What is the diagnosis and management of Vesico Ureteric Reflux (VUR) disease, including treatment options for patients with varying severity levels and those with a history of Urinary Tract Infections (UTIs) or renal scarring?

Vesicoureteral Reflux Disease: Comprehensive Overview

Definition and Pathophysiology

Vesicoureteral reflux (VUR) is an anatomical and/or functional disorder where urine flows retrograde from the bladder through the ureters to the kidneys, increasing the risk of pyelonephritis and renal scarring when urinary tract infections occur. 1

Primary VUR results from a defect in the valve mechanism at the ureterovesical junction, where the terminal ureter enters the bladder wall obliquely. 2 The abnormal length of the intravesical portion of the ureter, due to genetic mutations, prevents proper compression during bladder contraction, allowing reflux. 2

VUR itself does not cause renal damage postnatally, but when associated with recurrent infections, it leads to renal scarring. 1 The reflux nephropathy develops through reduced formation of normal renal parenchyma (hypoplasia or dysplasia), attributable to the same genes controlling ureter and ureterovesical junction development. 2

Epidemiology and Natural History

• VUR affects approximately 1% of all children, with higher prevalence in females (14% vs 29% in boys among children with febrile UTIs). 1, 3
• Spontaneous resolution occurs in nearly 80% of grades I-II VUR and 30-50% of grades III-V VUR within 4-5 years of follow-up. 1
• Resolution is particularly low for bilateral high-grade reflux. 1
• Negative predictive factors for resolution include renal cortical abnormalities, bladder dysfunction, and breakthrough febrile UTIs. 1

Clinical Consequences and Risk Stratification

VUR increases the risk of pyelonephritis when bladder infection occurs, and increases the risk of renal scarring when pyelonephritis develops, with an odds ratio of 2.8 for patients and 3.7 for renal units. 1

Long-term Complications:

• 10-20% of children with focal uptake defects on radionuclide scans develop hypertension or end-stage renal disease. 1
• Renal cortical abnormalities occur in 10% of patients with prenatal hydronephrosis and up to 30% with lower urinary tract dysfunction. 1
• Higher grades of VUR (IV-V) show renal damage in 47.9% of cases. 4

Initial Diagnostic Evaluation

Mandatory General Assessment (Standard):

On initial presentation, perform a comprehensive medical evaluation including height, weight, blood pressure measurement, and serum creatinine if bilateral renal cortical abnormalities are present. 1

Urinalysis and Culture (Recommendation):

• Urinalysis for proteinuria and bacteriuria is required. 1
• If urinalysis indicates infection, obtain urine culture and sensitivity. 1

Imaging Protocol:

Voiding cystourethrography (VCUG) remains the gold standard for diagnosing VUR and determining grade (I-V classification). 1

Alternative modalities include:

• Contrast-enhanced voiding urosonography (ceVUS) 1
• Nuclear cystography 1
• Magnetic resonance VCUG 1

Renal ultrasound is recommended to assess the upper urinary tract for hydronephrosis and structural abnormalities. 1

DMSA renal imaging can be obtained to assess kidney scarring and function, particularly in patients with grades III-V reflux, younger children, abnormal ultrasound, or recurrent febrile UTIs. 1

Bladder and Bowel Dysfunction Assessment (Standard):

Symptoms of bladder and bowel dysfunction (BBD) must be sought in the initial evaluation, including urinary frequency, urgency, prolonged voiding intervals, daytime wetting, perineal/penile pain, holding maneuvers, and constipation/encopresis. 1

BBD is strongly associated with VUR and affects treatment outcomes. 1 Many parents are unaware of abnormal toileting patterns, making careful inquiry essential. 1

Treatment Goals and Rationale

The three primary goals are: (1) prevent recurring febrile UTIs, (2) prevent renal injury, and (3) minimize treatment and follow-up morbidity. 1

Patient and Family Education (Standard):

Family education must include discussion of the rationale for treating VUR, potential consequences of untreated VUR, equivalency of certain treatment approaches, assessment of adherence likelihood, and accommodation of parental preferences when treatment choices offer similar risk-benefit balance. 1

Management Strategies

Continuous Antibiotic Prophylaxis (CAP)

Recent evidence challenges the long-standing convention of universal CAP use in children with VUR. 1

• CAP does not significantly reduce repeat symptomatic UTI (RR 0.68,95% CI 0.39-1.17) or febrile UTI (RR 0.77,95% CI 0.47-1.24) at two years. 5
• However, CAP reduces the risk of new or progressive renal damage on DMSA scan at 1-3 years (RR 0.35,95% CI 0.15-0.80). 5
• CAP increases bacterial drug resistance threefold (RR 2.94,95% CI 1.39-6.25). 5
• To prevent one child from developing kidney damage over 2-3 years, 33 children would need long-term antibiotic prophylaxis (assuming 8% baseline risk). 5

Treatment without CAP may be acceptable in the proper clinical setting, though specific criteria have not been definitively determined. 1 Clinical parameters permitting more selective therapy include presence of BBD and history of UTI. 1

Special Consideration for Infants <1 Year:

Children younger than 1 year are more likely to suffer significant morbidity with acute pyelonephritis and are less able to communicate symptoms, leading to potential diagnostic delays. 1 The evidence for CAP effectiveness is limited in this age group, requiring more cautious decision-making. 1

Surgical and Endoscopic Treatment

When comparing long-term antibiotic prophylaxis to surgical/endoscopic correction plus antibiotics for 1-24 months, the risk of symptomatic UTI was not significantly different at any time point. 5

Combined surgical and antibiotic treatment reduces febrile UTI by 57% at five years (RR 0.43,95% CI 0.27-0.70) but does not decrease the risk of new or progressive renal damage. 5

To prevent one additional child from developing febrile UTI by five years, eight children would require combined surgical and antibiotic treatment. 5

Endoscopic Treatment:

• Endoscopic treatment with dextranomer microspheres provides cure rates approaching 90% in several studies. 3
• Minimally invasive and well tolerated 3
• Effective in various complicated cases 3
• Open surgery should be reserved for the approximately 10% of children not responding to endoscopic treatment and patients with refluxing primary megaureter. 3

Surgical Complications:

• Postoperative obstruction occurs in 0-7% of surgical cases and 0% in endoscopic studies. 5
• Laparoscopic and robot-assisted laparoscopic reimplantations show safe and effective outcomes. 6

Treatment Decision Algorithm:

Treatment decisions should be based on multiple factors beyond reflux grade alone: 3, 6

• Age and sex 6
• History of pyelonephritis and renal damage 6
• Grade of reflux 6
• Presence of bladder bowel dysfunction 6
• Circumcision status 6
• Bilateral versus unilateral disease 1
• Ipsilateral renal function 4
• Associated urinary tract anomalies 4
• Parental compliance and preference 4

For high-risk patients (symptomatic with high-grade reflux and abnormal kidneys), surgical intervention should be considered. 4

Follow-Up and Monitoring

Long-term Surveillance:

• Regular monitoring includes height, weight, and blood pressure at each visit. 7
• Repeat renal ultrasound every 6-12 months initially. 7, 8
• Serum creatinine monitoring, particularly if bilateral renal cortical abnormalities are present. 7, 8
• Urinalysis for proteinuria and hematuria. 7
• DMSA imaging may be considered for follow-up to detect new renal scarring, especially after febrile UTIs. 8

Critical Pitfalls and Caveats

The International Reflux Study in Children demonstrated equivalence of CAP (medical therapy) and surgical therapy, but recent studies show CAP may not benefit all children with VUR. 1

Most studies evaluating CAP included limited numbers of grade IV reflux and no grade V reflux, with small overall patient numbers and limited individual study power. 1

BBD treatment must be initiated regardless of VUR status and may include timed voiding, adequate fluid intake, constipation treatment, pelvic floor physical therapy, and stopping midnight awakening routines. 7

In women contemplating pregnancy, VUR correction should be strongly considered due to the risk of recurrent pyelonephritis. 2

Video-urodynamic studies are important when secondary VUR is suspected, such as in severe neurogenic bladder dysfunction or boys with suspected posterior urethral valves. 1