Practice Essentials
Vesicoureteral reflux (VUR), or the retrograde flow of urine from the bladder into the ureter, is an anatomic and functional disorder that can result in substantial morbidity, both from acute infection and from the sequelae of reflux nephropathy.
Signs and symptoms
Most children with VUR present in two distinct groups: those with hydronephrosis and those with clinical urinary tract infection (UTI). Hydronephrosis is often identified antenatally by means of ultrasonography (US). These children typically progress through evaluation and treatment in the absence of clinical illness.
Even for experienced pediatricians, the diagnosis of UTI in children can be difficult, for the following reasons:
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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
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Older children may report voiding symptoms or abdominal pain
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Pyelonephritis in young children is more likely to manifest as vague abdominal discomfort rather than as the classic flank pain and tenderness observed in adults
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The presence of fever, while highly suggestive of pyelonephritis, is not reliable enough to lead to the diagnosis
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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.
As with the history, few findings on physical examination suggest VUR or UTI. Fever, flank or abdominal tenderness, or an enlarged palpable kidney may be present.
See Clinical Presentation for more detail.
Diagnosis
Diagnosis of UTI depends on obtaining accurate urine culture findings. Although the white blood cell (WBC) count, serum levels of C-reactive protein (CRP), and other blood tests are often used to assist with the diagnosis, no laboratory tests can reliably distinguish cystitis from pyelonephritis. However, other laboratory tests have the following uses:
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Serum chemistries are used to assess for baseline renal function
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A complete blood count (CBC) can assist in tracking the response to treatment
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Urinalysis helps determine if proteinuria is present, which possibly indicates renal impairment
Imaging studies are the basis of diagnosis and management of VUR. The standard imaging tests include renal and bladder US and voiding cystourethrography (VCUG). Indications for imaging studies are as follows:
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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
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Children with antenatally identified hydronephrosis should be evaluated postnatally; however, US 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 VUR with VCUG or radionuclide cystography (RNC), some authorities now advocate that children with a history of febrile UTI undergo a dimercaptosuccinic acid (DMSA) renal scan, to assess for evidence of kidney involvement, kidney scarring, or both; if DMSA scan findings are positive, VCUG is recommended.
One approach is to perform RNC as the initial screening test in girls and then to perform standard VCUG when VUR is observed. Other clinicians use VCUG for the initial diagnosis and use RNC for follow-up studies. The 2011 American Academy of Pediatrics (AAP) guidelines for management of UTI in children aged 2-24 months recommended that VCUG not be performed after an initial febrile UTI. [1] (These guidelines were reaffirmed in 2016. [2] )
Voiding cystourethrography
VCUG is the criterion standard in diagnosis of VUR, providing precise anatomic detail and allowing grading of the reflux. [3] The International Classification System for VUR is as follows [4] :
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Grade I - Reflux into nondilated ureter
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Grade II - Reflux into renal pelvis and calyces without dilation
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Grade III - Reflux with mild to moderate dilation and minimal blunting of fornices
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Grade IV - Reflux with moderate ureteral tortuosity and dilation of pelvis and calyces
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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. However, some children demonstrate reflux only during an episode of cystitis.
Radionuclide cystography
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Instillation of technetium-99m pertechnetate into the bladder and observation with a gamma camera is a highly sensitive test for VUR
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Advantages include substantially lower radiation doses than with VCUG and the potential for increased sensitivity because of the ability to conduct prolonged periods of observation
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Disadvantages primarily consist of the poor anatomic detail, especially of the male urethra
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Grade I reflux is poorly detected by this study, because the distal ureters are commonly obscured by the bladder
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Grading by nuclear cystography is limited to mild, moderate, and severe grades.
See Workup for more detail.
Management
General principles of management in children with known VUR are as follows [5] :
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Spontaneous resolution of VUR is common in young children but is less common as puberty approaches
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Severe reflux is unlikely to spontaneously resolve
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Sterile reflux, in general, does not result in reflux nephropathy
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Long-term antibiotic prophylaxis in children is safe
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Surgery to correct VUR is highly successful in experienced hands
Surveillance
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Still frequently used among older children with VUR, especially boys who have never had a UTI
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Children with low-grade VUR, especially those who have never had a UTI, are sometimes followed on surveillance without antibiotic prophylaxis
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Infrequently used among those with high-grade VUR; antibiotic prophylaxis is usually well tolerated, and there are medicolegal concerns regarding the risk of kidney damage while on surveillance
Antibiotic prophylaxis
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Started once a child has completed treatment of the initial UTI
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Discontinued if no VUR is seen on imaging studies
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If VUR is present, prophylactic antibiotics are continued until the VUR resolves or is surgically corrected, or the child grows old enough that prophylaxis is deemed no longer necessary
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The 2011 AAP guidelines argued that antimicrobial prophylaxis is not effective at preventing UTI in children with VUR and that there is little value in diagnosing UTI because little can be done about it, short of surgery [1] ; however, data from the RIVUR trial called these assumptions into question [6]
Antibiotics are used as follows:
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The typical dose is one fourth of the therapeutic dose
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Antibiotics are usually administered as suspensions once daily, typically in the evening to maximize overnight drug levels in the bladder
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In neonates with antenatally diagnosed hydronephrosis and in infants younger than 8 weeks who have been treated for UTI, the agent of choice is amoxicillin
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For older children, the most common antibiotics used are trimethoprim-sulfamethoxazole, nitrofurantoin, and penicillins
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Cephalosporins are used less often
The prophylactic regimen also includes regular follow-up care and imaging (eg, renal US and VCUG or nuclear cystography every 12-18 months).
Children with dysfunctional elimination require aggressive bladder and bowel management. In toilet-trained children with recurrent UTI, voiding postponement behaviors, incomplete emptying, and constipation are extremely common and may be much more important etiologic factors than the reflux itself. Anticholinergic medication, in conjunction with timed voiding, may improve symptoms of dysfunctional voiding and reduces the risk of infection in select patients.
Surgical care
Accepted indications for surgical treatment include the following:
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Breakthrough febrile UTIs despite adequate antibiotic prophylaxis
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Severe reflux (grade V or bilateral grade IV) that is unlikely to spontaneously resolve, especially if renal scarring is present
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Mild or moderate reflux in females that persists as the patient approaches puberty, despite several years of observation
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Poor compliance with medications or surveillance programs
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Poor renal growth or function or appearance of new scars
Virtually all open antireflux operations involve reconstruction of the ureterovesical junction 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. Options include open antireflux surgery via an extravesical or an intravesical approach and endoscopic antireflux treatment.
See Treatment and Medication for more detail.
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. It takles either of the following forms:
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Primary reflux - VUR in an otherwise normally functioning lower urinary tract
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Secondary reflux - VUR 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 VUR has been recognized as an anatomic phenomenon for centuries, it was not until relatively recently that the substantial morbidity and mortality associated with the condition were 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 VUR may result in reduced prevalence of renal complications. The subsequent developments in the medical and surgical management of VUR formed the basis of the evolving field of pediatric urology.
The objectives in the current treatment of VUR are twofold, as follows:
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The first goal is the prevention of episodes of acute pyelonephritis with its associated morbidity and mortality
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The second goal is to prevent the scarring of the kidney associated with VUR (reflux nephropathy), which increases the risk of hypertension and renal failure in children and adults with VUR
Controversy persists over the optimal management of VUR, specifically with respect to the timing, technique, and benefits of surgical correction. Guidelines have been published by the American Urological Association (AUA). [7] (See Guidelines.)
Pathophysiology
After entering the bladder through the muscular hiatus of the detrusor, 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 antenatally identified and presumably sterile reflux, the data overwhelmingly 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 the severity of reflux nephropathy in patients with VUR. [2, 8, 5]
Scarring may result from a single episode of pyelonephritis, especially in very young patients. Ransley and Risdon named this occurrence the "big bang" effect. [9] 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.
Etiology
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 have favored 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 VUR 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 VUR. 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 VUR 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 VUR 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.
Epidemiology
United States statistics
The overall prevalence of VUR is not known, 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 did not clearly characterize their subject populations. The evidence is clear that the prevalence of VUR is higher among children with UTIs (15-70%, depending on age). Among infants antenatally identified with hydronephrosis on ultrasonography (US), approximately one third were postnatally found to have VUR.
The incidence of reflux clearly is influenced by genetic factors, though specific modes of inheritance have yet to be identified. Siblings of children with VUR have a 25-33% risk of also having VUR, 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. [10]
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 VUR, with associated morbidity. As a middle ground, some pediatric urologists screen newborn siblings of children with VUR but do not screen their older, asymptomatic siblings.
International statistics
Many large studies have been performed in Europe, where the prevalence of VUR 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.
Age-related demographics
VUR 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 reported prevalence figures 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. [8]
Sex-related demographics
UTIs are more common in females, as one might expect from the anatomic differences. This leads to greater screening and, therefore, diagnosis of VUR in females. However, among all children with UTI, boys are more likely to have VUR than girls are (29% of males vs 14% of females). Boys also tend to have higher grades of VUR diagnosed at younger ages, but their reflux is more likely to resolve.
Race-related demographics
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 antenatal registry of 1019 patients with antenatal hydronephrosis and found a 15% incidence of VUR in African American patients enrolled in the registry. Although VUR 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 VUR and because of the wide variation of genes with intermarriage, excluding any group from evaluation is difficult.
Although VUR 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.
Prognosis
With modern antibiotics and supportive care, mortality from acute pyelonephritis in children with VUR is very rare.
Primary reflux
Studies comparing medical management with surgical treatment of primary VUR 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 two groups, though surgically treated patients have a lower prevalence of pyelonephritis. 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 VUR, 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.
