Angela M. Arlen, MD
Kathleen Kieran, MD, FAAP, FACS
Christopher S. Cooper, MD, FAAP, FACS
BASICS
DESCRIPTION
• Vesicoureteral reflux (VUR) is the retrograde flow of urine from the bladder into the ureter and/or kidney
• Primary VUR occurs in the absence of underlying lower urinary tract dysfunction
• Secondary VUR is associated with abnormally increased pressures or anatomy in the bladder or urethra
EPIDEMIOLOGY
Incidence
• Incidence is ∼1% (1)[C]
• 30% in those with a febrile UTI
• 16.2% in those with prenatal hydronephrosis
• VUR detection varies with indication for radiographic evaluation, eg, 31% of children with UTIs and 17.2% of those without sonographic renal abnormalities had VUR (1)[C]
Prevalence
N/A
RISK FACTORS
• Caucasian race
• Younger age
• Female
• Family history
• Conditions associated with VUR secondary to anatomic anomalies: Bladder exstrophy, prune belly syndrome, ureteral duplication
• Obstructing bladder pathologies can create hostile and excessive storage and emptying pressures that eventually overwhelm a normal antirefluxing intramural flap–valve mechanism: Posterior urethral valves, myelodysplasia
• Severe voiding dysfunction
Genetics
• Likely autosomal dominant with incomplete penetrance
• Seen in 27–51% of siblings of children with VUR; up to 100% in identical twins
• Seen in 50–66% of children of parents with VUR
PATHOPHYSIOLOGY
• The normal ureter enters the bladder at an oblique angle through the bladder wall; with bladder filling on contraction, the ureter is compressed and retrograde flow of urine (reflux) is prevented
• Primary VUR is associated with a functionally shortened submucosal tunnel
• Secondary VUR occurs in the setting of abnormal lower urinary tract function with resulting increase in bladder pressures
• VUR is graded on a scale of I–V:
– I: Ureter only
– II: Renal pelvis and calyces without dilatation
– III: Renal pelvis and calyces with calyceal blunting
– IV: Renal pelvis and calyces with ureteral tortuosity
– V: Severe ureteral tortuosity
ASSOCIATED CONDITIONS
• Primary VUR: Hydronephrosis, UTI, bladder/bowel dysfunction
– Also ipsilateral or contralateral renal anomalies: Ureteral duplication, ureteral ectopia, ureterocele, lulticystic dysplastic kidney (MCDK) or ureteropelvic junction (UPJ) obstruction
• Secondary VUR: All of the above, as well as neurogenic bladder, posterior urethral valves, prune belly syndrome, bladder exstrophy
GENERAL PREVENTION
• Primary VUR: None
• Secondary VUR: Optimizing lower urinary tract function to prevent elevated pressure and decreased bladder compliance
DIAGNOSIS
HISTORY
• Typically asymptomatic
• Frequently found on evaluation of patients with history of hydronephrosis, pyelonephritis, or UTIs
• Obtain careful history of UTI and other infections, fevers, abdominal or flank pain, dysuria, elimination habits
• Review antenatal imaging, gestational course, postnatal growth and development
PHYSICAL EXAM
• Complete physical exam for baseline functional information
• Neurologic exam for spina bifida
• Abdominal and pelvic exam:
– Palpable kidneys secondary to hydronephrosis
– Palpable bladder secondary to incomplete emptying
– CVA tenderness
– Suprapubic tenderness
– Circumcision status in males
• Poor somatic growth seen in some patients with renal insufficiency
• Blood pressure should be compared with age-adjusted normative values
• Identify or exclude causes of secondary VUR, eg, neurogenic bladder
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Voided specimen urine for assessment of proteinuria, evidence of infection
– Catheterized urine samples are more accurate for diagnosis of infection but are more costly and invasive; collect in patients with high index of suspicion based on voided sample or in patients with history of VUR
• Cultures sent only when urinalysis or clinical presentation is suspicious for infection
• Serum creatinine and electrolytes are not routinely checked unless significant sonographic anomalies in renal units, history of multiple febrile UTIs, or significant renal scarring on radionuclide imaging; evaluate at initial diagnosis and again only when substantial change in clinical condition
• Annual CBC appropriate in patients taking daily sulfamethoxazole or nitrofurantoin
Imaging
• Voiding cystourethrogram (VCUG) or radionuclide cystogram
• Renal ultrasound and nuclear medicine scan may suggest presence of VUR but are not sensitive or specific enough for definitive diagnosis
• Renal ultrasound utilized to help define upper tract anatomy, eg, hydronephrosis or duplicated systems, assess quality of renal parenchyma, ensure adequate renal growth
• Renal scintigraphy (DMSA scan) is the gold standard for detection of renal scarring
– Differential renal function
– Diagnosis of acute pyelonephritis/scarring
Diagnostic Procedures/Surgery
• Uroflowmetry to screen for abnormal voiding pattern in toilet-trained children may be useful
• Urodynamics to evaluate bladder compliance and function in children with secondary VUR
• Routine cystoscopy is avoided, but can be considered preoperatively to further evaluate duplication, diverticula, or ureteral ectopia
Pathologic Findings
Patients with reflux nephropathy and renal scarring may have increased deposition of collagen and scar tissue in the renal parenchyma
DIFFERENTIAL DIAGNOSIS
• Should be based on the abnormal symptom or clinical finding that prompted the evaluation
– UTI: Dysuria, lower tract infection vs. pyelonephritis
– Hydronephrosis: Physiologic hydronephrosis, ureterovesical junction obstruction, ureteropelvic junction obstruction, congenital megaureter
– Always consider secondary causes when evaluating for VUR
TREATMENT
GENERAL MEASURES
• Counsel parents on pathophysiology and natural history of VUR: Causes, comorbid conditions, potential sequelae, likelihood of resolution, risks and benefits of alternative treatment plans
• Spontaneous resolution of primary reflux is common and depends on initial grade of reflux, gender, age, voiding dysfunction, presence of renal scarring, and timing of VUR on VCUG
• Goal of intervention is to prevent renal scarring, recurrent febrile UTI, and long-term complications such as hypertension and renal insufficiency
MEDICATION
First Line
• Prophylactic daily antibiotics to keep urine sterile, preferentially given at bedtime to maximize urinary retention
– <2 mo age: Amoxicillin 20 mg/kg/d
– ≥2 mo of age: Trimethoprim–sulfamethoxazole 2 mg/kg/d (concentrates in urine); nitrofurantoin is an alternative, but liquid is expensive and bad tasting
ALERT
American Academy of Pediatrics (2011): meta-analysis of 6 randomized controlled studies demonstrated no difference in rates of UTI between patients taking prophylactic antibiotics and those not taking prophylactic antibiotics (2)[A].
• Findings met strenuous objection from pediatric urology community based on multiple methodologic flaws
• Majority of urologists continue to endorse prophylactic antibiotics in patients being followed conservatively, and consider exceptions case by case
Second Line
• Management of elimination habits:
– Constipation: Encourage daily soft bowel movement, consider polyethylene glycol, probiotics
– Urinary urgency and/or urge incontinence refractory to behavioral modification: Addition of an anticholinergic (eg, oxybutynin)
SURGERY/OTHER PROCEDURES
• Surgical intervention recommended for persistent VUR, worsening renal function, recurrent UTIs (3)[A]
• May be performed endoscopically or via open approach
– Tailor approach to clinical presentation, medical history, anatomy, shared goals of clinician and patient
• Endoscopic intervention:
– Benefit of using natural orifice, avoiding incision/scar; typically same-day surgery
– Success rate dependent on surgeon, reflux grade, and bulking agent; typically 70–85%
– Injection of bulking agent in and around ureteral orifice
– Only 1 currently in use in US: Deflux, Salix (dextranomer–hyaluronic acid copolymer)
• Ureteral reimplantation:
– Higher success rate (95–99%)
– Can be performed via intra- or extravesical approach
– Laparoscopic/robotic approaches have success rates comparable to open
• If VUR persists after either approach, surgery may be repeated
– These patients must be vigorously evaluated for secondary cause of VUR, such as dysfunctional elimination
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• Treatment of constipation and voiding dysfunction, including adherence to a bowel regimen, increased hydration and a timed voiding schedule is mandatory in children with VUR and elimination dysfunction
• Selective use of anticholinergic medications
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Overall resolution rate according to grade:
– Grade I: Over 90%
– Grade II: 70–80%
– Grade III: 50–60%
– Grade IV: 10–30%
– Grade V: <10%
• Likelihood of resolution depends on many factors: Age, gender, laterality, reflux grade, volume of bladder at onset of reflux, presence/absence of voiding dysfunction (4)[B]
• Online neural network available: http://godot.urol.uic.edu/urocomp/svm_vur.html (5)[B]
• Bladder and bowel dysfunction shown to decrease and delay resolution
• Ureteral duplication associated with delay in time to resolution, but not significantly with changes in overall resolution rate
COMPLICATIONS
• Renal insufficiency
– Reflux nephropathy most common cause of renal failure in children, often associated with renal scarring
Scarring occurs from infection in renal parenchyma; prophylactic antibiotics keep urine sterile
May manifest as hypertension, proteinuria, elevated serum creatinine, decreased GFR
Severe cases may progress to chronic renal insufficiency and end-stage renal disease
– Dysplastic renal parenchyma
Increased risk with high-grade VUR
Sonography, serial creatinine, proteinuria, blood pressure checks may help identify these patients
FOLLOW-UP
Patient Monitoring
• Patients with VUR:
– Annual complete physical exam with blood pressure check and urinalysis (proteinuria, infection)
– Serial imaging: No consensus on interval, but general agreement of renal ultrasound and cystography every 1–2 yr
• After surgical correction or spontaneous resolution:
– Annual blood pressure check and urinalysis (proteinuria, infection)
– Use of routine sonography is debated
– VCUG or nuclear cystography should be considered with symptoms of pyelonephritis or new sonographic abnormalities
• Siblings of children with VUR should undergo renal ultrasonography; VCUG reserved for cases of symptoms or ultrasound abnormalities (6)[A]
Patient Resources
National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC): http://kidney.niddk.nih.gov/kudiseases/pubs/vesicoureteralreflux/
REFERENCES
1. Elder JS. Vesicoureteral reflux. In: Kliegman R, Nelson WE, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier /Saunders; 2011:1834–1838.
2. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. Clinical Practice Guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128:595–610.
3. Cooper CS, Austin JC. Vesicoureteral reflux: Who benefits from surgery? Urol Clin N Am. 2004;31:535–541.
4. Knudson MJ, Austin JC, McMillan ZM, et al. Predictive factors of early spontaneous resolution in children with primary vesicoureteral reflux. J Urol. 2007;178:1684–1688.
5. Shiraishi K, Matsuyama H, Nepple KG, et al. Validation of a prognostic calculator for prediction of early vesicoureteral reflux resolution in children. J Urol. 2009;182:687–690.
6. Skoog SJ, Peters CA, Arant BS Jr, et al. Pediatric VUR guidelines panel summary report: Clinical practice guidelines for screening siblings of children with VUR and neonates/infants with prenatal hydronephrosis. J Urol.2010;184:1145–1151.
ADDITIONAL READING
None
See Also (Topic, Algorithm, Media)
• Urinary Tract Infection (UTI), Complicated, Pediatric
• Urinary Tract Infection (UTI), Pediatric
• Vesicoureteral Reflux, Adult
• Vesicoureteral Reflux, Pediatric Image 
CODES
ICD9
• 593.70 Vesicoureteral reflux unspecified or without reflux nephropathy
• 753.5 Exstrophy of urinary bladder
• 756.71 Prune belly syndrome
ICD10
• N13.70 Vesicoureteral-reflux, unspecified
• Q64.10 Exstrophy of urinary bladder, unspecified
• Q79.4 Prune belly syndrome
CLINICAL/SURGICAL PEARLS
• VCUG should be performed in children with febrile UTI and non–toilet-trained infants with UTI, and in other children as clinically indicated.
• All children with VUR should be assessed for dysfunctional elimination to reduce the likelihood of UTI.