Vesicoureteral Reflux

Galen and Asclepiades described the valve action of the ureterovesical junction as early as the second century CE. In 1903, Sampson and Young described the functional flap-valve mechanism at the level of the ureterovesical junction, which is created by the oblique course of the ureter within the intramural portion of the bladder wall. In 1913, Legueu and Papin described a patient with hydronephrosis and hydroureter in whom urine was shown refluxing through a widely patent ureteral orifice.

In his report on cystography in 1914, Kretschmer demonstrated that 4 of the 11 children he studied had reflux. In 1929, Gruber noted that the incidence of VUR varied based on the length of the intravesical ureter and muscularity of the detrusor backing. Paquin reported that the tunnel length–to–ureteral diameter ratio should be approximately 5:1 to prevent reflux. In the mid-to-late 1950s, Hutch postulated the causal relationship between VUR and chronic pyelonephritis in a cohort of patients with spinal cord injury, and, in 1959, Hodson demonstrated that renal parenchymal scarring is more common in children with VUR and UTIs.

Ransley and Ridson confirmed the studies of Tanagho in 1975 by showing that reflux could be experimentally created in animals by modifying the ureterovesical junction; in subsequent studies, they were able to show the correlation between reflux, renal papilla anatomy, pyelonephritis, and renal injury. At the same time, Smellie and Normand performed long-term studies of patients with reflux; they documented the natural history of patients treated medically.[6]

At the same time, Paquin, Hutch, Lich and Gregoire, Daines and Hudson, Politano and Leadbetter, Glenn and Anderson, and Cohen developed and popularized various surgical techniques for treating VUR. The International Reflux Grading System was adopted in the early 1980s, and the International Reflux Study compared medical approaches with surgical approaches to reflux. Finally, endoscopic treatment for reflux was introduced in the late 1980s. In recent years, Noe and colleagues showed a genetic predisposition for reflux. In addition, the widespread use of antenatal ultrasonography has allowed identification of fetuses with urinary tract abnormalities, which can result in diagnosis of reflux prior to the development of UTIs.

The normal valve mechanism of the ureterovesical junction includes oblique insertion of the intramural ureter, adequate length of the intramural portion of the ureter, and strong detrusor support.

The ureter is composed of 3 muscle layers: inner longitudinal, middle circular, and outer longitudinal. The outer longitudinal layer is enveloped by ureteral adventitia. The inner longitudinal layer of smooth muscle passes through the ureteral hiatus, continues distally beyond the ureteral orifice into the trigone, and intertwines with the smooth muscle fibers of the contralateral ureter, forming the Bell muscle of the trigone and posterior urethra. The middle circular muscle fibers, outer longitudinal muscle fibers, and periureteral adventitia merge with the bladder wall in the upper part of the ureteral hiatus to form the Waldeyer sheath. This sheath attaches the extravesical portion of the ureter to the ureteral hiatus.

When the ureter inserts into the trigone, the distal end of the ureter courses through the intramural portion of the bladder wall at an oblique angle. The intramural tunnel length–to–ureteral diameter ratio is 5:1 for a healthy nonrefluxing ureter. As the bladder fills with urine and the bladder wall distends and thins, the intramural portion of the ureter also stretches, thins out, and becomes compressed against the detrusor backing. This process allows a continual antegrade flow of urine from the ureter into the bladder but prevents retrograde transmission of urine from the bladder back up to the kidney; thus, a healthy intramural tunnel, within the bladder wall, functions as a flap-valve mechanism for the intramural ureter and prevents urinary reflux.

An abnormal intramural tunnel (ie, short tunnel) results in a malfunctioning flap-valve mechanism and VUR. When the intramural tunnel length is short, urine tends to reflux up the ureter and into the collecting system. Pacquin reports that refluxing ureters have an intramural tunnel length–to–ureteral diameter ratio of 1.4:1. To prevent reflux during ureteral reimplantation, the physician must obtain a minimum tunnel length–to–ureteral diameter ratio of 3:1.

The human kidney contains two types of renal papillae: simple (convex) papilla and compound (concave) papilla. Compound papillae predominate at the polar regions of the kidney, whereas simple papillae are located at nonpolar regions. Approximately 66% of human papillae are convex and 33% are concave.

Intrarenal reflux or retrograde movement of urine from the renal pelvis into the renal parenchyma is a function of intrarenal papillary anatomy. Simple papillae possess oblique, slitlike, ductal orifices that close upon increased intrarenal pressure. Thus, simple papillae do not allow intrarenal reflux. However, compound papillae possess gaping orifices that are perpendicular to the papillary surface that remain open upon increased intrarenal pressure. These gaping orifices allow free intrarenal reflux.

Patients with uncorrected VUR may develop renal scarring and impaired renal growth. Renal scars are often present at initial diagnosis and usually develop during the first years of life. Persistent intrarenal reflux causes renal scarring and eventual reflux nephropathy. Reflux nephropathy leads to impaired renal function, hypertension, and proteinuria.

Two types of urine may enter the renal papillae: infected urine or sterile urine. Intrarenal reflux of infected urine appears to be primarily responsible for the renal damage. The presence of bacterial endotoxins (lipopolysaccharides) activates the host's immune response and a release of oxygen free radicals. The release of oxygen free radicals and proteolytic enzymes results in fibrosis and scarring of the affected renal parenchyma during the healing phase.

Initial scar formation at the infected polar region distorts local anatomy of the neighboring papillae and converts simple papillae into compound papillae. Compound papillae, in turn, perpetuate further intrarenal reflux and additional renal scarring. Thus, a potentially vicious cycle of events may occur after initial intrarenal introduction of infected urine. Compound papillae are most commonly found at the renal poles, where renal scarring is most commonly observed. Renal scan (DMSA) reveals these lesions focally. Diffuse lesions on renal scan are believed to be due to renal dysplasia, which results from abnormal kidney development. It is observed in patients who have higher grades of reflux (IV and V) and who have never had any evidence of UTI or pyelonephritis. As described by Yeung et al, these kidneys may have very low or no function in 5% of girls and 78% of boys.[7]

Intrarenal reflux of sterile urine (under normal intrapelvic pressures) has not been shown to produce clinically significant renal scars. Treatment with long-term low-dose antibiotic prophylaxis to maintain sterile urine appears seems to inhibit renal scarring in children with uncomplicated VUR.[6, 8] Thus, renal lesions appear to develop only in the setting of intrarenal reflux in combination with UTI. One exception to this may include intrarenal reflux of sterile urine in the setting of abnormally high detrusor pressures.

Hodson et al completely obstructed the urethra of Sinclair miniature piglets and created an artificially high intravesical pressure that was transmitted to the renal pelvis. Intrarenal reflux of sterile urine in this highly pressurized system led to the formation of renal lesions. Apparently (at least in animal model studies), sterile reflux may also produce scarring but only with high intravesical pressures (eg, infravesical outlet obstruction or poorly compliant neurogenic bladder).

Renal lesions are associated with higher grades of reflux. Pyelonephritic scarring may, over time, cause serious hypertension due to activation of the renin-angiotensin system. Scarring related to VUR is one of the most common causes of childhood hypertension. Wallace reports that hypertension develops in 10% of children with unilateral scars and in 18.5% with bilateral scars. Among adults with reflux nephropathy, 34% ultimately develop hypertension. Approximately 4% of children with VUR progress to end-stage renal failure. Renal units with low-grade reflux may grow normally, but high grades of reflux are associated with renal growth retardation.

Bladder outlet obstruction (functional or anatomical), learned voiding abnormalities (eg, nonneurogenic neurogenic bladder, or Hinman syndrome), and gastrointestinal dysfunction may cause VUR. Unphysiologically elevated intravesical pressures are common with all of these abnormalities. Children with overactive bladder (eg, detrusor hyperreflexia, detrusor instability) generate a high intravesical pressure, which can exacerbate pre-existing VUR or cause secondary VUR. These children empty their bladder relatively well, with minimal postvoid residual urine.

Acquired voiding dysfunction (eg, Hinman syndrome [nonneurogenic neurogenic bladder]) produces functional bladder outlet obstruction from voluntary contraction of the external sphincter during urination. These children generate high intravesical pressure, develop detrusor instability, and have high postvoid residual urine volumes. Encopresis and constipation are also common in this setting.

Primary causes of VUR include the following:

• Short or absent intravesical ureter
• Absence of adequate detrusor backing
• Lateral displacement of the ureteral orifice
• Paraureteral (Hutch) diverticulum

Secondary causes of VUR include the following:

• Cystitis or UTI
• Bladder outlet obstruction
• Neurogenic bladder
• Detrusor instability

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 proposed a polygenic mode of inheritance, whereas others have suggested autosomal or sex-linked transmission.

VUR affects 1% to 2% of all children, and up to one-third of children with VUR will experience urinary tract infection (UTI).[2]  The incidence of VUR in children with febrile UTIs is estimated to be 30-40%.[3]

VUR is 10 times as common in white children as in black children, and children with red hair are recognizably at an increased risk. VUR is more prevalent in male newborns, but VUR seems to be 5-6 times more common in females older than one year than in males. The incidence decreases as patient age increases.

At present, the incidence of prenatally diagnosed hydronephrosis caused by VUR ranges from 17-37% in the pediatric population, and approximately 20-30% of children with VUR present with renal lesions. The incidence of VUR in children and young adults with end-stage renal failure (chronic renal insufficiency [CRI]) that necessitates therapy (dialysis or transplantation) is about 6%. VUR is the fifth-most-common cause of CRI in children.[9]

The success rate of ureteral reimplantation performed by experienced surgeons is higher than 95%. Following surgical repair, the incidence of pyelonephritis significantly decreases (in comparison to medical management with long-term antibiotic therapy); however, the incidence of cystitis or renal scarring is the same following both medical and surgical management of vesicoureteral reflux (VUR).

Endoscopic treatment carries a lower success rate than open surgical treatment but offers an alternative to either medical treatment or open surgical treatment. Unfortunately, to date, no long-term, multi-institutional study has been carried out to evaluate and compare the three management options. Outcome measures should consider not only resolution of reflux but also long-term renal health and rate of UTIs.

Vesicoureteral reflux (VUR) may be suspected in the prenatal period, when transient dilatation of the upper urinary tract is noted in conjunction with bladder emptying. Approximately 10% of neonates diagnosed prenatally with dilatation of the upper urinary tract will be found to have reflux postnatally. It should be noted that VUR cannot be diagnosed prenatally.

In general, VUR does not cause any specific signs or symptoms unless complicated by urinary tract infection (UTI). In other words, VUR is almost always asymptomatic unless it has led to a kidney infection (febrile UTI). Clinical signs and symptoms associated with a febrile UTI in a neonate may include irritability, persistent high fever, and listlessness. In cases of VUR and febrile UTI associated with a serious underlying urinary tract abnormality, the neonate could present with respiratory distress, failure to thrive, renal failure, flank masses, and urinary ascites.

Older children may more clearly communicate signs and symptoms associated with a UTI (eg, urgency, frequency, dysuria, incontinence), but unless the UTI is associated with a fever, there is little reason to suspect VUR.

Different imaging strategies have been proposed for children presenting with febrile urinary tract infection (UTI) to identify significant vesicoureteral reflux (VUR) while minimizing patient morbidity, radiation exposure, and financial burden. None of these imaging strategies is universally accepted. 

Because VUR and UTI may affect renal structure and function, performing renal ultrasound to assess the upper urinary tract is recommended by the American Urological Association (AUA), with optional dimercaptosuccinic acid (DMSA) renal scanning to assess the status of the kidneys for scarring and function.[10]

The American Academy of Pediatrics (AAP) recommends that all febrile infants with UTIs undergo renal and bladder ultrasonography (RBUS). Voiding cystourethrography (VCUG) should not be performed routinely after the first febrile UTI; VCUG is indicated if RBUS reveals hydronephrosis, scarring, or other findings that would suggest either high-grade VUR or obstructive uropathy, as well as in other atypical or complex clinical circumstances.[11]  

The American College of Radiology (ACR) recommends febril infants < 2 months with UTIs undergo renal US. However the ACR cautions that US has low sensitivity for detecting VUR and its main benefit is the detection of congenital renal abnormalities such as hydronephrosis, duplex renal system, hydroureter, and ureterocele.  In febrile children >2 months with UTIs responding well to treatment , the ACR finds no need for imaging.  In children with complicated and/or recurrent UTIs, both renal US and VCUG are indicated.[12]

The “top-down approach” (TDA) aims at restricting the number of VCUGs and its associated morbidity while identifying patients with clinically significant reflux. In this approach, children presenting with febrile UTIs are acutely investigated with DMSA renal scans to identify renal parenchymal inflammation. Those with evidence of renal involvement are offered VCUG and late DMSA scan to identify VUR and permanent renal scarring, respectively.

Although TDA can identify clinically significant VUR with high sensitivity, some lesions seen on DMSA scans are attributed to congenital dysplasia and unrelated to UTI. Ionizing radiation exposure, financial costs, limited availability of DMSA scans in the acute setting, variability in interpreting the results, and low yield of actionable findings on DMSA scans are other limitations.[4]  

Perform urinalysis and urine culture in all neonates born with antenatal or postnatal hydronephrosis to rule out UTI. More than 90% of newborns void within the first 24 hours.

The serum creatinine level of a neonate reflects that of maternal creatinine (ie, 1 mg/dL) in the first 24 hours of life; thus, repeat the serum creatinine assessment after at least 24 hours. The average serum creatinine level in a healthy neonate is approximately 0.4 mg/dL.

Obtain serum electrolytes in neonates with antenatal hydronephrosis due to VUR because they may have a dysplastic kidney on the affected side. Check for acidosis.

The recommended radiographic evaluation for VUR includes a voiding cystourethrography (VCUG),  a renal-bladder ultrasonography, and a nuclear renal technetium-99m–labeled dimercaptosuccinic acid (DMSA) scan.[13]

In sexually active adolescent girls, renal-bladder ultrasonography may be used to screen for renal abnormalities following a febrile UTI. If any abnormality is seen, conduct further workup studies with VCUG to rule out VUR.

VCUG, which provides clear anatomic detail and allows accurate grading of the degree of reflux, remains the gold standard tool to identify VUR. However, the test is usually a traumatic experience to both patients and their families due to the need for catheterization. Additionally, it carries a risk of introducing infection into the urinary tract. More importantly, it identifies a population with clinically-insignificant VUR that may never come to clinical attention, leading to potential overtreatment. 

Voiding cystourethrography/radionuclear cystourethrography technique

Perform the VCUG while the patient is awake and include a voiding phase. Appearance of the urethra is important to determine if the child has some degree of voiding dysfunction or, in males, if the child has posterior urethral valves. VUR is graded based on appearance of contrast in the ureter and upper collecting system during the voiding phase of the cystography. The VCUG also helps to evaluate the bony structures such as the lower spine and the pelvic architecture. It may also show whether the child has excessive feces in the colon.

In a neonate or small child, place a pediatric feeding tube rather than a Foley catheter in the urinary bladder. The Foley balloon may lead to a false diagnosis of a ureterocele or evoke an involuntary bladder spasm, complicating the test.

After filling the bladder with contrast, remove the feeding tube and allow the child to void.

The voiding phase of the cystography is considered the most important part of the test for assessing reflux. Perform the VCUG, rather than nuclear cystography, during the initial evaluation of a patient with suspected reflux; this provides good anatomic information about the lower urinary tract.

Allowing the bladder to fill and to empty several times (cycling) increases the sensitivity of the study. See the image below.

A voiding cystourethrogram (VCUG) of a patient with grade III vesicoureteral reflux (VUR). Note that the contrast flows up the ureter and into the renal pelvis. The calyces are sharp, and no evidence of hydronephrosis exists.

Renal and bladder ultrasonography

Obtain renal ultrasonography to evaluate the presence and degree of hydronephrosis. If hydronephrosis is present, inspect the ureters for dilatation. A dilated ureter in the presence of hydronephrosis may indicate VUR; however, hydronephrosis with an undilated ureter implies ureteropelvic junction obstruction.

Evaluate the appearance of the renal parenchyma and size of the kidneys. Abnormal or dysplastic kidneys are smaller and appear brighter or more echogenic. The presence of the corticomedullary junction indicates a normal kidney.

Ultrasonography is also a good modality to monitor kidney growth over time.

Evaluation of the bladder (prevoid and postvoid, measurement of bladder thickness) provides additional information about the lower urinary tract and bladder function. Bladder ultrasonography helps to reveal bladder-wall thickness, a dilated ureter, and the presence of a ureterocele or ectopic ureter. It also gives information about incomplete bladder emptying due to voiding dysfunction.

Compare renal size over time to assess renal growth.

Renal ultrasonography has not been demonstrated to be a reliable modality for revealing renal lesions, but obvious renal scarring can be seen in more severe cases.

Nuclear renal scan

DMSA is considered the best nuclear agent for visualizing the cortical tissue, evaluating renal function, and revealing the presence of renal scars. To detect pyelonephritis and renal scarring associated with reflux, use Tc-99m–labeled DMSA renal scintigraphy. Pyelonephritis impairs renal tubular uptake of a radionuclide isotope, causing cortical photon defects on the DMSA scan. Persistent photopenic defects on the DMSA scan represent renal scarring and irreversible renal damage.

The DMSA scan is used to confirm suspected pyelonephritis and to evaluate the effectiveness of VUR medical management. Patterns of abnormal radionuclide may also help to differentiate between renal lesions caused by infections (focal areas of low uptake, usually upper and lower poles of the kidney) from diffuse decreased uptake seen in renal dysplasia due to abnormal renal development.

The presence of photopenic areas within the kidney reflects a history of previous pyelonephritis.

Development of new photopenic areas within the renal cortex, especially in the polar regions, indicates new scar formation.

Diffuse decreased uptake of the radionuclide may indicate renal dysplasia.

Several authors have advocated DMSA renal scan as the first study following a febrile UTI. Patients found to have renal lesions on DMSA were found to have a higher incidence of UTIs and VUR, thus preselecting patients who needed to undergo VCUG (top-to-bottom approach to the evaluation of VUR).

Timing of DMSA scanning is critically important. To assess for resultant kidney scarring following an episode of pyelonephritis, wait at least 6 months to obtain the DMSA because of the strong potential for false-positive results due to residual effects of the infection.

Cystoscopy 

Cystoscopy plays a very limited role in VUR diagnosis. Conduct this study when the anatomy of the urethra, bladder, or upper tracts is incompletely defined with radiographic evaluation and when ureterocele is suspected.

Perform a video urodynamic evaluation with filling cystometrography and a pressure-flow study with electromyography in any child with a suspected secondary cause of VUR.

Filling cystometrography entails filling the bladder with a feeding tube and monitoring bladder pressures during filling and voiding. Normal bladder pressures should be less than 40 cm of water; however, the bladder pressure increases transiently to 60-80 cm of water during voiding.

Perform filling cystometrography to evaluate for overactive detrusor contractions, bladder compliance, and detrusor leak point pressure, which are significant risk factors for VUR.

High detrusor pressure and low urinary flow rate during voiding cystometrography indicates bladder outlet obstruction. This may be due to posterior urethral valves in boys, detrusor sphincter dyssynergia, or Hinman syndrome in children. Bladder outlet obstruction is another secondary cause of VUR.

Urodynamics

Perform urodynamics in patients with secondary VUR caused by lower urinary tract dysfunction. Lower urinary tract dysfunction, which may cause secondary VUR, includes overactive bladder, spinal cord injury, and bladder outlet obstruction.

The International Reflux Grading system classifies VUR into 5 grades, depending on the degree of retrograde filling and dilatation of the renal collecting system. This system is based on the radiographic appearance of the renal pelvis and calyces on a voiding cystogram, as follows:

• Grade I: Urine backs up into the ureter only, and the renal pelvis appears healthy, with sharp calyces.

• Grade II: Urine backs up into the ureter, renal pelvis, and calyces. The renal pelvis appears healthy and has sharp calyces.

• Grade III: Urine backs up into the ureter and collecting system. The ureter and pelvis appear mildly dilated, and the calyces are mildly blunted.

• Grade IV: Urine backs up into the ureter and collecting system. The ureter and pelvis appear moderately dilated, and the calyces are moderately blunted.

• Grade V: Urine backs up into the ureter and collecting system. The pelvis is severely dilated, the ureter appears tortuous, and the calyces are severely blunted.

Clinical management of vesicoureteral reflux (VUR) is complex and should be individualized. The main health concern in patients with VUR is the occurrence of febrile urinary tract infection (UTI) or pyelonephritis, which may lead to renal scarring, hypertension, and renal insufficiency. On the other hand, VUR has a high rate of spontaneous resolution, especially in young patients and with low-grade VUR.The goals of treatment are to minimize over-treatment in patients with low risk of UTI and to prevent renal scarring. 

Three approaches are used to treat children with vesicoureteral reflux (VUR), as follows:

• Active surveillance
• Medical treatment
• Surgical treatment

The International Reflux Study found that children can be managed nonsurgically with little risk of new or increased renal scarring, provided they are maintained infection free. The chance of spontaneous resolution of reflux is high in children younger than 5 years with grades I-III reflux and in children younger than 1 year (especially boys). Even higher grades of reflux (grades IV-V) may resolve spontaneously as long as the child remains infection free. Estrada and colleagues have published comprehensive nomograms to predict spontaneous resolution of VUR.[14, 15]

Thus, the philosophy of medical management is based on the knowledge that low-grade reflux resolves spontaneously and sterile reflux does not damage the kidney. Medical management involves the following:

• Administering long-term suppressive antibiotics
• Correcting the underlying voiding dysfunction (if present)
• Conducting follow-up radiographic studies (eg, voiding cystourethrography [VCUG], nuclear cystography, dimercaptosuccinic acid [DMSA] scan) at regular intervals

The philosophy of surgical management is based on the knowledge that high-grade reflux and persistent reflux in adolescents is not likely to resolve with continued medical therapy, especially in grade III reflux or greater. Another consideration in opting for surgical reflux management is the effect of repeated testing on patients and parents. In addition, lack of compliance with medical treatment may also dictate a surgical approach. Surgical therapy options include open surgical procedures and endoscopic injection of a bulking agent.

Relative indications for surgical management of VUR include the following;

• Grades IV and V reflux
• Persistent reflux despite medical therapy (beyond 3 y)
• Breakthrough UTIs in patient who are receiving antibiotic prophylaxis
• Lack of renal growth
• Multiple drug allergies that preclude the use of prophylaxis
• A desire to terminate antibiotic prophylaxis (either by the physician or the patient/parents)
• Medical noncompliance.

Absolute indications for surgical management include the following:

• Breakthrough pyelonephritis
• Progressive renal scarring in patients receiving antibiotic prophylaxis
• An associated ureterovesical junction abnormality

Ureteral reimplantation is contraindicated as a first-line therapy in patients with secondary VUR, which may arise as an inappropriate increase in detrusor filling pressure. Causes of secondary reflux include chronic bladder outlet obstruction, neurologic disorders (eg, myelomeningocele, spinal cord injury), and overactive bladder. All of these disease processes lead to poor bladder compliance; therefore, treating detrusor dysfunction before performing ureteral reimplantation is recommended. If the physician neglects the bladder and proceeds with ureteral implantation first, the risk of recurrent reflux is high, or, if the bladder wall is abnormally thickened, the risk of distal ureteral obstruction is greater after surgical treatment. Contraindications to surgery include detrusor instability or Hinman syndrome.

Bladder and bowel training is the mainstay of conservative treatment. Measures for a bladder regimen include behavior modification protocol to ensure that the child empties his/her bladder completely at regular intervals (every 3 h), adequate hydration, and constipation prevention.

Constipation is a symptom of that is common in patients with VUR and increases the risk of UTI and should be addressed aggressively. Maintaining a good level of hydration prevents constipation and contributes to the prevention of UTI, as it stimulates more frequent micturition. A diet rich in fibers may help in obtaining soft stools. Persistent constipation should be treated with laxatives.[1]

Circumcision may also be part of the conservative management in boys younger than 1 year of age, as it decreases UTI risks.

Timed voiding with or without biofeedback, a regular bowel regimen, and intermittent catheterization are the cornerstones of treating dysfunctional voiding due to Hinman syndrome.

Children with detrusor instability are treated with anticholinergic medications, fluid intake monitoring, and timed voiding observation. Ensure that the anticholinergic therapy does not exacerbate pre-existing constipation.

Spontaneous resolution rates decrease as patient age increases and with higher grades of reflux. Consider recommending surgical intervention in children with reflux that has persisted for more than 3 years with no improvement in the grade of reflux if it is grade II or greater.

Continuous antibacterial prophylaxis decreases the incidence of pyelonephritis and subsequent renal scarring for low-to-moderate grades of reflux. Therefore, nonsurgical management is appropriate for mild-to-moderate VUR (ie, grades I-IV) in the absence of breakthrough infections or anatomic abnormalities, as discussed above.

Antibiotic therapy must cover all likely pathogens in the context of this clinical setting. In the case of repeat UTIs in patients with VUR, long-term antibiotic prophylaxis was not shown to be preventive and increased the risk of bacterial resistance to treatment drugs in further infections by 3-fold.[16]

The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial evaluated the role of antimicrobial prophylaxis in the prevention of recurrent UTI and renal scarring in 607 children with VUR. Study participants received trimethoprim-sulfamethoxazole (TMP-SMX) or placebo and were followed for 2 years. Renal scarring was evaluated by baseline and follow-up. At the end of the study, 10% of the children had renal scarring. Antimicrobial prophylaxis did not decrease the risk of renal scarring. Children with renal scarring were significantly older (median age, 26 versus 11 months; P=0.01), had a second UTI before enrollment (odds ratio [OR], 2.85; 95% confidence interval [95% CI], 1.38 to 5.92), were more likely to be Hispanic (OR, 2.22; 95% CI, 1.13 to 4.34), and had higher grades of VUR (OR, 2.79; 95% CI, 1.56 to 5.0). The proportion of new scars in renal units with grade 4 VUR was significantly higher than in units with no VUR (OR, 24.2; 95% CI, 6.4 to 91.2).[17]

TMP-SMX is an effective antibiotic used to treat uncomplicated UTIs and prevent recurrent infections. Trimethoprim can be used alone (without sulfa) in patients with a sulfa allergy and is available in a liquid form. 

Double-suppressive regimens of TMP-SMX every morning and nitrofurantoin every evening may be effective when single-agent prophylaxis fails. Adult dosing is 5-10 mg/kg/d PO. Dosing in toilet-trained children > 3 months is 5-10 kg/d PO hs. It is not recommended in children < 3 months.

Nitrofurantoin is an antibiotic used specifically for uncomplicated lower UTIs. It does not alter gastrointestinal bacterial flora and achieves high concentration in urine. It is not indicated for use in pyelonephritis or perinephric abscess.  Adult dosing is 5-10 mg/kg/d PO. Dosing in children >3 months is 1-2 mg/kg/d PO hs.

In children < 3 months, amoxicillin is preferred. This semisynthetic penicillin derivative has broad-spectrum antibiotic activity against gram-positive and gram-negative bacteria (beta-lactamase negative). It is effective for treatment of uncomplicated or recurrent cystitis and also may be used as a long-term suppressive agent to prevent recurrent cystitis. However, rates of microbial resistance to amoxicillin have been steadily increasing over the last 20 years. Adult dosing is 250-500 mg PO tid or 500-875 mg PO bid. Pediatric dosing is 5 mg/kg/d PO.

Anticholinergics

These agents are bladder relaxant medications that control detrusor overactivity, which is a common secondary cause of VUR. Secondary causes of reflux from poor bladder compliance may be effectively treated with proper use of anticholinergic agents.

Oxybutynin (Ditropan) inhibits action of acetylcholine on smooth muscle and has direct antispasmodic effect on smooth muscles, which in turn cause bladder capacity to increase and uninhibited contractions to decrease. Adult dosing is 5 mg PO bid/tid; dosing of oxybutynin extended release (Ditropan XL) is 5-30 mg PO qd. Pediatric dosing is 1-5 mg PO bid/tid; dosing of the extended-release formulation is not established.

Tolterodine tartrate (Detrol, Detrol LA) is a competitive muscarinic receptor antagonist for overactive bladder. It differs from other anticholinergic types in that it has selectivity for urinary bladder over salivary glands. It exhibits a high specificity for muscarinic receptors and has minimal activity or affinity for other neurotransmitter receptors and other potential targets, such as calcium channels. In adults, dosing is 1-2 mg PO bid; dosing of tolterodine tartrate extended release (Detrol LA) is 2-4 mg PO qd (adjust dose according to individual response and tolerability). Pediatric dosing is not established.

Ureteral reimplantation

Surgery (ureteral reimplantation or ureteroneocystostomy) is the definitive method of correcting primary reflux, especially in the setting of anatomic abnormalities. Surgical principles of successful reimplantation include the following:

1. Creating a long submucosal tunnel to provide a 5:1 tunnel-to-diameter ratio
2. Providing good detrusor muscle backing
3. Avoiding ureteric kinking
4. Creating a tunnel in the fixed area of the bladder

Standard antireflux ureteral reimplantation procedures include the transtrigonal (Cohen), intravesical (Leadbetter-Politano), and extravesical detrusorrhaphy (Lich-Gregoir) techniques. The common goal of these operations is to prevent VUR by creating an effective flap-valve mechanism at the ureterovesical junction.

Complications due to ureteral reimplantation of the ureters occur in less than 1% of cases, and include the following:

• Bleeding in the retroperitoneal space
• Infections
• Ureteral obstruction
• Injury to adjacent organs
• Persistent reflux

Of note, surgical correction of VUR has not been demonstrated to decrease the frequency of recurrent nonfebrile UTIs. These infections occur in the lower tract, thereby indicating that the risk to the kidneys may have been reduced by preventing ascent of the bacteria to the upper urinary tract. The antireflux therapy does not completely prevent pyelonephritis, as a small percentage of patients who have undergone antireflux surgery re-present with pyelonephritis. These infections may be due to the host predisposition to infection rather than to anatomic factors.

Several investigators have reported that laparoscopic and robotic surgery may be a possible alternative to open ureteral reimplantation. Animal and human studies have demonstrated the feasibility of the technique but have not shown a significant improvement over currently available techniques. Advantages to these techniques are more obvious in the older patient who may have decreased pain and convalescence time.

Endoscopic treatment

The principle of this procedure is to inject, under cystoscopic guidance, a biocompatible bulking agent underneath the intravesical portion of the ureter in a submucosal location. The bulking agent elevates the ureteral orifice and distal ureter in such a way that the lumen is narrowed, preventing regurgitation of urine up the ureter but still allowing its antegrade flow. The procedure is performed with general anesthesia on an outpatient basis and has received increasing attention.[18, 19]  See the image below.

View of a ureteral orifice before and after endoscopic treatment.

Over the last 20 years, several bulking agents have been evaluated. These include polytetrafluoroethylene (PTFE or Teflon), collagen, autologous fat, polydimethylsiloxane, silicone, chondrocytes, dextranomer/hyaluronic acid (Dx/HA)[20]  and polyacrylate-polyalcohol copolymer (PPC).[21]  Concerns about PTFE particle migration have precluded approval by the US Food and Drug Administration (FDA) for use in children, and compounds such as collagen and chondrocytes have not stood the test of time.

Dextranomer/hyaluronic acid (Deflux, Q-Med USA) is the only FDA-approved endoscopic treatment of VUR in children. An initial clinical trial showed that this method was effective in treating reflux. A meta-analysis by Elder et al demonstrated that, after one treatment, the resolution rate of reflux per ureter for grades I and II was 78.5%; grade III, 72%; grade IV, 63%; and grade V, 51%, all compounds being considered.[1] Retreatment can be performed up to 3 times, bringing the aggregate rate of resolution to 85%. Improvement in injection techniques may yield better results.

Since its approval, the overall success rate after a second injection has been reported between 68% and 92%, depending mainly on the reflux grade. The success rate after a single injection is 50–70%.[22]  Complications are rare with the procedure, with transient ureteral obstruction and UTIs being the most commonly reported.

Introduced in 2008, PPC (Vantris, Promedon, Cordoba, Argentina) is a biocompatible, synthetic, non-absorbable bulking agent used outside the United States. A 5-year prospective follow-up reported successful resolution of reflux was 86.4% after single injection, 99.4% after a second injection, and 100% after the third. The only serious complication observed was late ureteral obstruction after PPC injection correcting high-grade reflux, which required ureteral re-implantation in 8% of children.[21]

Prior to antireflux surgery, obtain informed consent.

Discuss potential risks and complications (eg, persistent reflux, ureteral stricture, development of de novo contralateral reflux, ureteral obstruction, infection, bleeding).

Document the absence of UTI prior to surgery. If a UTI is noted, surgery should postponed until the infection is eradicated by administering broad-spectrum intravenous or oral antibiotics.

The procedure is as follows:

1. After satisfactory induction of a general anesthetic, place the patient in a supine fashion, with legs in the frog-leg position.
2. Sterilize the patient with povidone-iodine soap from umbilicus to mid-thigh and drape the patient so that the urethra may be accessed with the lower abdomen in the center of the field.
3. Create a low transverse incision approximately 1 cm above the symphysis pubis.
4. Carry the incision down to the rectus abdominis muscle.
5. Divide the rectus fascia in the midline and mobilize it from the underlying rectus muscles.
6. Bluntly separate the rectus and pyramidalis muscles at the midline, thus exposing the prevesical space and bladder.
7. Carefully dissect the peritoneum off the dome of the bladder and develop the lateral perivesical space.

At this point, further dissection varies based on the type of ureteral reimplantation planned.

Extravesical (Lich-Gregoir) reimplantation

The procedure is as follows:

1. Fully mobilize the bladder from the space of Retzius and lateral pelvic sidewalls with a gentle blunt dissection.
2. Insert a self-retaining abdominal wall retractor.
3. Identify the ipsilateral obliterated hypogastric artery.
4. Locate the ureter medial to the pelvic portion of the obliterated hypogastric artery. Free the refluxing ureter down to its insertion into the bladder wall.
5. Use electrocautery to incise the bladder muscle down to mucosa for a distance of 3-5 cm from the ureterovesical junction. Undermine the lateral edges of the incision to create a trough that forms a new bed for the ureter.
6. Carefully lay the ureter in the newly created trough. Then, close the detrusor muscle over the ureter with interrupted 2-0 or 3-0 absorbable sutures.
7. Consider leaving a closed-suction drain in the prevesical space and leave the Foley catheter indwelling.
8. Remove the Foley catheter 24-48 hours after surgery and remove the drain 24 hours later.

Extravesical detrusorrhaphy (Hodgson-Zaontz)

The procedure is as follows:

1. Following the initial dissection, extravesically dissect out the ureter down to the ureterovesical junction. Dissect the terminal ureter free from perivesical tissues but leave its attachment to the bladder mucosa intact.
2. Perform electrocautery to incise the bladder muscle down to the mucosa for a 5-cm arc around the ureterovesical junction. Undermine the lateral edges of the incision to create a trough that will form a new bed for the ureter. It is important not to open the mucosa of the bladder.
3. Telescope the ureter into the bladder so it courses within a long subepithelial tunnel. Neither a ureteral stent nor a perivesical drain is needed.
4. Leave the indwelling Foley catheter overnight.

Intravesical reimplantation

The procedure is as follows:

1. Following the initial dissection, open the bladder in the midline using electrocautery.
2. Place a self-retaining retractor.
3. Cannulize the refluxing ureter with a 3.5-5F feeding tube. Secure the tube to the distal ureter with a traction suture.
4. Create a circumferential incision around the ureteral orifice. With careful dissection, the distal ureter is completely freed from the intramural portion of the bladder.
5. Then, fashion a new submucosal tunnel 4-5 times the diameter of the ureter using sharp and blunt dissection.

The nomenclature for the different types of intravesical reimplantation vary based on the location of the new ureteral hiatus (where the ureter enters the bladder wall) and the course of the ureter, as follows:

• The Politano-Leadbetter repair creates a new ureteral hiatus more cephalad to the original ureteral hiatus.

• The Glenn-Anderson repair creates a new ureteral hiatus more distal to the original hiatus.

• The Cohen repair creates a ureteral tunnel that is directed laterally across the trigone (transtrigonal) toward the contralateral side.

After reimplanting the ureter with adequate detrusor backing, a feeding tube may be left in the ureter to prevent ureteral obstruction from postsurgical edema. A trend has emerged for not leaving a stent in the ureter unless transient obstruction is a concern.

The feeding tube may be brought out either through the urethra in females or through a separate stab incision in the lower quadrant of the abdomen. It may also be brought out through the incision.

Drain the bladder with a Foley catheter. Close the bladder in 2 layers with running 3-0 absorbable sutures.

Endoscopic treatment

After induction of satisfactory general anesthesia, the patient is placed in the relaxed lithotomy position and the genitalia and perineum are prepared in a sterile manner.

Cystourethroscopy is carried out using a deflected lens scope. The bladder and ureteral orifices are inspected.

An injection needle is then advanced, bevel up to the ureteral orifice. The orifice is kept open by hydrodistending it with irrigation fluid; the needle is then advanced into the ureter. A submucosal puncture is made and the bulking material is slowly injected.

As it spreads in the submucosal space, the material elevates the intravesical ureter, and the orifice acquires an inverted smile appearance. The needle is slowly withdrawn after between 0.5 and 2 mL of material has been injected. A second injection may be carried out at the base of the newly created mound to further elevate the ureteral orifice.

The bladder is emptied and reinspected. Any bleeding vessels may be cauterized with a Bugbee electrode.

Continue intravenous antibiotic administration until the patient is tolerating a diet.

Manage bladder spasms with anticholinergic medication or belladonna and opium (B&O) suppositories. Diazepam can also be helpful for severe bladder spasms.

Discharge the patient within 1-2 days.

Continue postoperative antibiotic prophylaxis until radiographic findings confirm complete resolution of reflux.

Obtain a postoperative renal ultrasonography in 1-2 months. Perform follow-up renal ultrasonography in one year. If the results are normal, patients can be seen as needed.

Perform nuclear cystography in 3 months following any surgical treatment. However, in children who poorly tolerate cystography, it is reasonable to consider forgoing the follow-up cystography following open surgery, given the high (>98%) success rates. Perform interval renal ultrasonography annually for 3 years.

Complications include the following:

• Persistent, transient, contralateral reflux
• Postoperative ureteral obstruction
• Hematuria
• Urosepsis
• Anuria

Persistent, transient, contralateral reflux

Persistent reflux of the reimplanted ureter and development of de novo reflux of the contralateral side are usually temporary and resolve spontaneously. Transient postoperative reflux is usually caused by detrusor instability of the healing bladder.

Persistent reflux of the ipsilateral ureter in the absence of secondary causes (eg, poorly compliant bladder) is usually caused by a technical error. Some technical problems associated with ureteral reimplantation include inadequate ureteral mobilization, short intramural tunnel, inadequate anchoring of the ureter, and inappropriate placement of the ureteral orifice. Reoperate in this setting or consider endoscopic treatment if the reflux is grade III or less.

Most contralateral reflux is caused by recurrent or previously undiagnosed reflux that is now evident in the absence of the pop-off valve, which was previously provided by the refluxing ureter. Physicians can manage most of these patients conservatively, and patient symptoms usually subside spontaneously.

If a patient experiences persistent or severe vesicoureteral reflux (VUR) following repair, perform a thorough workup, including urodynamics, imaging, and cystoscopy. Correct failed repairs or poor tunnels with repeat surgical repair.

Postoperative ureteral obstruction

Ureteral edema, intraureteral blood clots or mucous, bladder spasms, or submucosal bladder hematoma may cause acute ureteral obstruction in the early postoperative period. Ureteral angulation or ureteral hiatus that is made too tight may also cause acute ureteral obstruction. Ischemia, an incorrect tunnel construction, or an incorrect tunnel position may cause chronic postoperative ureteral obstruction.

When diagnosing ureteral obstruction, conduct renal ultrasonography, intravenous pyelography, or nuclear renography to confirm diagnosis. Most postoperative ureteral obstructions resolve spontaneously; however, temporary ureteral stenting may be necessary. Nephrostomy tube placement is rarely required. Ureteroscopic dilation and stent placement may correct mild obstruction or stenosis. Percutaneous placement of a nephrostomy tune may be necessary if a transvesical approach is not achievable.

Repeat reimplantation may be required for more severe cases. Ensure that the ureter is transected outside the bladder during reoperation and consider using a psoas hitch or transureteroureterostomy because of its inadequate length.

Bladder diverticula may complicate reimplantation surgery either at the site of bladder closure or at the reimplantation site. This may necessitate reoperation if the diverticula drains poorly or is associated with reflux or an obstruction.

Urinary extravasation indicates incomplete healing of the bladder or implanted ureterovesical junction. Prolonged catheterization or stenting is warranted.

Hematuria

Gross hematuria after ureteral reimplantation is common. Persistent bleeding or clots indicate inadequate hemostasis at the time of operation. Hematuria is often self-limited and does not require operative intervention; however, continue prolonged catheterization until hematuria resolves. Patients rarely need transurethral fulguration or reoperation.

Urosepsis

Urosepsis is due to an untreated UTI or ureteral obstruction. To prevent sepsis, clear preoperative urine cultures of infection. If ureteral obstruction causes urosepsis, relieve the obstruction promptly and institute the appropriate antibiotics.

Anuria

Anuria is rare and may indicate dehydration or bilateral ureteral obstruction. Provide therapy via intravenous fluid challenges and furosemide. Check ureteral catheters for patency. If ureteral catheters were not used, obtain upper tract imaging studies such as ultrasonography to rule out bilateral ureteral obstruction. Manage bilateral ureteral obstruction with percutaneous nephrostomy tubes.

Yearly ultrasonography helps to monitor renal growth, to detect hydronephrosis, and to evaluate bladder anatomy and voiding dynamics (filling and emptying). However, this is not mandatory, especially if the patient has not had evidence of febrile UTI and has had normal findings on initial ultrasonography.

Radionuclide cystography every year to every 24 months helps monitor presence or resolution of VUR and helps to grade the amount of reflux. Compare with earlier studies to determine a trend toward resolution.

Obtain nuclear cystography during regular follow-up studies in a patient with known reflux. Although not as anatomically accurate as the standard VCUG, nuclear cystography provides adequate information regarding the current status of VUR. The main advantage of performing nuclear cystography is that it exposes the child to less radiation and may be more sensitive in revealing VUR.

Consider a DMSA scan if the child develops evidence of pyelonephritis, and this should be performed at least 6 months after resolution of the pyelonephritis.

Guidelines on management of vesicoureteral reflux (VUR) have been published by the following organizations:

• American Urological Association(AUA) ^[10]
• European Association of Urology (EAU) ^[5]

American Urological Association guidelines

In 2017, the  confirmed the validity of its 2010 guidelines for the management of VUR in children, which serve as a good resource for patients, parents, and physicians.[10] Recommendations for antibiotic prophylaxis vary according to age at diagnosis.

For initial management of VUR in children < 1 year, recommendations are as follows[10] :

• Continuous antibiotic prophylaxis (CAP), if child has a history of a febrile urinary tract infection (UTI)
• Offer CAP for VUR grades III–V, if child has no history of febrile UTI 
• Consider CAP for VUR grades I-II, if child has no history of febrile UTI

For initial management of VUR in children > 1 year, recommendations are as follows[10] ​:

• CAP for the child with bladder/bowel dysfunction and VUR due to the increased risk of UTI while bladder/bowel dysfunction (BBD) is present and being treated 
• CAP may be considered for the child with a history of UTIs in the absence of BBD
• Observational management without CAP, with prompt initiation of antibiotic therapy for UTIs, may be considered for the child with VUR in the absence of bladder/bowel dysfunction, recurrent febrile UTIs, or renal cortical abnormalities 
• Surgical intervention for VUR, including both open and endoscopic methods, may be used. 

If symptomatic breakthrough UTI occurs (manifest by fever, dysuria, frequency, failure to thrive, or poor feeding), a change in therapy is recommended. If symptomatic breakthrough urinary tract infection occurs, the clinical scenario will guide the choice of treatment alternatives; this includes VUR grade, degree of renal scarring, if any, and evidence of abnormal voiding patterns (bladder/bowel dysfunction) that might contribute to UTI, as well as parental preferences.

Patients receiving CAP with a febrile breakthrough UTI should be considered for open surgical ureteral reimplantation or endoscopic injection of bulking agents for intervention with curative intent. However, if there is no evidence of pre-existing or new renal cortical abnormalities, changing to an alternative antibiotic agent is an option prior to surgical intervention with curative intent.

Patients not receiving CAP who develop a febrile UTI should begin CAP. 

European Association of Urology guidelines

The EAU guidelines note that because of the lack of robust prospective randomized controlled trials of VUR, their recommendations are based on consensus.[5]

Diagnosis

• If routine prenatal ultrasound (US) detects dilatation of the upper urinary tract, the EAU recommends performing postnatal US (delayed until the first week after birth, to allow resolution of the oliguria that normally occurs in the first 48 hours or so postnatally) followed by a voiding cystourethrogram (VCUG) if the US shows dilatation. The guidelines note that that up to 25% of newborns with upper urinary tract dilatation have VUR.
• In children who experience a proven febrile UTI in the first 2 years of life, the EAU recommends VCUG, followed by a nuclear renal scan with dimercaptosuccinic acid (DMSA) if the VCUG shows reflux. An alternative approach is to perform an initial DMSA scan close to the time of a febrile UTI, followed by VCUG if the DMSA scan reveals kidney involvement.
• Children with VUR who have symptoms suggestive of lower urinary tract dysfunction (LUTD; eg, urgency, wetting, constipation or holding maneuvers) should undergo an extensive history and examination, including voiding charts, uroflowmetry and residual urine determination, to confirm the diagnosis of LUTD.

Treatment

The EAU guidelines provide recommendations on conservative and surgical therapy for VUR. Conservative therapy has the objective of preventing febrile UTI, and comprises the following:

• Watchful waiting
• Intermittent or continuous antibiotic prophylaxis
• Bladder rehabilitation in patients with LUTD
• Consideration of circumcision during early infancy
• Regular follow-up with imaging studies (eg, VCUG, nuclear cystography, or DMSA scan)

Surgical treatment of VUR consists of endoscopic injection of bulking agents or ureteral re-implantation.                   

EAU treatment recommendations are as follows:

• Initially treat all patients diagnosed within the first year of life with CAP, regardless of the grade of reflux or presence of renal scars.
• Offer immediate, parenteral antibiotic treatment for febrile breakthrough infections.
• Offer definitive surgical or endoscopic correction to patients with frequent breakthrough infections.
• Offer open surgical correction to patients with persistent high-grade reflux and endoscopic correction for lower grades of reflux.
• Initially manage all children presenting at age one to five years conservatively.
• Offer surgical repair to children above the age of one year who present with high-grade reflux and abnormal renal parenchyma.
• Offer close surveillance without antibiotic prophylaxis to children presenting with lower grades of reflux and without symptoms.
• Ensure that a detailed investigation for the presence of lower urinary tract dysfunction (LUTD) is done in all and especially in children after toilet-training. If LUTD is found, the initial treatment should always be for LUTD.
• Offer surgical correction, if parents prefer definitive therapy to conservative management.

The guidelines suggest selecting the most appropriate management option based on the following:

• Presence of renal scars
• Clinical course
• Grade of reflux
• Ipsilateral kidney function
• Bilaterality
• Bladder function
• Associated anomalies of the urinary tract
• Age and gender
• Compliance
• Parental preference

The EAU guidelines also offer treatment and follow-up recommendations based on risk groups (ie, high, moderate, low).[5]