renal tissues.
  • Although not all scarred kidneys in children with hypertension produce excess renin, resection of renal units in cases where unilateral renal vein renin levels are elevated substantially (ratio >1.5) can result in resolution of hypertension.
  • Improvements in management may result in decreased rates of hypertension among adults who had childhood reflux.
  • The most devastating outcome of reflux nephropathy is renal failure. The true incidence of chronic renal insufficiency among refluxing children is uncertain. Older studies consistently attributed 15-30% of renal failure in children and young adults to chronic pyelonephritis and reflux nephropathy. However, one transplant series attributed just 2.2% of cases to chronic pyelonephritis. Most authorities now agree that, although renal failure is a devastating complication of vesicoureteral reflux, it actually affects only a small minority of children with reflux.

Race

Reflux is more common in white children than in those of other races. This disparity extends to children with antenatal hydronephrosis. The editor of this article reviewed his prenatal registry of 1019 patients with prenatal hydronephrosis and found a 15% incidence of vesicoureteral reflux in African American patients enrolled in the registry. Although vesicoureteral reflux is less common in black children, screening is still recommended after a single UTI in this population. Because little is known about the specific genetic linkage of vesicoureteral reflux and because of the wide variation of genes with intermarriage, excluding any group from evaluation is difficult.

Although vesicoureteral reflux is much less common in other ethnic groups, the range of severity and rate of spontaneous resolution (grade for grade) are similar between the races.

Sex

UTIs are more common in females, as one might expect given the anatomic differences. This leads to greater screening and, therefore, diagnosis of vesicoureteral reflux in females. However, among all children with UTI, boys are more likely to have vesicoureteral reflux than girls (29% of males vs 14% of females). Boys also tend to have higher grades of vesicoureteral reflux diagnosed at younger ages, but their vesicoureteral reflux is more likely to resolve.

Age

Vesicoureteral reflux is more common among infants and progressively resolves in a substantial proportion of children; thus, prevalence decreases as children age. One study of patients who presented with UTI demonstrated prevalence rates of 70% in patients younger than 1 year, 25% in patients aged 4 years, 15% in those aged 12 years, and 5.2% in adult patients.²

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Most children with vesicoureteral reflux (VUR) present in 2 distinct groups.

• The first group presents with hydronephrosis, often prenatally identified using ultrasonography. These children typically progress through evaluation and treatment in the absence of clinical illness.
• The second group presents with clinical urinary tract infection (UTI). Even for experienced pediatricians, the diagnosis of UTI in children can be difficult.
• • Children often present with nonspecific signs and symptoms. Infection in infants can manifest as failure to thrive, with or without fever. Other features include vomiting, diarrhea, anorexia, and lethargy.
  • Older children may report voiding symptoms or abdominal pain.
  • Pyelonephritis in young children is more likely to manifest with vague abdominal discomfort rather than with the classic flank pain and tenderness observed in adults. The presence of fever, while highly suggestive of pyelonephritis, is not reliable enough to lead to the diagnosis.
  • Even today, children occasionally present with advanced reflux nephropathy, manifesting as headaches or congestive heart failure from untreated hypertension, or with uremic symptoms from renal failure.
  • A small group of children without evidence of UTI present with symptoms of sterile reflux, which can include flank or abdominal pain before or during voiding, as well as double voiding or incomplete emptying resulting from delayed drainage of urine out of the upper tracts.

Physical

As with the history, few findings on physical examination suggest vesicoureteral reflux or UTI.

• Fever, flank or abdominal tenderness, or an enlarged palpable kidney may be present;
• In the absence of reliable historical or physical findings, diagnosis depends on laboratory testing and imaging, as well as family history.

Causes

The cause of the defect in primary reflux is unknown.

• The existence of a strong genetic component is indicated by the high rate of reflux in relatives of patients with reflux, but the mechanism of transmission is not clear. Some investigators favor a polygenic mode of inheritance, whereas others have suggested autosomal or sex-linked transmission with variable penetrance.
• The possibility that UTI may cause reflux has also been investigated. Indeed, a subset of patients has been identified in whom reflux was detectable only during an episode of cystitis. However, most authorities think that UTI and reflux are independent variables and that rates of vesicoureteral reflux are higher in children with UTI because these children are actively screened for reflux. The cause-and-effect picture is even less clear in children with secondary reflux.
• Rates of reflux are likely increased in the setting of congenital bladder outlet obstruction and neurogenic bladder. More than 50% of boys with posterior urethral valves have vesicoureteral reflux. Similar results were seen in a series of children undergoing urodynamic studies for neurogenic bladder.
• Dysfunctional voiding, with its inherent increase in intravesical pressure, likely also results in reflux, even in otherwise healthy children. Uninhibited bladder contractions, often associated with contraction of the voluntarily controlled external urinary sphincter to prevent wetting, increase intravesical pressure. The combination of high-pressure voiding and vesicoureteral reflux increases the risk of pyelonephritis beyond that of the child with low-pressure reflux.
• Confounding all of these data is the fact that urodynamic studies on children are difficult to perform and evaluate; this is true especially with infants, in whom normal reference data are sparse. Whether vesicoureteral reflux observed in association with voiding dysfunction and obstruction is a direct result of that dysfunction or simply a component of a grossly abnormal urinary tract is not known.
• A unique and complex group of children presents with dysfunctional elimination, which consists of a symptom complex heralded by infection, severe constipation, and daytime wetting. Despite the primary urinary tract presentation, the primary focus should be in the management of constipation and bowel habits. A subset of these children have infrequent voiding and incomplete bladder emptying, which further increases the likelihood of UTI.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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 Studies

• 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.
• 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.⁵
  • • 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.

Other Tests

• 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.

Procedures

• 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.

Histologic Findings

• 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The treatment of children with reflux aims to prevent kidney infection, kidney damage, and the complications of kidney damage. Treatment options include surveillance, medical therapy, and surgical therapy. Walker summarized the following general principles of management in children with known vesicoureteral reflux (VUR): (1) spontaneous resolution of vesicoureteral reflux is common in young children but is less common as puberty approaches, (2) severe reflux is unlikely to spontaneously resolve, (3) sterile reflux, in general, does not result in reflux nephropathy, (4) long-term antibiotic prophylaxis in children is safe, and (5) surgery to correct vesicoureteral reflux is highly successful in experienced hands.³

• Surveillance is infrequently used for numerous reasons. Although no large randomized trials have been conducted establishing the efficacy of prophylactic antibiotics in prevention of either urinary tract infection (UTI) or renal scarring, several decades of clinical practice have demonstrated that antibiotic prophylaxis is usually well-tolerated, and clinicians are reluctant not to offer some treatment. Medicolegal concerns regarding the risk of kidney damage while on surveillance have likewise limited the use of this approach. Surveillance is still frequently used among older children with vesicoureteral reflux, especially boys who have never had a UTI.
• Initial treatment of the child with a UTI involves supportive care and prompt administration of appropriate antibiotics.
• • Timely institution of antibiotic therapy has been shown to be critical in preventing scar formation in kidneys with pyelonephritis.
  • Animal studies have demonstrated that permanent renal damage occurs if antibiotics are not started within 72 hours, although other studies indicate an even shorter window of opportunity. For this reason, clinicians must maintain a high index of suspicion for UTI in children.
  • Medical treatment with prophylactic antibiotics remains the mainstay of initial management of vesicoureteral reflux (see Medication). Because vesicoureteral reflux spontaneously resolves in most children, medical management allows this natural history to take its course while providing some measure of protection against recurrent UTI and renal injury.
  • Prophylaxis should be started once a child has completed treatment of the initial UTI (see Medication) and continues at least until imaging reveals vesicoureteral reflux. If no vesicoureteral is seen, prophylaxis is discontinued. If vesicoureteral reflux is present, prophylactic antibiotics are continued until (1) vesicoureteral reflux resolves, (2) vesicoureteral reflux is surgically corrected, or (3) the child grows old enough that prophylaxis is deemed no longer necessary.
• Virtually all children with a new diagnosis of grade I-IV reflux, and some with grade V, are given a trial of medical treatment. This consists of antibiotics dosed at one fourth of the therapeutic dosage and regular follow-up care and imaging. A typical routine includes renal ultrasonography and VCUG or nuclear cystography every 12-18 months.
• • Since a substantial number of children experience spontaneous resolution of vesicoureteral reflux (50-85% of cases with grade I-III), medical treatment spares this group the morbidity of surgery while protecting the kidneys from further damage.
  • Once follow-up imaging demonstrates resolution of vesicoureteral reflux, antibiotics are discontinued. The importance of conscientious follow-up care during medical management cannot be overemphasized. Lack of compliance with medications or surveillance imaging may result in progression of reflux nephropathy and renal failure in children who are susceptible.
• In boys with persistent vesicoureteral reflux who have not had recurrent UTIs, antibiotics are often discontinued as the boys approach puberty. However, because of concerns about future pregnancies, surgery may be recommended in girls approaching puberty who have persistent vesicoureteral reflux (see Follow-up).
• In recent years, the role of prophylaxis with antibiotics has been challenged.
• • Several studies have failed to find any decrease in the incidence of UTIs in children with vesicoureteral reflux who take antibiotics. However, all of these studies have significant flaws that make it difficult to state with certainty that antibiotics prophylaxis is ineffective. Furthermore, decades of clinical experience has suggested that, in many children, antibiotic prophylaxis is a key component of management.
  • Ongoing studies, including a large randomized trial of antibiotic prophylaxis in children with vesicoureteral reflux funded by the National Institute of Health, will hopefully shed more light on the proper role of antibiotics.
  • However, note that these uncertainties apply only to the role of antibiotics in prevention. The role of antibiotics in the treatment of acute UTI is not debatable, and failure to institute appropriate therapeutic antibiotics in the setting of pyelonephritis (kidney infection) is associated with permanent renal injury and scarring. Children at risk for such infection, such as those with vesicoureteral reflux, need prompt and timely evaluation of possible UTI to prevent such outcomes.
• Bladder and bowel management for dysfunctional elimination is as follows:
• • Anticholinergic medication, in conjunction with timed voiding, may improve symptoms of dysfunctional voiding and reduces the risk of infection. Anticholinergic agents should be used in select patients so as not to compound the problems of incomplete bladder emptying or worsening constipation.
  • A few of these patients benefit from some form of bladder training to achieve balanced, low-pressure voiding with coordinated relaxation of the external sphincter and pelvic floor. In children with primary bowel elimination problem, treatment with enemas, dietary changes, and stool bulking agents, in coordination with a pediatric gastroenterologist, is critical for success.

Surgical Care

• Open antireflux surgery
• • The decision to proceed to antireflux surgery is based on many factors, and the medical, social, and emotional needs of the patient and the family must be considered. Accepted indications for surgical treatment include the following: (1) breakthrough febrile UTIs despite adequate antibiotic prophylaxis; (2) severe reflux (grade V or bilateral grade IV) that is unlikely to spontaneously resolve, especially if renal scarring is present; (3) mild or moderate reflux in females that persists as the patient approaches puberty, despite several years of observation; (4) poor compliance with medications or surveillance programs; and (5) poor renal growth or function or appearance of new scars.
  • Virtually all open antireflux operations involve reconstruction of the ureterovesical junction (UVJ) to create a lengthened submucosal tunnel for the ureter, which functions as a one-way valve as the bladder fills. Dozens of procedures have been described. Surgery for vesicoureteral reflux should be performed by a qualified pediatric urologist, experienced in multiple techniques, allowing tailoring of the surgery to the unique anatomic circumstances of the individual patient.
• • Although several studies have shown that antireflux surgery decreases the incidence of pyelonephritis, randomized trials of antibiotic prophylaxis versus surgical therapy plus antibiotic prophylaxis have not shown a difference in development of nonfebrile UTI, renal scarring, or renal failure. However, most of these studies were statistically underpowered, and the true benefit of antireflux surgery is still incompletely understood.
• Intravesical approach
• • The bladder is opened anteriorly via a low abdominal incision. The ureters are separated from their attachments to the bladder muscle and connective tissue and repositioned under a submucosal tunnel to create the necessary 5:1 length-to-diameter ratio.
  • Developed in the 1950s, the prototypical intravesical operation is the Politano-Leadbetter procedure. The ureter is dissected completely free of its attachments and passed through a new muscular hiatus created higher on the bladder wall. The ureter is then passed down through a submucosal tunnel, and the orifice is sutured to the mucosa at its original meatal position. This procedure has a reported success rate of 97-99%.
  • An evolution of the Politano-Leadbetter procedure is the Cohen cross-trigonal technique, which is probably the most popular intravesical repair performed today. In this repair, the original muscular hiatus is used, but the ureter is dissected from its attachments and pulled across the trigone through a submucosal tunnel, and the meatus is sutured into a new position at the end of the tunnel. Reported rates of success range from 97-99% with this technique as well.
• Extravesical approach
• • This was developed in an effort to avoid the time and morbidity associated with the cystotomy and ureteral anastomosis required for intravesical repair. It is particularly useful in patients with unilateral reflux.
  • Developed concurrently in Europe and the United States, the Lich-Gregoire repair approaches the bladder via the retroperitoneum. The ureter is dissected from the detrusor, but the orifice is left intact. A narrow furrow in the detrusor then is created, down to but not disrupting the mucosa, extending cephalad from the ureteral orifice. The distal ureter is then laid into this furrow and the detrusor closed over it. Although early American results were disappointing, further experience and modifications have demonstrated success rates comparable to the standard intravesical techniques.
  • One complication of the extravesical approach is postoperative urinary retention, which generally resolves spontaneously. Judicious use of bipolar electrocautery during the posterior bladder dissection can reduce incidence of this complication to less than 5%. Rare reports of permanent voiding dysfunction and retention in patients undergoing bilateral extravesical procedures have led some surgeons to use this technique only for unilateral cases.
• Endoscopic antireflux surgery
• • The most dramatic change in the treatment of vesicoureteral reflux over the past decade has been the rapid growth in the use of endoscopic treatment. Although these techniques have been used in Europe for many years, only since the introduction (and approval by the US Food and Drug Administration [FDA] in 2001) of injectable dextranomer/hyaluronic acid copolymer (DHA) has endoscopic treatment become widespread in the United States. The perceived benefits of endoscopic treatments include short surgical time, low surgical morbidity, comparable success rates, and preservation of the option for subsequent open surgical repair.
  • Some clinicians are now advocating endoscopic treatment as initial management for newly diagnosed vesicoureteral reflux. They argue that immediate antireflux surgery obviates the need for long-term antibiotics and repeated imaging studies. However, such a strategy inevitably results in the overtreatment of a large number of children because vesicoureteral reflux spontaneously resolves in most children, and even those with persistent vesicoureteral reflux may not have a clinical indication for antireflux surgery. Finally, the true long-term success rates for endoscopic treatment with DHA are still to be determined.
  • Endoscopic techniques involve injection of a bulking substance into the muscular posterior wall of the UVJ. The resulting bulking effect compresses the ureteral lumen and provides a substitute for the normal muscular backing of the transmural ureter.
  • Some authors emphasize the importance of creating a large mound or "volcanic" appearance of the bulking agent under the orifice, compressing the orifice into a slit. Other authors have described an intramural injection, in which the distal ureter is distended with a jet of saline from the cystoscope, allowing the injection needle to be advanced into the submucosa of the intramural ureter at 6 o'clock.
  • In general, success (resolution of vesicoureteral reflux on postprocedure imaging) rates with endoscopic treatment are significantly lower than those reported for open antireflux surgery. A meta-analysis of over 5000 patients undergoing endoscopic treatment with various bulking agents found a success rate of 74% after one injection and 85% after one or more injections.⁶ The success rate in this meta-analysis among the DHA studies was 69% after one injection.
  • Most studies of endoscopic treatment have found that success rates are lower for higher grades of vesicoureteral reflux (the very patients most likely to need antireflux surgery). The meta-analysis found a success rate of 63% after one injection for grade IV vesicoureteral reflux.
  • Single center reports have noted significantly higher success rates with DHA, with resolution rates of over 90% with one or more injections at some centers.
  • Other bulking agents have been used extensively in Europe, in particular, polytetrafluoroethylene (Teflon). Although thousands of patients have undergone treatment with Teflon over the past 30 years, persistent concerns over the safety of this bulking agent have limited its use in the United States.
  • Other bulking agents that have been reported include autologous fat, blood, and chondrocytes; bovine collagen; and polydimethylsiloxane. Although all have certain advantages, concerns over particle migration, carcinogenesis, and technical handling problems have limited their use.
  • Children who undergo endoscopic antireflux surgery need continued follow-up. They require postprocedure imaging, including voiding cystourethrography (VCUG) at 3-4 months postsurgery. Patients should be maintained on antibiotic prophylaxis until resolution of vesicoureteral reflux is confirmed.
  • Recent studies of endoscopic surgery with DHA have found that as many as 25% of children whose vesicoureteral reflux was cured on the initial VCUG (3-4 mo) VCUG subsequently had recurrence of vesicoureteral reflux on delayed VCUG (12 mo). The reasons for late failure of endoscopic therapy are uncertain, but may include reabsorption of the injected material, migration of the injected material, or secondary patient factors such as dysfunctional voiding. Some clinicians are now recommending additional VCUG at 12-18 months postsurgery because of concerns over the durability of DHA implant. 
  • Delayed adverse effects of DHA antireflux surgery appear to be uncommon. However, recent studies have observed that the DHA implants can strongly resemble a kidney stone in the distal ureter on CT scanning, apparently due to calcification of the DHA implant. Because many children who undergo DHA injection for treatment of vesicoureteral eventually undergo CT scan for numerous reasons, treating physicians and radiologists must recognize that DHA implants may produce a misleading appearance on CT scanning.

Consultations

• Good communication between the urologist and primary care physician is essential for the effective management of vesicoureteral reflux. This is especially true for children being treated medically, in whom regular follow-up care and prompt evaluation and treatment of breakthrough UTI are critical in preventing renal damage.
• Involvement of a pediatric nephrologist is indicated for children at risk of or manifesting evidence of reflux nephropathy.

Diet

• Children with frequent UTIs often have concurrent problems with constipation and poor bowel habits. Institution of a bowel program in these children can reduce the frequency of infection.
• High-fiber diets combined with a stool softener, such as docusate (Colace), can improve bowel function and reduce colonic and rectal dilation.
• For severe cases, daily polyethylene glycol (Miralax) is often used.

Activity

• Children with vesicoureteral reflux can engage in normal activity.
• Toilet hygiene, especially proper wiping technique in girls, should be taught to children of appropriate age to reduce the frequency of UTI.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Antibiotics

These are used for maintenance of sterile urine. Antibiotic agents used for prophylaxis in children with vesicoureteral reflux (VUR) are chosen for their efficacy in the urinary tract, safety, and tolerability. The typical dose is one fourth of the therapeutic dose. They are usually administered as suspensions once daily, typically in the evening to maximize overnight drug levels in the bladder. In neonates with antenatally diagnosed hydronephrosis and in infants younger than 8 weeks who have been treated for urinary tract infection (UTI), the agent of choice is amoxicillin. For older children, the most common antibiotics used are trimethoprim-sulfamethoxazole, nitrofurantoin, and penicillins. The cephalosporins are used less often.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Febrile urinary tract infection (UTI) with signs of pyelonephritis in children with vesicoureteral reflux (VUR) requires admission and also treatment with parenteral antibiotics to prevent renal damage. This is particularly true in children who are dehydrated, unable to retain oral intake, or toxic.
• Hospitalization after open antireflux surgery typically lasts 48-72 hours. Children are discharged once they tolerate a regular age-appropriate diet, their pain is managed with oral pain medication, and they are active at an age-appropriate level. Endoscopic antireflux surgery is generally performed as outpatient surgery.

Further Outpatient Care

• Children on medical management of vesicoureteral reflux are regularly seen on an annual basis (see Treatment). Routine evaluation includes urinalysis and urine culture, appropriate imaging, and blood pressure measurement. Parents must understand the need for proper evaluation and urine culture if they suspect UTI. In some cases, parents are taught to perform urinalysis at home. Positive home urinalysis results should prompt formal testing at a physician's office.
• After surgical correction of vesicoureteral reflux, patients are seen in the clinic 2-6 weeks after discharge with renal ultrasonography or renal scintigraphy to exclude upper tract obstruction.
• Patients continue taking prophylactic antibiotics until a second return visit 3-6 months postoperatively, at which time voiding cystourethrography (VCUG) or nuclear cystography is performed.
• Some have abandoned the practice of a follow-up VCUG or radionuclide cystography (RNC) after open surgical treatment because success rates are high. Antibiotic therapy is usually stopped after normal postnatal ultrasonography results are obtained.
• If VCUG or RNC is performed postoperatively and reveals resolution of reflux, antibiotics are discontinued, and no further invasive studies are necessary unless the child develops further febrile UTIs.
• Some clinicians continue to observe children with vesicoureteral reflux periodically with blood pressure checks and renal ultrasonography.

In/Out Patient Meds

• See Medication.

Complications

• Postsurgical obstruction after open antireflux surgery
• • Most cases of postoperative upper tract obstruction are mild, produce no symptoms, and spontaneously resolve. These cases are due to edema at the ureteroneocystostomy site, blood clots, or mucous causing mechanical obstruction. Cases of severe obstruction often have a delayed presentation (1-2 wk or more) and may be associated with flank or abdominal pain, nausea, and vomiting.
  • Ultrasonography reveals dilation on the affected side, although this can be difficult to assess in patients who had significant dilation preoperatively.
  • High-grade obstruction is usually due to ischemia of the implanted ureteral segment with resulting fibrosis and stricture. This is a rare complication.
  • Occasionally, patients may present with intermittent obstruction due to kinking of the reimplanted ureter with bladder filling.
  • Treatment for high-grade obstruction is surgical revision of the obstructed system. Percutaneous nephrostomy for temporary drainage may be required if the patient is symptomatic or toxic.
• Persistent vesicoureteral reflux after open antireflux surgery
• • Modern series consistently report success rates greater than 95% for antireflux surgery.
  • In cases in which reflux persists postoperatively, initial observation with continued antibiotic prophylaxis is indicated. Reoperation is generally reserved for patients with persisted febrile UTI despite prophylaxis.
  • A very high percentage of patients in whom surgery has failed have voiding dysfunction, thus urodynamic evaluation should be considered in these patients, especially if reoperation is considered. Even so, a substantial majority of patients with reflux at the first postoperative study have complete resolution at the 1-year follow-up point.
• Persistent vesicoureteral reflux after endoscopic antireflux surgery: Initial management is often repeat injection. Many investigators report routinely injecting up to 3 separate times. Patients who fail multiple injections should be reevaluated and treated for causes of secondary vesicoureteral reflux. Patients with persistent vesicoureteral reflux and indications for surgical correction should proceed to open surgery.
• New contralateral vesicoureteral reflux after unilateral antireflux surgery: New onset of vesicoureteral reflux in a renal unit that had no vesicoureteral reflux on preoperative imaging occurs in 10-32% of patients after open correction and 7-14% of patients after endoscopic correction. In general, the new vesicoureteral reflux is thought to be of low grade and may be more likely to spontaneously resolve; however, data are lacking in this area.

Prognosis

• Primary reflux
• • Studies comparing medical management with surgical treatment of primary vesicoureteral reflux have demonstrated that both have excellent long-term outcomes if surveillance is conscientious and compliance is good.
  • Rates of reflux nephropathy are similar in the 2 groups, although surgically treated patients have a lower prevalence of pyelonephritis.
  • Recent studies of adults with childhood reflux and children presenting to a pediatric nephrology clinic have shown that the prevalence of reflux nephropathy in these groups is substantially lower than in historical series. Whether this phenomenon is a result of aggressive treatment of vesicoureteral reflux, changes over time in definitions of reflux nephropathy, or other factors is not known.
• Secondary reflux
• • Treatment of children with secondary reflux continues to pose challenges to pediatricians and urologists.
  • A clear understanding of bladder function is essential.
  • Other children have complex combinations of reflux, obstruction, and bladder and renal dysfunction that require a concerted multidisciplinary approach to achieve the maximum potential benefit of therapy.

Patient Education

• Effective education of parents and effective communication with the primary care physician are essential if medical management is to be successful.
• Poor compliance and untreated episodes of UTI are likely to lead to reflux nephropathy.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Sources of medicolegal risk in the diagnosis and treatment of vesicoureteral reflux (VUR) primarily result from missed urinary tract infections (UTIs) and complications of surgery.
• Especially in young children, the diagnosis of UTI can be difficult. Signs and symptoms of UTI can be nonspecific, and the pediatrician must maintain a high index of suspicion.
• • Failure to diagnose and treat UTI in the setting of reflux can result in renal damage after only a single infection; thus, prompt treatment is critical.
  • Also important in reducing liability is early involvement of the parents. The parents must be made aware of the presenting signs and symptoms of infection and must understand the need for prompt evaluation of the sick child with known vesicoureteral reflux. Parents who understand the disease process and feel empowered to actively assist in the treatment of their child are less likely to turn to litigation if the outcome is unfavorable.
• As with any operation, surgery for correction of vesicoureteral reflux includes the risk of complications.
• • As always, the key to reducing liability risk lies in obtaining complete and honest informed consent.
  • Parents need to understand that 100% success rates cannot be guaranteed and that surgical complications, while uncommon, do occur.
  • Stressing the lower success rates for antireflux surgery in children with abnormal bladder function, detrusor sphincter dyssynergia, and dysfunctional elimination syndrome is important.
  • The process of informed consent should not be a rushed or cursory rubber stamp by nervous parents in the preoperative holding area. It should involve careful discussion in a relaxed setting, with full opportunity for questions to be answered. Parents and patients who feel ignored or ill informed by their physicians are much more likely to become litigious if outcomes are unfavorable.

Special Concerns

• The impact of vesicoureteral reflux on pregnancy is controversial, but most data suggest that women with childhood vesicoureteral reflux have an increased risk of complications during pregnancy.
• Numerous studies have suggested that pregnant women with vesicoureteral reflux and/or renal scarring are more likely to have pyelonephritis, hypertension, preeclampsia, obstetric intervention, low birthweight babies, and miscarriage. Although the causal association of vesicoureteral reflux and reflux nephropathy with these obstetric outcomes is well-documented, surgical repair is often recommended in girls with vesicoureteral reflux that persists as puberty approaches.
• Although previous work suggested that the rate of miscarriage remained elevated even in girls who had undergone reimplant surgery, more recent analysis of the data shows that the rate of miscarriage is indeed decreased in these patients, compared to girls with persistent reflux who did not undergo surgical repair.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on UTI. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics. Apr 1999;103(4 Pt 1):843-52. [Medline].
2. Smellie JM, Prescod NP, Shaw PJ, et al. Childhood reflux and urinary infection: a follow-up of 10-41 years in 226 adults. Pediatr Nephrol. Nov 1998;12(9):727-36. [Medline].
3. Walker RD. Vesicoureteral reflux and urinary tract infection in children. In: Gillenwater JY, Grayhack JT, eds. Adult and Pediatric Urology. 3^rd ed. Mosby-Year Book; 1996:2259-96.
4. Ransley PG, Risdon RA. Reflux nephropathy: effects of antimicrobial therapy on the evolution of the early pyelonephritic scar. Kidney Int. Dec 1981;20(6):- Risdon RA. [Medline].
5. 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. Nov 1992;148(5 Pt 2):1667-73. [Medline].
6. Elder JS, Diaz M, Caldamone AA, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol. Feb 2006;175(2):716-22. [Medline].
7. Atala A, Keating MA. Vesicoureteral reflux and megaureter. In: Campbell, MF, Retik AB, Vaughan E, Walsh PC, eds. Campbell's Urology. 7^th ed. Philadelphia, PA: WB Saunders Co; 1997:1859-916.
8. Belman AB. Vesicoureteral reflux. Pediatr Clin North Am. Oct 1997;44(5):1171-90. [Medline].
9. Birmingham Reflux Study Group. Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux in children: five years' observation. Br Med J (Clin Res Ed). Jul 25 1987;295(6592):237-41. [Medline].
10. International Reflux Study Committee. Medical versus surgical treatment of primary vesicoureteral reflux. Pediatrics. Mar 1981;67(3):392-400. [Medline].
11. Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol. Jun 2004;171(6 Pt 1):2413-6. [Medline].
12. Koo HP, Bloom DA. Lower ureteral reconstruction. Urol Clin North Am. Feb 1999;26(1):167-73, x. [Medline].
13. Vallee JP, Vallee MP, Greenfield SP, et al. Contemporary incidence of morbidity related to vesicoureteral reflux. Urology. Apr 1999;53(4):812-5. [Medline].

Article Last Updated: Sep 9, 2008