eMedicine Specialties > Urology > Hydronephrosis and Ureter Disorders

Vesicoureteral Reflux

Marc Cendron, MD, Associate Professor of Surgery, Harvard School of Medicine; Consulting Staff, Department of Urological Surgery, Children's Hospital Boston

Updated: Dec 15, 2008

Introduction

Vesicoureteral reflux (VUR) is characterized by the retrograde flow of urine from the bladder to the kidneys. VUR may be associated with urinary tract infection (UTI), hydronephrosis, and abnormal kidney development (renal dysplasia). The relation of these conditions to VUR is discussed in this article.

Unrecognized VUR with concomitant UTI may lead to long-term effects on renal function and overall patient health. Some individuals with VUR are at an increased risk pyelonephritis, hypertension, and progressive renal failure. However, the severity of VUR greatly varies and thus may affect patients differently. Some individuals have a genetic predisposition to renal injury. Evaluation of VUR treatment outcomes should consider not only resolution of reflux over time but also resolution of UTIs and the overall health of the kidneys. The evaluation and management of VUR in children is currently undergoing re-evaluation, as guidelines for treatment are being rewritten. (For additional information on pediatric vesicoureteral reflux, see the article Vesicoureteral Reflux in eMedicine’s Pediatric volume.)

Early diagnosis and vigilant monitoring of VUR are the cornerstones of management. Voiding cystourethrography (VCUG) or radionuclear cystourethrography (RNC) is used to confirm the diagnosis of VUR. A dimercaptosuccinic acid (DMSA) renal scan is used to evaluate for any renal abnormalities. Until the reflux resolves or the reflux is surgically treated, the patient should undergo yearly monitoring with renal ultrasonography (to evaluate renal growth) and cystography (RNC or VCUG). Prophylactic antibiotics are prescribed to reduce the risk of bacterial infection of the bladder while reflux is present. Bladder management to ensure good lower urinary tract hygiene should be considered in children who have undergone toilet training.

History of the Procedure

Galen and Asclepiades described the valve action of the ureterovesical junction as early as the second century AD. 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.¹

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, with the widespread use of antenatal ultrasonography, prenatal diagnosis of VUR has been made possible.

Problem

VUR is defined as retrograde regurgitation of urine from the urinary bladder up the ureter and into the collecting system of the kidneys. 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.

Frequency

Historically, epidemiologic studies using VCUG in presumably healthy neonates, infants, and children reported that the incidence of VUR is less than 1% in healthy children. However, this figure is probably an underestimation because no large population studies have been performed to assess the true incidence of VUR; in addition, reflux is discovered in selected patients such as those who present with a hydronephrosis or UTI or who have a family history of VUR.

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.

The incidence of VUR is much higher in children with UTIs (ie, 40-50%). Approximately 13,000 children younger than 17 years are hospitalized annually in the United States for the treatment of pyelonephritis. UTIs account for more than 1.1 million physician office visits among children younger than 18 years, and about 25,000 visits to urologists are for evaluation and treatment of VUR.

Today, 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.²

VUR has a definite genetic component, but the exact mode of inheritance remains unknown. Currently, researchers hypothesize that VUR is inherited dominantly with a variable penetrance. Up to 76% of index-case patients (ie, patients with reflux) develop VUR in utero, and up to 34% of patients with reflux have siblings who are also affected.

Etiology

• Primary causes
  • Short or absent intravesical ureter
  • Absence of adequate detrusor backing
  • Lateral displacement of the ureteral orifice
  • Abnormal configuration of the ureteral orifice (eg, stadium, horseshoe, golf hole)
• Secondary causes
  • Cystitis or UTI
  • Bladder outlet obstruction
  • Detrusor instability
  • Duplicated collecting system
  • Paraureteral (Hutch) diverticulum

Pathophysiology

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.³

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.^1,4 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 (a neurogenic condition), 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.

Presentation

The clinical presentation of VUR may occur in the prenatal period, when transient dilatation of the upper urinary tract is noted in conjunction with bladder emptying when the examination is carried out later in gestation (>28 wk). Approximately 10% of neonates diagnosed prenatally with dilatation of the upper urinary tract will be found to have reflux postnatally.

VUR may be diagnosed in a neonate who presents with respiratory distress, persistent vomiting, failure to thrive, renal failure, flank masses, and urinary ascites and may subsequently be diagnosed with severe UTI.

Older children may present with symptoms of UTI (eg, urgency, frequency, dysuria) and nocturnal and diurnal enuresis. Other constitutional symptoms include failure to thrive and gastrointestinal disturbances (eg, nausea, vomiting).

Indications

The goals of medical intervention in patients with vesicoureteral reflux (VUR) are to allow normal renal growth, to prevent UTI and pyelonephritis, and to prevent renal failure. Initiate medical management in prepubertal children with grades I-III reflux and most children with grade IV reflux.

Relative indications for surgical management of VUR include 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, and a desire to terminate antibiotic prophylaxis (either by the physician or the patient/parents). Absolute indications for surgical management include medical noncompliance with medical therapy, breakthrough pyelonephritis, progressive renal scarring in patients receiving antibiotic prophylaxis, and an associated ureterovesical junction abnormality.

Relevant Anatomy

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.

Contraindications

Ureteral reimplantation is contraindicated as a first-line therapy in patients with secondary vesicoureteral reflux (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.

Workup

Laboratory Studies

• 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 vesicoureteral reflux (VUR) because they may have dysplastic kidney on the affected side. Check for acidosis.

Imaging Studies

• The recommended radiographic evaluation for VUR includes a VCUG, renal-bladder ultrasonography, and nuclear renal scan (DMSA).
  • Perform VCUG and renal-bladder ultrasonography in any child with documented UTI before age 5 years, any child with pyelonephritis, and any male child with a symptomatic UTI.
  • A renal-bladder ultrasonography may be used to screen older children with UTI. If ultrasonographic findings are abnormal, conduct further workup studies with VCUG to rule out VUR.
  • Suggest that siblings or offspring of index cases with known VUR undergo cystographic screening during the first few months of life, as they are at a 30% risk of VUR.
  • During the initial workup in a patient with suspected reflux, perform the standard VCUG, which provides clear anatomic detail and allows accurate grading of the reflux degree. By filling and emptying the bladder several times (cycling) with the catheter still in the bladder, as described by Lebowitz, the yield of identifying VUR is clearly enhanced. The conventional cystography provides more anatomical accuracy than nuclear cystography; however, nuclear cystography is advantageous (used widely to monitor VUR) because of lower radiation exposure and increased sensitivity. Physicians can also use nuclear cystography to screen family members of a patient with known reflux.
• Voiding cystourethrography/radionuclear cystourethrography
  • 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.
• Renal and bladder ultrasonography
  • Obtain renal ultrasonography to evaluate the presence and degree of hydronephrosis. If hydronephrosis is present, inspect the ureters for dilatation. In a female patient, a dilated ureter in the presence of hydronephrosis usually indicates VUR; however, hydronephrosis in a male infant 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 the technetium 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.
  • Recently, 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).
• Follow-up imaging studies
  • Yearly ultrasonography helps to monitor renal growth, to detect hydronephrosis, and to evaluate bladder anatomy and voiding dynamics (filling and emptying).
  • Radionuclide cystography every year to every 18 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.
  • Perform DMSA scan if the child develops evidence of pyelonephritis.

Other Tests

• 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.

Diagnostic Procedures

• 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 uninhibited 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, detrusor sphincter dyssynergia, or Hinman syndrome in children. Bladder outlet obstruction is another secondary cause of VUR.

Treatment

Medical Therapy

Three therapeutic options are available to treat children with vesicoureteral reflux (VUR). They include medical treatment, surgical treatment, and surveillance (or observation).

The International Reflux Study has 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 they remain infection free.

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. The medical management involves administering long-term suppressive antibiotics, correcting the underlying voiding dysfunction (if present), and conducting yearly follow-up radiographic studies (eg, VCUG, nuclear cystography, DMSA scan) at regular intervals.

In 1997, the American Urological Association published a set of guidelines for the management of VUR in children that still serves as a good resource for patients, parents, and physicians.⁵ These guidelines are in the process of being rewritten.

The Pediatric Vesicoureteral Reflux Guidelines Panel has made the following recommendations for children with VUR:

Indications for antibiotic prophylaxis

• Children without renal scarring at diagnosis
  • Diagnosis made in infancy: All patients diagnosed at infancy (ie, <1 y) with grades I-V reflux should be treated initially with continuous prophylactic antibiotics.
  • Diagnosis made in children aged 1-5 years: When unilateral and/or bilateral grades I-IV reflux or unilateral grades III-V reflux are diagnosed in children aged 1-5 years, they should be treated initially with continuous prophylactic antibiotics.
  • Diagnosis made in children aged 6-10 years: Children diagnosed at age 6-10 years with unilateral and/or bilateral grades I-II reflux and unilateral grades III-IV reflux should be treated initially with continuous antibiotic prophylaxis. However, some are advocating withholding treatment in patients with grade I or II VUR, as most of these patients are at low risk for UTIs and pyelonephritis provided they have no voiding dysfunction or constipation.
• Children with renal scarring at diagnosis
  • Diagnosis made in infancy: Infants (ie, <1 y) with scarring at diagnosis and grades I-V reflux should be treated initially with continuous antibiotic prophylaxis.
  • Diagnosis made in children aged 1-5 years: Antibiotic prophylaxis is the preferred option for preschool-aged children (ie, 1-5 y) with renal scarring at diagnosis, unilateral and/or bilateral grades I-II reflux, unilateral grades III-IV reflux, and bilateral grades III-IV reflux.
  • Diagnosis made in children aged 6-10 years: In children diagnosed at age 6-10 years with renal scarring and unilateral and/or bilateral grades I-II reflux or unilateral grades III-IV reflux, antibiotic therapy is the preferred treatment option.

Correcting the voiding dysfunction nonsurgically

• Adjunctive 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.
• 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.
• Hydronephrosis observed on prenatal ultrasonography may be the first indication of VUR. Such neonates should receive antibiotic prophylaxis (ie, amoxicillin) and undergo VCUG within the first month after birth. At approximately 4 weeks, obtain a nuclear renal scan (ie, DMSA) if high-grade (IV or V) reflux is found.
• Correct any serum electrolyte abnormalities due to a malfunctioning kidney.

Medications

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.

Drug Category: Antibiotics -- Therapy must cover all likely pathogens in the context of this clinical setting.

Surgical Therapy

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.

Indications for surgery

• Children without renal lesions at diagnosis
  • Diagnosis made in infancy
    • In patients diagnosed with VUR in infancy (ie, <1 y), consensus is lacking regarding the role of continued antibiotic therapy versus surgery for those with persistent grades I-II reflux after a period of antibiotic prophylaxis.
    • However, surgical repair may be recommended in patients with persistent unilateral grades IV-V reflux or bilateral grades III-V reflux after a period of antibiotic therapy should the parents prefer definitive therapy over watchful management while receiving antibiotic prophylaxis.
  • Diagnosis made in children aged 1-5 years
    • In patients diagnosed with VUR at age 1-5 years, continuous antibiotic prophylaxis is the preferred option as an initial therapy for those with unilateral grade V reflux; however, surgical repair is a reasonable alternative for grades IV and V reflux.
    • In patients with bilateral grade V reflux, surgical repair is recommended.
    • Consensus is lacking regarding the role of continued antibiotics versus surgery in children with persistent grades I-II reflux after appropriate suppressive antibiotic therapy.
    • However, surgery is recommended for children with persistent grades III-V reflux in whom antibiotic therapy has not kept them infection-free.
    • Endoscopic treatment may be recommended in children with grade III to IV who have not shown any improvement in the reflux grade, who do not wish to receive further antibiotics, or who have had UTI.
  • Diagnosis made in children aged 6-10 years
    • In patients diagnosed with bilateral grades III-IV reflux at age 6-10 years, surgical repair is the preferred option, although continuous antibiotics is a reasonable alternative.
    • Patients with grade V reflux should undergo surgical repair. In patients with persistent grades I-II reflux after a period of antibiotic prophylaxis, consensus is lacking regarding the role of continued antibiotics versus surgery.
    • However, surgery is an option for persistent reflux in children with grades III-IV reflux in whom initial antibiotic therapy has failed. They can undergo either open surgical or endoscopic treatment.
• Children with renal lesions at diagnosis
  • Diagnosis made in infancy
    • In children diagnosed in infancy (ie, <1 y) with grade V reflux and scarring, continuous antibiotic prophylaxis is the preferred option as an initial treatment; primary surgical repair is a reasonable alternative.
    • If the kidney is noted to have poor function (<15% on DMSA scan) consider removing the kidney and the ureter down to the bladder.
    • Consensus is lacking regarding the role of continued antibiotics versus surgery in patients with persistent grades I-II reflux after a period of antibiotic prophylaxis. These patients may be candidates for endoscopic treatment.
    • In boys with persistent unilateral grades III-IV reflux, surgical repair is the preferred option. In addition, boys with persistent bilateral grades III-IV reflux, girls with persistent unilateral and/or bilateral grades III-IV reflux, and any children with persistent grade V reflux should undergo surgical repair with an option for endoscopic treatment in grades II-IV.
  • Diagnosis made in children aged 1-5 years
    • In children diagnosed at age 1-5 years with bilateral grades III-IV reflux and renal lesions, antibiotic therapy is the preferred option; however, surgical repair is a reasonable alternative.
    • Patients with unilateral and/or bilateral grade V disease and scarring should undergo surgical repair as initial treatment or nephroureterectomy if the kidney has been shown to have little or no function on DMSA scan.
    • Consensus is lacking regarding the role of continued antibiotics versus surgery for patients with persistent grades I-II reflux after a period of antibiotic prophylaxis.
    • Girls with persistent unilateral and/or bilateral grades III-IV reflux and boys with persistent bilateral grades III-IV reflux should undergo surgical repair, either open or endoscopic.
    • Surgery is also an option for boys with persistent unilateral grades III-IV reflux.
    • For patients with persistent grade V reflux who have not undergone surgery as initial treatment, surgical repair is recommended.
  • Diagnosis made in children aged 6-10 years
    • Patients diagnosed with bilateral grades III-IV reflux or grade V reflux at age 6-10 years can undergo surgical repair as initial treatment.
    • Consensus is lacking regarding the role of continued antibiotics versus surgery for patients who have persistent grades I-II reflux after a period of prophylaxis.
    • Patients with persistent unilateral grades III-IV reflux who have not undergone surgery as initial treatment should be offered either open surgical repair or endoscopic treatment.

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 (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, and (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 techniques. The common goal of these operations is to prevent VUR by creating an effective flap-valve mechanism at the ureterovesical junction.

Potential complications due to ureteral reimplantation of the ureters include bleeding in the retroperitoneal space, infections, ureteral obstruction, injury to adjacent organs, and persistent reflux. These occur in less than 1% of cases.

Of note, surgical correction of VUR has not been demonstrated to decrease the frequency of recurrent UTIs. Most of 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 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.

Endoscopic treatment

Puri and O'Donnel popularized endoscopic treatment of reflux in the 1980s. The principle of the 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.

Over the last 20 years, several bulking agents have been evaluated. These include polytetrafluoroethylene (PTFE or Teflon), collagen, autologous fat, polydimethylsiloxane, silicone, chondrocytes and, more recently, a solution of dextranomer/hyaluronic acid (Deflux). Concerns about PTFE particle migration have precluded FDA approval for use in children.

Other compounds such as collagen and chondrocytes have not stood the test of time. Recently, dextranomer/hyaluronic acid (Deflux, Q-Med USA) was FDA-approved for the treatment of VUR in children. Initial clinical trial showed that this method was effective in treating reflux. A recent meta-analysis by Elder et al demonstrates 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.⁶ Retreatment can be performed up to 3 times, bringing the aggregate rate of resolution to 85%. Improvement in injection techniques may yield better results. Unfortunately, long-term studies have not yet been carried out to assess the longevity of the material and its effectiveness over time in curing reflux. Complications are rare with the procedure, with transient ureteral obstruction and UTIs being the most commonly reported.

Preoperative Details

• 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 treated and eradicated.
• If infection is present, eradicate it by administering preoperative broad-spectrum intravenous or oral antibiotics.

Intraoperative Details

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

• Fully mobilize the bladder from the space of Retzius and lateral pelvic sidewalls with a gentle blunt dissection.
• Insert a self-retaining abdominal wall retractor.
• Identify the ipsilateral obliterated hypogastric artery.
• 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.
• 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.
• 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.
• Consider leaving a closed-suction drain in the prevesical space and leave the Foley catheter indwelling.
• Remove the Foley catheter 24-48 hours after surgery and remove the drain 24 hours later.

Extravesical detrusorrhaphy (Hodgson-Zaontz)

• 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.
• 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.
• Telescope the ureter into the bladder so it courses within a long subepithelial tunnel. Neither a ureteral stent nor a perivesical drain is needed.
• Leave the indwelling Foley catheter overnight.

Intravesical reimplantation

• Following the initial dissection, open the bladder in the midline using electrocautery.
• Place a self-retaining retractor.
• Cannulize the refluxing ureter with a 3.5-5F feeding tube. Secure the tube to the distal ureter with a traction suture.
• Create a circumferential incision around the ureteral orifice. With careful dissection, the distal ureter is completely freed from the intramural portion of the bladder.
• 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. Currently, 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.

Postoperative Details

• Continue intravenous antibiotic administration until the patient is tolerating a diet.
• Manage bladder spasms with anticholinergic medication or belladonna and opium (B&O) suppositories. Valium 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.

Follow-up

• Obtain a postoperative renal ultrasonography in 1-2 months.
• Perform nuclear cystography in 3 months if endoscopic treatment has been performed. The current trend is to forego the follow-up cystography, as 98% of findings are negative after an open surgical repair.
• Perform interval renal ultrasonography annually for 3 years.
• During the scheduled follow-up studies, monitor patient blood pressure and renal function and perform urinalysis.
• After confirming resolution of reflux, discontinue antibiotic prophylaxis.
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Bladder Control Problems.

Complications

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.

Outcome and Prognosis

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.

Future and Controversies

Whether minimally invasive therapy using periureteral-bulking agents will be the future of vesicoureteral reflux (VUR) treatment remains to be determined.

Several investigators have reported that laparoscopic 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.

Current research efforts are directed toward better understanding of the genetics of VUR, refining the diagnostic criteria in order to better identify patients who seem to be at increased risks for renal damage, and determining who would benefit most from definitive therapy. Finding molecular markers associated with renal injury will also help to guide the treatment of patients with VUR.

Multimedia

Media file 1: 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.

Media file 2: This is an example of grade V vesicoureteral reflux (VUR). Note the dilated renal pelvis and calyces. The ureter also is dilated and tortuous.

Media file 3: This is bilateral vesicoureteral reflux (VUR) with paraurethral (Hutch) diverticulum.

Media file 4: Vesicoureteral reflux (VUR). Nuclear cystogram showing reflux of radioisotope into left collecting system.

Media file 5: A dimercaptosuccinic acid (DMSA) scan in vesicoureteral reflux (VUR). Photopenic areas of the left kidney indicate renal scarring.

Media file 6: View of a ureteral orifice pre and post endoscopic treatment

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Keywords

vesicoureteral reflux, VUR, vesico-ureteral reflux, ureterovesical reflux, uretero-vesical reflux, reflux nephropathy, urinary reflux, retrograde urination, hydronephrosis, urinary tract infection, UTI, urine reflux, renal dysplasia, pyelonephritis, hypertension, progressive renal failure, ureteral reimplantation, intrarenal reflux, reflux nephropathy, secondary vesicoureteral reflux, secondary VUR

Contributor Information and Disclosures

Author

Marc Cendron, MD, Associate Professor of Surgery, Harvard School of Medicine; Consulting Staff, Department of Urological Surgery, Children's Hospital Boston
Marc Cendron, MD is a member of the following medical societies: American Academy of Pediatrics, American Urological Association, European Society for Paediatric Urology, Johns Hopkins Medical and Surgical Association, New Hampshire Medical Society, Society for Fetal Urology, and Society for Pediatric Urology
Disclosure: Nothing to disclose.

Medical Editor

Daniel B Rukstalis, MD, Director of Urological Services, Geisinger Medical Center, Geisinger Medical Group
Daniel B Rukstalis, MD is a member of the following medical societies: American Association for the Advancement of Science and American Urological Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Omeros Corporation Consulting fee Consulting

Chief Editor

Edward David Kim, MD, FACS, Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center
Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, and Tennessee Medical Association
Disclosure: Lilly Consulting fee Consulting; Astellas Consulting fee Speaking and teaching; Indevus Consulting fee Speaking and teaching

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