Clinical presentation, diagnosis, and course of primary vesicoureteral reflux

INTRODUCTION — The clinical significance of vesicoureteral reflux (VUR) has been based on the premise that VUR predisposes patients to acute pyelonephritis by transporting bacteria from the bladder to the kidney, which may lead to kidney scarring, hypertension, and chronic kidney disease (CKD). However, aspects of this long-held belief about VUR have been increasingly questioned. As a result, the clinical impact of VUR and its management remain uncertain and controversial.

The presentation, diagnosis, and clinical course of primary VUR will be reviewed here. The management of primary VUR is discussed elsewhere in the program. (See "Management of vesicoureteral reflux".)

DEFINITION AND PATHOGENESIS — VUR is the retrograde passage of urine from the bladder into the upper urinary tract. It is divided into two categories: primary and secondary based on the underlying pathogenesis.

Primary VUR — Primary VUR, the most common form of reflux, is due to incompetent or inadequate closure of the ureterovesical junction (UVJ), which contains a segment of the ureter within the bladder wall (intravesical ureter). Normally, reflux is prevented during bladder contraction by fully compressing the intravesical ureter and sealing it off with the surrounding bladder muscles.

In primary VUR, failure of this anti-reflux mechanism is due to a congenitally short intravesical ureter (figure 1). The intravesical ureter length may be genetically determined, which may explain the increased incidence in family members of patients with VUR.

Spontaneous resolution of primary low-grade VUR commonly occurs with patient growth [1]. As the bladder grows, the intravesical ureter increases in length, improving the function of the anti-reflux mechanism. (See 'Likelihood of resolution' below.)

Secondary VUR — Secondary VUR is a result of abnormally high voiding pressure in the bladder that results in failure of the closure of the UVJ during bladder contraction. Secondary VUR is often associated with anatomic (eg, posterior urethral valves) or functional bladder obstruction (eg, bladder bowel dysfunction [BBD] and neurogenic bladder) [2]. The degree and chronicity of obstruction can influence the severity of VUR. (See "Clinical presentation and diagnosis of posterior urethral valves", section on 'Vesicoureteral reflux' and "Myelomeningocele (spina bifida): Urinary tract complications".)

EPIDEMIOLOGY — Primary VUR is the most common urologic finding in children, occurring in approximately 1 percent of newborns [3]. The prevalence increases for neonates with prenatal hydronephrosis (up to 15 percent) [4,5], and for children with febrile urinary tract infections (UTIs) (ranging from 30 to 45 percent) [6].

The risk for primary VUR varies based on ethnicity, sex, and age. This was shown in a retrospective study from a single urban center in the United States that diagnosed VUR in 3661 of 15,504 children who were screened by a voiding cystourethrogram (VCUG) [7]. The following observations were made:

●Ethnicity – White children were three times more likely to have VUR than Black children. The maximal grade of reflux was significantly lower in Black children.

●Sex – In this cohort, females were twice as likely to have reflux as males. However, the sex difference is smaller in countries where circumcision is not routinely performed [8,9]. In contrast, there is a male predominance in patients who present with prenatal hydronephrosis [3,10]. (See 'Likelihood of resolution' below.)

●Age – Young children and infants (younger than two years of age) were more likely to have VUR than older children as there is spontaneous resolution with growth in the majority of affected children. (See 'Likelihood of resolution' below.)

In the United States, the predominance of female sex and White ethnicity appears to be greater in the subset of young children who are diagnosed after an episode of UTI. This was illustrated in the Randomized Intervention for Vesicoureteral Reflux (RIVUR) trial that reported that 81 percent of the 607 children with VUR diagnosed after febrile and/or symptomatic UTI were White and 92 percent were females [11]. In contrast, there is a male predominance in patients with prenatal presentation. In Europe and Asia, male predominance persists through early infancy most likely because neonatal circumcision is less commonly performed, resulting in a higher incidence of UTI, which may prompt an evaluation for VUR. (See 'Clinical presentation' below and "Urinary tract infections in children: Epidemiology and risk factors", section on 'Lack of circumcision'.)

GENETICS — There is a genetic predisposition for primary vesicoureteral reflux (VUR), as documented by a systematic review that found prevalence rates of 27.4 percent for siblings of a patient with VUR, and 35.7 percent for children of an affected parent [5]. The risk of VUR decreased as the age of the screened family member increased, at an estimated annual resolution rate of 4 percent. The familial rate was lower for more severe compared with milder forms of VUR (9.8 percent for Grades III to IV versus 16.7 percent for Grades I to II). (See 'Grading' below.)

Additional data supporting a genetic predisposition was provided by a small study of multiple gestation births that found a higher VUR rate in identical twins (12 out of 15 twin sets, 80 percent) compared with fraternal twins (11 out of 31 twin sets, 35 percent) [12].

Primary VUR appears to be genetically heterogeneous.

●In a study of 460 families, parametric linkage analysis using a dominant model revealed linkage to a region on chromosome 10q26 encompassing 69 genes [13].

●A second study using a similar approach for a large 97-member family with VUR and joint hypermobility, mapped the disorder to a locus on chromosome 6p [14]. Using whole exome sequencing, they identified a causal heterozygous missense variant in Tenascin XB, TNXB, a large extracellular matrix protein that regulates collagen deposition, indicating that perturbations in the extracellular matrix that supports the ureterovesical junction may predispose to VUR. These results are particularly compelling since VUR is associated with joint hypermobility in some children [15].

Research studies have also suggested a genetic susceptibility of individuals to kidney scarring, which may explain the variability in scarring in many children with VUR [16,17]. A study examined copy number variants in children from the RIVUR cohort and found that copy number variants (CNVs) implicated in the innate immune response were enriched in children with VUR compared with age- and ethnicity-matched controls [18].

CLINICAL PRESENTATION

Prenatal presentation — The presence of VUR is suggested by the finding of hydronephrosis on prenatal ultrasonography. Systematic reviews of the literature have reported estimated prevalence rates of 15 percent with a range of 10 to 40 percent in fetuses with prenatal hydronephrosis [4,5]. This variability is primarily due to differences in the definition of prenatal hydronephrosis and the indications for and timing of postnatal evaluation.

In the larger of the systematic reviews conducted by the American Urological Association (AUA), prenatal hydronephrosis was defined as a renal pelvic diameter (RPD) ≥4 mm during the second trimester and ≥7 mm during the third trimester [5]. The following findings were noted:

●In the 34 studies, VUR prevalence rate was 16.2 percent.

●RPD was not predictive of VUR.

●In nine studies, VUR was observed in 17 percent of infants who had prenatal hydronephrosis and a normal postnatal kidney ultrasound, demonstrating that a normal postnatal kidney ultrasound does not exclude the presence of VUR.

●The severity of VUR was equally distributed with one-third of patients with Grades I to II, a third with Grade III, and the remaining third with Grades IV to V. (See 'Grading' below.)

●Loss of renal parenchyma (kidney dysplasia) increased with the grade of reflux occurring in 6.2 percent of patients with Grades I to III and 47.9 percent of those with Grades IV to V.

●Data were insufficient to determine the rate of urinary tract infection (UTI) and the efficacy of prophylactic antibiotics.

There is a male predominance in patients with VUR who present prenatally. In one study of 155 consecutive infants with VUR, 75 percent were males, and patients with Grade V reflux were almost exclusively male [10]. In 54 percent of refluxing ureters, the reflux was mild to moderate (Grades I to III).

Postnatal presentation — Postnatal diagnosis of VUR is usually made after a diagnosis of a febrile UTI, and less commonly after family screening. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Imaging' and 'Screening of family members' below.)

Older toilet-trained children, especially females, with VUR diagnosed after an initial UTI have a higher likelihood of having bowel and bladder dysfunction (BBD) [19-23]. (See "Management of vesicoureteral reflux", section on 'Bladder and bowel dysfunction'.)

DIAGNOSIS — The diagnosis of VUR is based upon the demonstration of reflux of urine from the bladder to the upper urinary tract by either contrast voiding cystourethrogram (VCUG), ultrasound cystourethrogram (or contrast-enhanced voiding urosonography [ceVUS]) or radionuclide cystogram (RNC).

Diagnostic approach

Prenatal presentation — The diagnostic postnatal evaluation for VUR for infants prenatally diagnosed with hydronephrosis is controversial.

In our practices, we use the following approach, which avoids performing VCUG unnecessarily in the majority of infants with fetal hydronephrosis who do not have VUR [5,24,25]. VCUG is an invasive, relatively costly procedure requiring catheterization and radiation exposure, and is associated with catheter-acquired urinary tract infection (UTI) in approximately 1 percent of cases.

●Repeat kidney ultrasonography postdelivery. The timing is dependent upon whether there is bilateral or unilateral involvement, and the severity of fetal hydronephrosis. (See "Fetal hydronephrosis: Postnatal management".)

•Unilateral fetal hydronephrosis – Kidney ultrasound is optimally performed after the first week of delivery, when urine output is well-established (algorithm 1).

•Bilateral fetal hydronephrosis with RPD >10 – A kidney ultrasound should be performed soon after delivery (algorithm 2).

●VCUG is performed:

•If there is bilateral antenatal hydronephrosis in a male. (See "Fetal hydronephrosis: Postnatal management".)

•If the postnatal ultrasound shows persistent moderate or severe hydronephrosis (renal pelvic diameter [RPD] >10 mm), and/or ureteral dilatation. (See "Fetal hydronephrosis: Postnatal management", section on 'Persistent moderate to severe hydronephrosis'.)

•Selectively, if there is a family history of VUR. (See 'Screening of family members' below.)

●If the postnatal kidney ultrasonography demonstrates mild hydronephrosis (RPD ≤10 mm), we recommend conservative management with observation and monitoring for an episode of UTI. If observation is elected by the family, ultrasonography is repeated several months later. VCUG is recommended if there is persistent hydronephrosis or there is an episode of UTI [26]. (See "Fetal hydronephrosis: Postnatal management".)

●If the VCUG is normal and the RPD >15 mm, a functional renal scan with Tc99mMAG3 is performed to detect possible ureteral obstruction.

Postnatal presentation — The diagnostic assessment for VUR of children with UTI is controversial, as evidence to support the utility of routine imaging in reducing long-term sequelae (kidney scarring, hypertension, kidney failure) is limited.

In our practice, we use the following approach:

●A routine kidney and bladder ultrasound is obtained in any child after an initial UTI to assess the size and shape of the kidneys, and detect any kidney anatomical abnormality. Other experts in the field obtain ultrasonography after the first febrile UTI in children younger than two years who did not have a normal prenatal ultrasonography at a reputable center at >30 to 32 weeks of gestation and for children with poor growth, hypertension, or a family history of kidney or urologic disease; or in children of any age after recurrent UTI. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Ultrasonography'.)

●VCUG to diagnose VUR is recommended in the following clinical settings (see "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Indications'):

•Children of any age with a first febrile or symptomatic UTI with one or more of the following :

-Any anomalies on kidney ultrasound [27].

-The combination of temperature ≥39°C (102.2°F) and a pathogen other than E. coli [27]. Other experts in the field would perform a VCUG in children with a first well-documented febrile UTI with a temperature ≥39°C (102.2°F) regardless of the pathogen.

-Atypical clinical course

-Parental/caregiver preference.

-Concern with family/caregiver compliance regarding medical advice/care.

-Systemic signs of chronic kidney disease (eg, hypertension and poor growth); however, these patients usually are already identified by an abnormal kidney ultrasound.

•Children of any age with recurrent febrile or symptomatic UTI.

•Children with kidney ultrasound suggestive of kidney scarring and an uncertain history of UTI.

Imaging

VCUG versus RNC — The voiding cystourethrogram (VCUG) is the test of choice to establish the presence and degree of VUR. Radionuclide cystogram (RNC) is an alternative modality. However, despite the increased radiation exposure associated with VCUG, VCUG provides greater anatomic detail. Specifically, RNC does not reliably show bladder wall appearance or Grade I reflux. RNC also does not demonstrate urethral anatomy in boys, which may be important in secondary causes of VUR (eg, posterior urethral valves). For this reason, in many centers (including ours), RNC is not used as the initial study, but may be used to monitor for persistent reflux in follow up studies.

If a VCUG or RNC is performed in infants and young children, the procedure needs to be done in referral centers that have expertise both in catheterization and, in the case of VCUG, determination and minimization of radiation exposure. In these settings, the complications of the procedures can be reduced by using standardized protocol developed by the Urology and Radiology sections of the American Academy of Pediatrics (AAP), which focuses on patient safety by minimizing radiation exposure [28,29].

CeVUS (contrast-enhanced voiding urosonography) — Contrast-enhanced voiding urosonography is a relatively new technique employing an ultrasonographic contrast agent to image the lower urinary tract and detect VUR. Although catheterization is still necessary, this technique avoids radiation. It may be more sensitive in detecting some low-grade reflux, and it can be used to image the urethra in males. Further study of this modality is needed to determine whether there is a role for this imaging technique in detecting VUR. In addition, it would not be possible to assess the ureteral diameter ratio (UDR) with this technique (see below).

Grading — The International Reflux Study Group (IRSG) developed a classification system that grades the severity of VUR based upon the degree of retrograde filling and dilation of the renal collecting system demonstrated by VCUG (figure 2) [30]. It is important to note the subjectivity of assigning VUR grades because there is not perfect concordance even among expert readers, especially when differentiating between intermediate grades (II and III) [31,32]. This has implications when interpreting the literature and when making individual treatment decisions. In addition, it is important to use a standardized protocol for VCUG as changes in test parameters can influence test results. In our centers, we utilized the protocol developed by the AAP [29]:

●Grade I – Reflux only fills the ureter without dilation.

●Grade II – Reflux fills the ureter and the collecting system without dilation (image 1).

●Grade III – Reflux fills and mildly dilates the ureter and the collecting system with mild blunting of the calices.

●Grade IV – Reflux fills and grossly dilates the ureter and the collecting system with blunting of the calices. Some tortuosity of the ureter is also present.

●Grade V – Massive reflux grossly dilates the collecting system. All the calices are blunted with a loss of papillary impression, and intrarenal reflux may be present (image 2). There is significant ureteral dilation and tortuosity.

In the literature, the severity of reflux has been organized into two different classifications.

The first classification:

●Mild – Grades I and II

●Moderate – Grade III

●Severe – Grades IV and V

VUR has also been divided into:

●Low – Grades I through III

●High – Grades IV and V

A system based upon RNC findings utilizes three grades and correlates with the IRSG VUR grades as follows (picture 1) [33]:

●Grade 1 for mild reflux – VUR Grade I

●Grade 2 for moderate reflux – VUR Grades II and III

●Grade 3 for severe reflux – VUR Grades IV and V

The use of distal ureteral diameter ratio (UDR) has been promoted to grade VUR and eliminate the subjectivity of the IRSG system [34-36]. In this proposed schema, the pelvic ureteral width is measured at its greatest diameter and compared with the spinal distance between the bottom of L1 and the top of L3. The UDR has been shown to have better interobserver reliability, and appears to be a better predictor of outcome. Preliminary data have shown children with a lower UDR had fewer breakthrough infections over time, independent of the grade of VUR or the presence of bowel and bladder dysfunction (BBD), and UDR more accurately predicted surgical intervention, and spontaneous resolution of VUR with growth correlated well with the calculated UDR. However, further research is needed to validate these findings before this system is adopted to either replace or complement the grading system currently in use.

A Vesicoureteral Reflux Index has been proposed as another tool to predict clinical outcomes and ultimate resolution with somatic growth. The index is a six-point scale based upon sex, reflux grade, ureteral abnormalities, and reflux timing. Index scores have been predictive of breakthrough infection, grade improvement over time, and resolution [37,38]. Validation of this scoring system needs to be performed in other cohorts prior to its routine use in clinical practice.

Other imaging modalities — Other imaging techniques have been proposed that either eliminate the need for catheterization and/or radiation exposure. These include ultrasound and dimercaptosuccinic acid (DMSA) renal scan. However, a systematic review reported that neither kidney ultrasound nor DMSA renal scan is accurate enough to detect VUR of all grades in children with UTI [39].

●Kidney ultrasonography is limited in its sensitivity of detecting VUR, including cases of high-grade VUR, which may not demonstrate the associated findings of hydronephrosis or caliectasis. In the previously mentioned RIVUR trial of children with grades I to IV VUR, 90 percent of the initial kidney ultrasounds were normal [11]. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Ultrasonography'.)

●Although DMSA renal scan is an accurate means of detecting kidney dysmorphology secondary to VUR-related congenital kidney hypodysplasia or scarring from infection, the absence of these findings does not rule out VUR, and even cases of moderate to severe VUR may not be detected. (See "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Renal scintigraphy'.)

Indirect radionuclide or magnetic resonance imaging (MRI) cystography, thermal imaging after heating bladder urine with external devices, and the use of ultrasound with sonographic contrast agents are experimental modalities, which need to be confirmed as a cost-effective alternative to VCUG [40-48].

Indirect lab tests: Not clinically useful — Indirect urinary and serum markers (procalcitonin, cystatin C, urinary mRNA, C-reactive protein, matrix metalloproteinase 9, interleukins 6 and 8, and urinary proteome analysis) have been proposed as predictive tests for VUR; however, none of these methodologies are as accurate as cystography in making the diagnosis of VUR.

FURTHER EVALUATION

Index patient — Because of the association between VUR and kidney scarring, which may lead to chronic kidney disease (CKD), 2010 revised guidelines from the American Urological Association (AUA) suggest that an initial evaluation of the kidney status, growth parameters, and blood pressure should be performed in any child with VUR [49]. The guidelines were based on a systematic review of the available literature; however, the strength of these guidelines was limited because of the lack of well-designed clinical trials.

In our practice, we incorporate these guidelines in our evaluation of a child with VUR as follows:

●Performing a comprehensive medical examination, which includes measurement of height, weight, and blood pressure.

●Laboratory assessment in patients with kidney scarring includes:

•Urinalysis to detect proteinuria.

If the urinalysis is positive for protein, a first morning urine protein/creatinine ratio should be performed because proteinuria may be an indication of significant CKD. (See "Evaluation of proteinuria in children", section on 'Measurement of urinary protein'.)

If pyuria or bacteria is present, a urine culture should be obtained to screen for urinary tract infection (UTI). (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Urine culture'.)

•Serum creatinine (measure of estimated glomerular filtration rate) is obtained in patients with bilateral kidney involvement and in patients with a solitary kidney. A serum creatinine is obtained to assess kidney function (estimated glomerular filtration rate).

●Kidney imaging should be performed to assess the status of the kidneys. Kidney ultrasound will exclude other congenital conditions that cause hydronephrosis. Dimercaptosuccinic acid (DMSA) renal scan is superior in detecting renal cortical abnormalities compared with other imaging modalities and should be obtained in patients who are at risk for scarring or appear to have loss of renal parenchyma on kidney ultrasound. (See 'Kidney scarring' below and "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Imaging'.)

●Bladder and bowel (voiding) dysfunction (BBD) is associated with VUR and recurrent UTI in older, toilet-trained children. BBD also prolongs the time to spontaneous VUR resolution. As a result, the initial evaluation should identify if there are symptoms indicative of BBD (eg, urinary frequency and urgency, daytime wetting, constipation, and encopresis), so that interventions to improve bladder and bowel function can be initiated. (See "Evaluation and diagnosis of bladder dysfunction in children" and "Management of bladder dysfunction in children" and "Management of vesicoureteral reflux", section on 'Bladder and bowel dysfunction'.)

Screening of family members — The screening of family members is controversial with debate concerning the risk and benefits of screening, because there are no data on the outcome of treated versus untreated affected first-degree family members (ie, offspring or siblings) [50]. Our approach, which is consistent with the AUA guidelines, is to selectively screen immediate family members with a kidney and bladder ultrasound and voiding cystourethrogram (VCUG) or radionuclide cystogram (RNC) [5,51,52]. We screen younger siblings and offspring (under age five years) when there is a history of BBD or UTI, or if there is concern that the family/caregiver will not be compliant in seeking medical attention when there are symptoms suggestive of UTI or unexplained fever [51,53].

Although data are limited, available evidence suggest there is increased risk of kidney scarring in siblings of patients with high-grade VUR. In an observational study of 300 siblings of 259 patients with high-grade VUR (ie, Grades III to V), almost one-quarter of the 212 siblings who underwent DMSA renal scan had evidence of kidney scarring [54]. In a second publication from the same center, the risk for renal cortical abnormalities was increased in siblings with a previous UTI, siblings with high-grade reflux, and siblings who were over one year of age [51].

PROGNOSIS AND COMPLICATIONS

Likelihood of resolution — There is spontaneous VUR resolution in the majority of cases with primary VUR [11,55-57]. The likelihood of resolution increases as the severity of reflux decreases, when the age at diagnosis is <2 years and there is only unilateral involvement (figure 3) [55-62]. Data limited to patients diagnosed prenatally shows similar rates of spontaneous resolution and association with the severity of reflux [56,61,62].

A review of the literature reported the following resolution rates based on severity, unilateral versus bilateral involvement, and age (figure 3) [55]:

●Grades I and II – By five years of age, spontaneous resolution occurred in 80 percent of patients. The likelihood of resolution was not dependent upon age at presentation or whether the reflux was unilateral or bilateral (laterality of reflux).

●Grade III – Age at presentation and laterality of reflux had major effects on resolution of reflux. The oldest group of children (5 to 10 years of age) with bilateral reflux had less than 20 percent resolution over five years. In contrast, there was a 70 percent resolution rate in the youngest group of children (one to two years) with unilateral disease.

●Grade IV – There was a 60 percent resolution rate for unilateral disease and a less than 10 percent resolution rate for bilateral reflux over five years, regardless of age at presentation.

●Grade V – Spontaneous resolution is rare, except for in male infants who have a resolution rate of about 30 percent in the first year of life [58,59].

A subsequent retrospective study from a single tertiary center reported similar findings of increased likelihood of spontaneous resolution in patients diagnosed before one year of age, with lower grades of VUR, prenatal hydronephrosis, and unilateral involvement [57]. In this cohort, the rate of spontaneous resolutions based on VUR grades were as follows:

●Grade I – 72 percent

●Grade II – 61 percent

●Grade III – 49 percent

●Grade IV to V – 32 percent

Recurrent urinary tract infection — Children with VUR are at risk for recurrent febrile or symptomatic urinary tract infections (UTIs), especially those with more severe VUR.

This was illustrated in the Randomized Intervention for Vesicoureteral Reflux (RIVUR) trial of 607 children with VUR, which compared the effectiveness of trimethoprim-sulfamethoxazole (TMP-SMX) and placebo over a two-year follow-up period [11]. In this cohort, children with Grade III or IV VUR were more likely to have febrile or symptomatic UTI than those with Grade I or II VUR (23 versus 14 percent). In addition, prophylactic antibiotic therapy compared with placebo was associated with a lower risk of recurrent UTI (13 versus 24 percent). While these episodes of infection are not always associated with kidney scarring, they are associated with hospitalization, emergency department, and physician visits; loss of school days for children; and loss of work days for caregivers. (See "Management of vesicoureteral reflux", section on 'Antibiotic prophylaxis'.)

In subsequent publications using data from the RIVUR trial and a study of children who had one or two febrile or symptomatic UTIs but no VUR (Careful Urinary Tract Infection Evaluation [CUTIE]), children who had both VUR and BBD had the highest risk of recurrent symptomatic or febrile UTI [19,63].

Loss of renal parenchyma — Kidney scarring can cause hypertension and this does not depend on the severity of scarring. Bilateral scarring may be associated with decreased kidney function and progressive CKD. It is caused by the following mechanisms:

●Acquired scarring due to reflux-related recurrent pyelonephritis

●Abnormal kidney development resulting in congenital renal hypodysplasia (see "Renal hypodysplasia")

Kidney scarring — VUR is a risk factor for recurrent pyelonephritis and potentially subsequent kidney scarring [64-66]. The risk of scarring increases with the severity of reflux. As a result, we continue to perform VCUG in at-risk children with febrile UTIs to detect possible VUR and provide treatment plans for those diagnosed with high-grade VUR (Grades III to V). (See "Management of vesicoureteral reflux", section on 'Management'.)

Support for this approach is provided by the previously discussed RIVUR trial that demonstrated an increase in subsequent kidney scarring detected by dimercaptosuccinic acid (DMSA) renal scans from a baseline rate of 4 to 11 percent at the end of the two-year follow-up [11]. This rate of kidney scarring is significantly lower than previously published retrospective data and may be due to the close monitoring of patients, including early diagnosis and prompt treatment of UTI, and a relatively short duration of follow-up of two years. In a subsequent publication, the risk of kidney scarring was associated with an older age at enrollment (26 versus 11 months), having a previous second UTI before enrollment, higher grade of VUR, and Hispanic ethnicity [64]. In this cohort, renal units with grade IV VUR had a much greater risk of developing scars than units without VUR (odds ratio [OR] 24.2, 95% CI 6.4-91.2).

Further support is provided by a meta-analysis of individual patient data from nine observational studies including 1280 children (0 to 18 years) with a first UTI. In this study, the risk of kidney scarring was also increased in children with VUR compared with children without VUR (41 versus 17 percent), and increased with increasing grades of VUR [66]. In this analysis, the presence of Grade IV or V VUR was the strongest predictor of kidney scarring, although only 4 percent of patients had this degree of reflux.

In a study comparing patients with VUR from the RIVUR trial with children who had one or two febrile or symptomatic UTIs but no VUR from the CUTIE study, the risk of kidney scars was 10.2 versus 5.6 percent in children with VUR versus no VUR [63]. Although there was a trend towards increased risk of scarring with VUR, this difference was not statistically significant (adjusted odds ratio 2.05, 95% CI 0.86-4.87). These results should be interpreted with caution, as the number of patients with scarring in these two studies was small, and kidney scarring was not a primary end-point for these two studies.

Congenital renal hypodysplasia — Population-based studies have shown that renal hypoplasia or dysplasia resulting in reduced renal parenchymal mass may be observed in patients diagnosed prenatally with VUR [67-69]. In these studies, imaging typically demonstrated globally small kidneys with smooth kidney outlines consistent with renal hypodysplasia and not scarring [67,68]. In a large Japanese cohort of children with congenital kidney and urinary tract anomalies (CAKUT), the presence or history of VUR was not an associated risk factor with progression of chronic kidney disease (CKD) even though the rate of UTI was significantly higher in those with VUR as compared with those without VUR [70]. These data support the thesis that VUR is only a concomitant finding in patients with renal hypodysplasia and plays no causative role in the reduction of renal parenchyma. (See "Renal hypodysplasia", section on 'Progression to end stage renal disease (ESRD)'.)

However, despite the findings of the Japanese survey, we continue to be concerned that postnatal episodes of pyelonephritis may also play a role in kidney scarring in with congenital renal hypodysplasia. As a result, in our practice, we continue to treat patients with high-grade reflux (Grades III to V). (See "Management of vesicoureteral reflux", section on 'Grades III to V'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vesicoureteral reflux".)

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●Basics topics (see "Patient education: Prenatal hydronephrosis (The Basics)" and "Patient education: Vesicoureteral reflux in children (The Basics)")

SUMMARY AND RECOMMENDATIONS — Vesicoureteral reflux (VUR) is the retrograde passage of urine from the bladder into the upper urinary tract.

●VUR is divided into two categories based on the underlying pathogenesis (see 'Definition and pathogenesis' above):

•Primary VUR, the most common form of reflux, is due to incompetent or inadequate closure of the ureterovesical junction (UVJ) that contains a segment of the ureter within the bladder wall (intravesical ureter) (figure 1).

•Secondary VUR is a result of abnormally high voiding pressure in the bladder that results in failure of the closure of the UVJ during bladder contraction.

●Primary VUR occurs in approximately 1 percent of newborns. However, there is a significant rate of spontaneous resolution with growth, especially for patients with low-grade reflux (Grades I and II). (See 'Epidemiology' above and 'Likelihood of resolution' above.)

●VUR presents:

•Prenatally as antenatal hydronephrosis on prenatal ultrasound. (See 'Prenatal presentation' above.)

•Postnatally typically after an initial febrile illness or UTI, or, less commonly, after family screening of an index case. (See 'Postnatal presentation' above.)

●The diagnosis of VUR is based upon the demonstration of reflux of urine from the bladder to the upper urinary tract by either contrast voiding cystourethrogram (VCUG) or radionuclide cystogram (RNC). (See 'Diagnosis' above.)

●In our practice, the following diagnostic approaches are used:

•Prenatal presentation – An initial postnatal kidney ultrasound is performed in all patients who present with prenatal hydronephrosis. A VCUG is performed in infants with persistent postnatal abnormal ultrasound findings or who develop a urinary tract infection (UTI).

•Postnatal presentation – VCUG is obtained in children after a first febrile or symptomatic UTI who have an anomaly on kidney ultrasound, have hypertension or poor growth, or a have combination of temperature ≥39°C (102.2°F) and a pathogen other than Escherichia coli. Other factors to consider are atypical clinical course, family/caregiver preference, and evaluation of compliance regarding medical care after discussion with the family/caregiver. (See 'Postnatal presentation' above and "Urinary tract infections in infants older than one month and young children: Acute management, imaging, and prognosis", section on 'Voiding cystourethrogram'.)

●VCUG is the imaging test of choice to diagnose the presence and establish the degree of VUR. The severity of VUR is dependent upon the degree of retrograde filling and dilation of the renal collecting system. Established grading systems based upon VCUG findings are used to measure the severity of VUR (figure 2). (See 'Grading' above.)

●Children with VUR are at risk for recurrent febrile or symptomatic UTIs, especially those with more severe VUR. (See 'Recurrent urinary tract infection' above.)

●Loss of renal parenchyma is a common finding in patients with VUR. It may lead to decreased kidney function, and in some affected individuals with severe bilateral involvement to chronic kidney disease (CKD). Reduction in renal parenchyma is caused by the following mechanisms:

•Acquired scarring is caused by renal parenchymal infection, which can occur in those with any grade of reflux, but is more common in those with higher VUR grades (III to V). (See 'Kidney scarring' above.)

•Congenital renal hypodysplasia. (See 'Congenital renal hypodysplasia' above.)

●We suggest the following evaluation be performed in all children with VUR (Grade 2C) (see 'Further evaluation' above):

•Medical evaluation including measurements of height, weight, and blood pressure, and identifying any patient with symptoms indicative of voiding dysfunction.

•Urinalysis.

•Serum creatinine if there is bilateral involvement or in a patient with a solitary kidney.

•Kidney imaging with kidney ultrasound and in selected patients, dimercaptosuccinic acid (DMSA) renal scan.

•We suggest initial selective screening for VUR in younger siblings or offspring of the index case (Grade 2B).

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John T Herrin, MBBS, FRACP, and Gordon McLorie, MD, FRCSC, FAAP, who contributed to an earlier version of this topic review.